Antibiotics in late clinical development.

PubMed

Fernandes, Prabhavathi; Martens, Evan

2017-06-01

Most pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections caused by multi-drug resistant bacteria, because the return on investment has been mostly negative for antibiotics that received marketing approved in the last few decades. In contrast, a few small companies have taken on this challenge and are developing new antibiotics. This review describes those antibiotics in late-stage clinical development. Most of them belong to existing antibiotic classes and a few with a narrow spectrum of activity are novel compounds directed against novel targets. The reasons for some of the past failures to find new molecules and a path forward to help attract investments to fund discovery of new antibiotics are described. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity.

PubMed

Boy, Nikolas; Heringer, Jana; Brackmann, Renate; Bodamer, Olaf; Seitz, Angelika; Kölker, Stefan; Harting, Inga

2017-04-24

Without neonatal initiation of treatment, 80-90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment. No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients. While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.

Late injury of cancer therapy on the female reproductive tract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grigsby, P.W.; Russell, A.; Bruner, D.

1995-03-30

The purpose of this article is to review the late effects of cancer therapy on the female reproductive tract. The anatomic sites detailed are the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries. The available pathophysiology is discussed. Clinical syndromes are presented. Tolerance doses of irradiation for late effects are rarely presented in the literature and are reviewed where available. Management strategies for surgical, radiotherapeutic, and chemotherapeutic late effects are discussed. Endpoints for evaluation of therapeutic late effects have been formulated utilizing the symptons, objective, management, and analytic (SOMA) format. Late effects on the female reproductive tract from cancer therapymore » should be recognized and managed appropriately. A grading system for these effects is presented. Endpoints for late effects and tolls for the evaluation need to be further developed. 61 refs., 9 figs., 13 tabs.« less

Practice of Clinical Supervision.

ERIC Educational Resources Information Center

Holland, Patricia E.

1988-01-01

Clinical supervision remained grounded in empirical inquiry as late as Morris Cogan's writings on the subject in 1973. With the acknowledgment of Thomas Kuhn's (1962) paradigm shift, educational theory and practice developed interpretive methodologies. An interpretive reflection on Cogan's rationale offers insights into the current, matured…

Late postacute neurologic rehabilitation: neuroscience, engineering, and clinical programs.

PubMed

Bach-y-Rita, Paul

2003-08-01

This lecture highlights my career in rehabilitation research. My principal efforts in rehabilitation have been to study (1) mechanisms of brain plasticity related to reorganization of the brain and recovery of function; (2) late postacute rehabilitation; (3) sensory substitution; and (4) rehabilitation engineering. A principal goal has been to aid in the development of a strong scientific base in rehabilitation.

XRCC3 polymorphisms are associated with the risk of developing radiation-induced late xerostomia in nasopharyngeal carcinoma patients treated with intensity modulation radiated therapy.

PubMed

Zou, Yan; Song, Tao; Yu, Wei; Zhao, Ruping; Wang, Yong; Xie, Ruifei; Chen, Tian; Wu, Bo; Wu, Shixiu

2014-03-01

The incidence of radiation-induced late xerostomia varies greatly in nasopharyngeal carcinoma patients treated with radiotherapy. The single-nucleotide polymorphisms in genes involved in DNA repair and fibroblast proliferation may be correlated with such variability. The purpose of this paper was to evaluate the association between the risk of developing radiation-induced late xerostomia and four genetic polymorphisms: TGFβ1 C-509T, TGFβ1 T869C, XRCC3 722C>T and ATM 5557G>A in nasopharyngeal carcinoma patients treated with Intensity Modulation Radiated Therapy. The severity of late xerostomia was assessed using a patient self-reported validated xerostomia questionnaire. Polymerase chain reaction-ligation detection reaction methods were performed to determine individual genetic polymorphism. The development of radiation-induced xerostomia associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for equivalent uniform dose. A total of 43 (41.7%) patients experienced radiation-induced late xerostomia. Univariate Cox proportional hazard analyses showed a higher risk of late xerostomia for patients with XRCC3 722 TT/CT alleles. In multivariate analysis adjusted for clinical and dosimetric factors, XRCC3 722C>T polymorphisms remained a significant factor for higher risk of late xerostomia. To our knowledge, this is the first study that demonstrated an association between genetic polymorphisms and the risk of radiation-induced late xerostomia in nasopharyngeal carcinoma patients treated with Intensity Modulation Radiated Therapy. Our findings suggest that the polymorphisms in XRCC3 are significantly associated with the risk of developing radiation-induced late xerostomia.

[Clinical and neurologic characteristic and principles of therapy of late-onset Myasthenia gravis].

PubMed

Kosachev, V D; Alekseeva, T M; Khalmurzina, A N

2016-01-01

In the present work the results of the clinic-epidemiological analysis of 223 patients with the onset of the myasthenia at 60 y. o. and later, admitted and treated in the clinic of neurology for the passed 25years are represented. A dynamic growth of incidence of the late-onset myasthenia through the passed 10 years was administered. We administered a prevalence of the generalized form of the myasthenia gravis (61,5 %). The whole clinical table of the myasthenia was developed during an year in 76,7 % of the cases. A wide range of the concomitant somatic pathology in this group of the patients (especially, with a cardio-vascular pathology - 93,3 %) was found to worsen the course of the myasthenia itself. We found that the set of the therapeutic measures in myasthenia in the elderly is determined by the course of the myasthenia and the multiple organ failure due to the concomitant diseases. The scheme of complex corrective therapy of myasthenia gravis in elderly was developed.

Bioresorbable scaffolds for percutaneous coronary interventions

PubMed Central

Gogas, Bill D.

2014-01-01

Innovations in drug-eluting stents (DES) have substantially reduced rates of in-segment restenosis and early stent thrombosis, improving clinical outcomes following percutaneous coronary interventions (PCI). However a fixed metallic implant in a vessel wall with restored patency and residual disease remains a precipitating factor for sustained local inflammation, in-stent neo-atherosclerosis and impaired vasomotor function increasing the risk for late complications attributed to late or very late stent thrombosis and late target lesion revascularization (TLR) (late catch-up). The quest for optimal coronary stenting continues by further innovations in stent design and by using biocompatible materials other than cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding, local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics have been recently developed. These devices have been utilized in selected clinical applications so far providing preliminary evidence of safety showing comparable performance with current generation drug-eluting stents (DES). Herein we provide a comprehensive overview of the current status of these technologies, we elaborate on the potential benefits of transient coronary scaffolds over permanent stents in the context of vascular reparation therapy, and we further focus on the evolving challenges these devices have to overcome to compete with current generation DES. Condensed Abstract:: The quest for optimizing percutaneous coronary interventions continues by iterative innovations in device materials beyond cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding; local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics were recently developed. These devices have been utilized in selected clinical applications providing preliminary evidence of safety showing comparable intermediate term clinical outcomes with current generation drug-eluting stents. PMID:25780795

Data-driven management using quantitative metric and automatic auditing program (QMAP) improves consistency of radiation oncology processes.

PubMed

Yu, Naichang; Xia, Ping; Mastroianni, Anthony; Kolar, Matthew D; Chao, Samuel T; Greskovich, John F; Suh, John H

Process consistency in planning and delivery of radiation therapy is essential to maintain patient safety and treatment quality and efficiency. Ensuring the timely completion of each critical clinical task is one aspect of process consistency. The purpose of this work is to report our experience in implementing a quantitative metric and automatic auditing program (QMAP) with a goal of improving the timely completion of critical clinical tasks. Based on our clinical electronic medical records system, we developed a software program to automatically capture the completion timestamp of each critical clinical task while providing frequent alerts of potential delinquency. These alerts were directed to designated triage teams within a time window that would offer an opportunity to mitigate the potential for late completion. Since July 2011, 18 metrics were introduced in our clinical workflow. We compared the delinquency rates for 4 selected metrics before the implementation of the metric with the delinquency rate of 2016. One-tailed Student t test was used for statistical analysis RESULTS: With an average of 150 daily patients on treatment at our main campus, the late treatment plan completion rate and late weekly physics check were reduced from 18.2% and 8.9% in 2011 to 4.2% and 0.1% in 2016, respectively (P < .01). The late weekly on-treatment physician visit rate was reduced from 7.2% in 2012 to <1.6% in 2016. The yearly late cone beam computed tomography review rate was reduced from 1.6% in 2011 to <0.1% in 2016. QMAP is effective in reducing late completions of critical tasks, which can positively impact treatment quality and patient safety by reducing the potential for errors resulting from distractions, interruptions, and rush in completion of critical tasks. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis.

PubMed

Maurer, Mathew S; Elliott, Perry; Comenzo, Raymond; Semigran, Marc; Rapezzi, Claudio

2017-04-04

Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain cardiac amyloidosis, in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late-phase clinical trials. In this review, we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis, and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected cardiac amyloidosis can impact the prognosis of patients in the modern era. © 2017 American Heart Association, Inc.

Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis

PubMed Central

Maurer, Mathew S.; Elliott, Perry; Comenzo, Raymond; Semigran, Marc; Rapezzi, Claudio

2017-01-01

Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis (CA) in everyday clinical practice, but the diagnosis continues to be made in patients with late stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain CA (AL-CA) in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late phase clinical trials. In this review we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected CA can impact the prognosis of patients in the modern era. PMID:28373528

Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity.

PubMed

Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

2005-05-07

To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus > or =60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). Concurrent chemotherapy and the maximal esophageal point dose > or =60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT.

Cognitive Impairment and Structural Abnormalities in Late Life Depression with Olfactory Identification Impairment: an Alzheimer's Disease-Like Pattern.

PubMed

Chen, Ben; Zhong, Xiaomei; Mai, Naikeng; Peng, Qi; Wu, Zhangying; Ouyang, Cong; Zhang, Weiru; Liang, Wanyuan; Wu, Yujie; Liu, Sha; Chen, Lijian; Ning, Yuping

2018-03-15

Late-life depression patients are at a high risk of developing Alzheimer's disease, and diminished olfactory identification is an indicator in early screening for Alzheimer's disease in the elderly. However, whether diminished olfactory identification is associated with risk of developing Alzheimer's disease in late-life depression patients remains unclear. One hundred and twenty-five late-life depression patients, 50 Alzheimer's disease patients, and 60 normal controls were continuously recruited. The participants underwent a clinical evaluation, olfactory test, neuropsychological assessment, and neuroimaging assessment. The olfactory identification impairment in late-life depression patients was milder than that in Alzheimer's disease patients. Diminished olfactory identification was significantly correlated with worse cognitive performance (global function, memory language, executive function, and attention) and reduced grey matter volume (olfactory bulb and hippocampus) in the late-life depression patients. According to a multiple linear regression analysis, olfactory identification was significantly associated with the memory scores in late-life depression group (B=1.623, P<.001). The late-life depression with olfactory identification impairment group had worse cognitive performance (global, memory, language, and executive function) and more structural abnormalities in Alzheimer's disease-related regions than the late-life depression without olfactory identification impairment group, and global cognitive function and logical memory in the late-life depression without olfactory identification impairment group was intact. Reduced volume observed in many areas (hippocampus, precuneus, etc.) in the Alzheimer's disease group was also observed in late-life depression with olfactory identification impairment group but not in the late-life depression without olfactory identification impairment group. The patterns of cognitive impairment and structural abnormalities in late-life depression with olfactory identification impairment patients were similar to those in Alzheimer's disease; olfactory identification may help identify late-life depression patients who are at a high risk of developing Alzheimer's disease.

Therapeutic Antibodies by Phage Display.

PubMed

Shim, Hyunbo

2016-01-01

Antibody phage display is a major technological platform for the generation of fully human antibodies for therapeutic purposes. The in vitro binder selection by phage display allows researchers to have more extensive control over binding parameters and facilitates the isolation of clinical candidate antibodies with desired binding and/or functional profiles. Since the invention of antibody phage display in late 1980s, significant technological advancements in the design, construction, and selection of the antibody libraries have been made, and several fully human antibodies generated by phage display are currently approved or in various clinical development stages. In this review, the background and details of antibody phage display technology, and representative antibody libraries with natural or synthetic sequence diversity and different construction strategies are described. The generation, optimization, functional and biophysical properties, and preclinical and clinical developments of some of the phage display-derived therapeutic antibodies approved for use in patients or in late-stage clinical trials are also discussed. With evolving novel disease targets and therapeutic strategies, antibody phage display is expected to continue to play a central role in the development of the next generation of therapeutic antibodies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A review of late-stage CNS drug candidates for the treatment of obesity.

PubMed

Heal, D J; Gosden, J; Smith, S L

2013-01-01

Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions.

Revisiting the Biomedicalization of Aging: Clinical Trends and Ethical Challenges

ERIC Educational Resources Information Center

Kaufman, Sharon R.; Shim, Janet K.; Russ, Ann J.

2004-01-01

Developments in the realms of medical innovation and geriatric clinical intervention impact our understanding of the nature of late life, the possibilities for health in advanced age, medical decision making, and family responsibility in ways that could not have been predicted 15 years ago. This essay begins to map new forms of biomedicalization…

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Robert J.; Jun, Brandon J.; Advanced Imaging Laboratory, Department of Radiology, Children's Hospital Los Angeles, Los Angeles, California

Purpose: In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials: Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results: Fractional anisotropy in the spleniummore » of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions: The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.« less

Optical Coherence Tomography for Quantitative Assessment of Microstructural and Microvascular Alterations in Late Oral Radiation Toxicity

NASA Astrophysics Data System (ADS)

Davoudi, Bahar

More than half of head-and-neck cancer patients undergo radiotherapy at some point during their treatment. Even though the use of conformed therapeutic beams has increased radiation dose localization to the tumor, resulting in more normal tissue sparing, still, in many head-and-neck cancer patients, the healthy tissue of the oral cavity still receives a sizeable amount of radiation. This causes acute and / or late complications in these patients. The latter occur as late as several months or even years after the completion of treatment and are typically associated with severe symptoms. Currently, the clinical method for diagnosing these complications is visual examination of the oral tissue surface. However, it has been well established that such complications originate in subsurface oral tissue layers including its microvasculature. Therefore, to better understand the mechanism of these complications and to be able to diagnose them earlier, there exists a need for subsurface monitoring of the irradiated oral tissue. Histology has been used as such a tool for research purposes; however, its use in clinical diagnosis is limited due to its invasive and hazardous nature. Therefore, in this thesis, I propose to use optical coherence tomography (OCT) as a subsurface, micron-scale resolution optical imaging tool that can provide images of oral tissue subsurface layers down to a depth of 1-2 mm (structural OCT), as well as images demonstrating vessel morphology (speckle variance OCT) and blood flow information (Doppler OCT). This thesis explains the development of an OCT setup and an oral probe to acquire images in-vivo. Moreover, it introduces a software-based quantification platform for extracting specific biologically-meaningful metrics from the structural and vascular OCT images. It then describes the application of the developed imaging and quantification platform in a feasibility clinical study that was performed on 15 late oral radiation toxicity patients and 5 age-matched healthy volunteers. The results of this clinical study show that: 1) the value of the developed metrics (such as epithelium to lamina propria thickness, vessel diameter, and blood velocity) is significantly different between the two cohorts; 2) radiation-induced abnormalities in structural OCT images are primarily observed in the regions where the total radiation dose exceeded ˜50 Gy. The results of this study demonstrate the promising ability of the developed OCT imaging and quantification platform to highlight biologically meaningful differences between late oral radiation toxicity patients and healthy volunteers in the structural and vascular images. This methodology may also be used in prognostic studies to monitor the efficacy of the medication prescribed to late oral radiation toxicity patients.

Practice, training, and research in neuropsychology in mainland China: challenges and opportunities.

PubMed

Chan, Raymond C K; Wang, Ya; Wang, Yi; Cheung, Eric F C

2016-11-01

This is an invited paper for a special issue. The objective was to review history, educational and training pathways, licensure and board certification, practice and compensation, and unique aspects of, or challenges faced by, neuropsychology in mainland China. Historical, scientific, and clinical literatures were reviewed and integrated. The history of neuropsychology in mainland China is traced back to the late 1930s. Educational pathways have not yet been fully formalized. Clinical practice generally occurs within rehabilitation settings, and medical license is required. The main challenge lies in the establishment of training guidelines and the expansion of neuropsychology to meet the tremendous needs of a large nation. Although the development and status of psychology has gradually gained momentum in mainland China, the development of neuropsychology has not shown significant advancement since the late 1930s.

Responses to highly active antiretroviral therapy and clinical events in patients with a low CD4 cell count: late presenters vs. late starters.

PubMed

Waters, L; Fisher, M; Anderson, J; Wood, C; Delpech, V; Hill, T; Walsh, J; Orkin, C; Bansi, L; Gompels, M; Phillips, A; Johnson, M; Gilson, R; Easterbrook, P; Leen, C; Porter, K; Gazzard, B; Sabin, C

2011-05-01

We investigated whether adverse responses to highly active antiretroviral therapy (HAART) associated with late HIV presentation are secondary to low CD4 cell count per se or other confounding factors. A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study of individuals starting HAART in 1998-2007 was carried out, comparing late presenters (presenting/starting HAART at a CD4 count <200 cells/μL) with late starters (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count<200 cells/μL), using 'ideal starters' (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count of 200-350 cells/μL) as a comparator. Virological, immunological and clinical (new AIDS event/death) outcomes at 48 and 96 weeks were analysed, with the analysis being limited to those remaining on HAART for>3 months. A total of 4978 of 9095 individuals starting first-line HAART with HIV RNA>500 HIV-1 RNA copies/mL were included in the analysis: 2741 late presenters, 947 late starters and 1290 ideal starters. Late presenters were more commonly female, heterosexual and Black African. Most started nonnucleoside reverse transcriptase inhibitors (NNRTIs); 48-week virological suppression was similar in late presenters and starters (and marginally lower than in ideal starters); by week 96 differences were reduced and nonsignificant. The median CD4 cell count increase in late presenters was significantly lower than that in late starters (weeks 48 and 96). During year 1, new clinical events were more frequent for late presenters [odds ratio (OR) 2.04; 95% confidence interval (CI) 1.19-3.51; P=0.01]; by year 2, event rates were similar in all groups. Amongst patients who initiate, and remain on, HAART, late presentation is associated with lower rates of virological suppression, blunted CD4 cell count increases and more clinical events compared with late starters in year 1, but similar clinical and immunological outcomes by year 2 to those of both late and ideal starters. Differences between late presenters and late starters suggest that factors other than CD4 cell count alone may be driving adverse treatment outcomes in late-presenting individuals.

Clinical classification of age-related macular degeneration.

PubMed

Ferris, Frederick L; Wilkinson, C P; Bird, Alan; Chakravarthy, Usha; Chew, Emily; Csaky, Karl; Sadda, SriniVas R

2013-04-01

To develop a clinical classification system for age-related macular degeneration (AMD). Evidence-based investigation, using a modified Delphi process. Twenty-six AMD experts, 1 neuro-ophthalmologist, 2 committee chairmen, and 1 methodologist. Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions. Delphi review of the 9-item set of statements resulting from the meeting. Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 μm), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group. The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD. Incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases.

PubMed

Chen, Qi; Wang, Yao; Zhao, Min; Hyett, Jonathan; da Silva Costa, Fabricio; Nie, Guiying

2016-07-01

Preeclampsia is a pregnancy specific disorder affecting 3-5% of pregnancies worldwide. It is clinically divided into early-onset and late-onset subtypes. Placental factors are involved in the pathogenesis of preeclampsia. Growth differentiation factor 15 (GDF15), a protein of the transforming growth factor beta superfamily, is highly expressed in the placenta. However, it is unclear whether the circulating levels of GDF15 are altered in preeclampsia at the time of or prior to disease presentation. Serum samples across three trimesters from 29 healthy pregnancies, third trimester sera from 34 women presenting with preeclampsia (early-onset n=16, late-onset n=18) and 66 gestation-age-matched controls, and sera at 11-13weeks of pregnancy from women who later did (n=36) or did not (n=33) develop late-onset preeclampsia, were examined for GDF15 by ELISA. Serum GDF15 levels increased significantly with gestation in normal pregnancy. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia compared to their gestation-age-matched controls. This reduction was apparent in both early-onset and late-onset subtypes, but it was more profound in late-onset cases. At 11-13weeks of gestation, however, serum levels of GDF15 were similar between women who subsequently did and did not develop late-onset preeclampsia. Serum GDF15 increased with gestation age, reaching the highest level in the third trimester. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia, especially in late-onset cases. However, serum GDF15 was not altered in the first trimester in women destined to develop late-onset preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Southeast Asian Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor.

PubMed

Higgs, Elizabeth S; Hayden, Frederick G; Chotpitayasunondh, Tawee; Whitworth, Jimmy; Farrar, Jeremy

2008-04-01

The Southeast Asia Influenza Clinical Research Network (SEA ICRN) (www.seaclinicalresearch.org) is a recently developed multilateral, collaborative partnership that aims to advance scientific knowledge and management of human influenza through integrated clinical investigation. The partnership of hospitals and institutions in Indonesia, Thailand, United Kingdom, United States, and Viet Nam was established in late 2005 after agreement on the general principles and mission of the initiative and after securing initial financial support. The establishment of the SEA ICRN was both a response to the re-emergence of the highly pathogenic avian influenza A(H5N1) virus in Southeast Asia in late 2003 and an acknowledgment that clinical trials on emerging infectious diseases require prepared and coordinated research capacity. The objectives of the Network also include building sustainable research capacity in the region, compliance with international standards, and prompt dissemination of information and sharing of samples. The scope of research includes diagnosis, pathogenesis, treatment and prevention of human influenza due to seasonal or novel viruses. The Network has overcome numerous logistical and scientific challenges but has now successfully initiated several clinical trials. The establishment of a clinical research network is a vital part of preparedness and an important element during an initial response phase to a pandemic.

Survivors of childhood cancer in South Australia attending a late-effects clinic: a descriptive report of psychological, cognitive, and academic late-effects.

PubMed

Roberts, Rachel M; Robins, Tamara; Gannoni, Anne F; Tapp, Heather

2014-01-01

This study provides a description of psychological late effects among a heterogeneous cohort of pediatric cancer survivors (N = 70) attending the South Australian Late-effects Clinic. Survivors reported more problems on the Strengths and Difficulties Questionnaire and the Child Behavior Checklist compared to normative data but no differences in Sluggish Cognitive Tempo scores. Forty-six percent of the sample reported school difficulties, and 12% of the sample age older than 15 reported smoking. Late-effects clinics should continue to monitor psychological well-being and health behaviors. Further research is recommended to determine whether sluggish cognitive tempo is a useful concept for the assessment of survivors.

Research and clinical aspects of the late effects of poliomyelitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halstead, L.S.; Wiechers, D.O.

1986-01-01

This book contains 32 selections. Some of the titles are: Late effects of Polio: Historical Perspectives; Sleep-Disordered Breathing as a Late Effect of Poliomyelitis; Clinical Subtypes, DNA Repair Efficiency, and Therapeutic Trials in the Post-Polio Syndromes; and Post-Polio Muscle Function.

Cancer Survivorship Care: Person Centered Care in a Multidisciplinary Shared Care Model.

PubMed

Loonen, Jacqueline J; Blijlevens, Nicole Ma; Prins, Judith; Dona, Desiree Js; Den Hartogh, Jaap; Senden, Theo; van Dulmen-Den Broeder, Eline; van der Velden, Koos; Hermens, Rosella Pmg

2018-01-16

Survivors of childhood and adult-onset cancer are at lifelong risk for the development of late effects of treatment that can lead to serious morbidity and premature mortality. Regular long-term follow-up aiming for prevention, early detection and intervention of late effects can preserve or improve health. The heterogeneous and often serious character of late effects emphasizes the need for specialized cancer survivorship care clinics. Multidisciplinary cancer survivorship care requires a coordinated and well integrated health care environment for risk based screening and intervention. In addition survivors engagement and adherence to the recommendations are also important elements. We developed an innovative model for integrated care for cancer survivors, the "Personalized Cancer Survivorship Care Model", that is being used in our clinic. This model comprises 1. Personalized follow-up care according to the principles of Person Centered Care, aiming to empower survivors and to support self management, and 2. Organization according to a multidisciplinary and risk based approach. The concept of person centered care is based on three components: initiating, integrating and safeguarding the partnership with the patient. This model has been developed as a universal model of care that will work for all cancer survivors in different health care systems. It could be used for studies to improve self efficacy and the cost-effectiveness of cancer survivorship care.

Recent developments in metabolic bone diseases: a gnathic perspective.

PubMed

Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D

2014-12-01

Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.

Quantitative Systems Pharmacology: A Case for Disease Models.

PubMed

Musante, C J; Ramanujan, S; Schmidt, B J; Ghobrial, O G; Lu, J; Heatherington, A C

2017-01-01

Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model-informed drug discovery and development, supporting program decisions from exploratory research through late-stage clinical trials. In this commentary, we discuss the unique value of disease-scale "platform" QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and Therapeutics.

ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies.

PubMed

Shah, Rashmi R; Morganroth, Joel

2013-04-01

The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical 'thorough QT/QTc (TQT) study', to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues. These include the gender of the study population, a reasonable approach to evaluating QTc changes in late stage clinical development and the recommended approach to correcting the measured QT interval. This commentary provides our observations and, when appropriate, recommendations, on these issues. We review briefly evidence that suggests that (i) the greater QT effect observed in females is not entirely related to differences in drug exposure and (ii) the Fridericia correction of measured QT interval is adequate for a majority of TQT studies. Until further evidence suggests otherwise, we recommend balanced gender representation in TQT studies, unless warranted otherwise, and for positive studies, subgroup analysis of key data by common demographic variables including the gender and ethnicity. We provide a general scheme for ECG monitoring in late phase clinical trials and consider that while intensive monitoring and centralized reading of ECGs in late phase clinical trials is the norm when a TQT study is positive, there are other circumstances that also call for high quality ECG reading. Therefore, locally read ECGs should only be acceptable as long as accurate high quality ECG data can be guaranteed. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruyck, Kim de; Van Eijkeren, Marc; Claes, Kathleen

2006-07-15

Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites inmore » TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.« less

Single-nucleotide polymorphisms studied for associations with urinary toxicity from (125)I prostate brachytherapy implants.

PubMed

Usmani, Nawaid; Leong, Nelson; Martell, Kevin; Lan, Lanna; Ghosh, Sunita; Pervez, Nadeem; Pedersen, John; Yee, Don; Murtha, Albert; Amanie, John; Sloboda, Ron; Murray, David; Parliament, Matthew

2014-01-01

To identify clinical, dosimetric, and genetic factors that are associated with late urinary toxicity after a (125)I prostate brachytherapy implant. Genomic DNA from 296 men treated with (125)I prostate brachytherapy monotherapy was extracted from saliva samples for this study. A retrospective database was compiled including clinical, dosimetric, and toxicity data for this cohort of patients. Fourteen candidate single-nucleotide polymorphism (SNPs) from 13 genes (TP53, ERCC2, GSTP1, NOS, TGFβ1, MSH6, RAD51, ATM, LIG4, XRCC1, XRCC3, GSTA1, and SOD2) were tested in this cohort for correlations with toxicity. This study identified 217 men with at least 2 years of followup. Of these, 39 patients developed Grade ≥2 late urinary complications with a transurethral resection of prostate, urethral stricture, gross hematuria, or a sustained increase in their International Prostate Symptom Score. The only clinical or dosimetric factor that was associated with late urinary toxicity was age (p = 0.02). None of the 14 SNPs tested in this study were associated with late urinary toxicity in the univariate analysis. This study identified age as the only variable being associated with late urinary toxicity. However, the small sample size and the candidate gene approach used in this study mean that further investigations are essential. Genome-wide association studies are emerging as the preferred approach for future radiogenomic studies to overcome the limitations from a candidate gene approach. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

PubMed

Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

2016-10-03

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na , is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

Dosimetric and clinical predictors of radiation-induced lung toxicity in esophageal carcinoma.

PubMed

Zhu, Shu-Chai; Shen, Wen-Bin; Liu, Zhi-Kun; Li, Juan; Su, Jing-Wei; Wang, Yu-Xiang

2011-01-01

Radiation-induced lung toxicity occurs frequently in patients with esophageal carcinoma. This study aims to evaluate the clinical and three-dimensional dosimetric parameters associated with lung toxicity after radiotherapy for esophageal carcinoma. The records of 56 patients treated for esophageal carcinoma were reviewed. The Radiation Therapy Oncology Group criteria for grading of lung toxicity were followed. Spearman's correlation test, the chi-square test and logistic regression analyses were used for statistical analysis. Ten of the 56 patients developed acute toxicity. The toxicity grades were grade 2 in 7 patients and grade 3 in 3 patients; none of the patients developed grade 4 or worse toxicity. One case of toxicity occurred during radiotherapy and 9 occurred 2 weeks to 3 months after radiotherapy. The median time was 2.0 months after radiotherapy. Fourteen patients developed late irradiated lung injury, 3 after 3.5 months, 7 after 9 months, and 4 after 14 months. Radiographic imaging demonstrated patchy consolidation (n = 5), atelectasis with parenchymal distortion (n = 6), and solid consolidation (n = 3). For acute toxicity, the irradiated esophageal volume, number of fields, and most dosimetric parameters were predictive. For late toxicity, chemotherapy combined with radiotherapy and other dosimetric parameters were predictive. No obvious association between the occurrence of acute and late injury was observed. The percent of lung tissue receiving at least 25 Gy (V25), the number of fields, and the irradiated length of the esophagus can be used as predictors of the risk of acute toxicity. Lungs V30, as well as chemotherapy combined with radiotherapy, are predictive of late lung injury.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez, Rodrigo O.; Angelita and Joaquim Gama Institute, Sao Paulo; Habr-Gama, Angelita, E-mail: gamange@uol.com.br

Purpose: To estimate the metabolic activity of rectal cancers at 6 and 12 weeks after completion of chemoradiation therapy (CRT) by 2-[fluorine-18] fluoro-2-deoxy-D-glucose-labeled positron emission tomography/computed tomography ([{sup 18}FDG]PET/CT) imaging and correlate with response to CRT. Methods and Materials: Patients with cT2-4N0-2M0 distal rectal adenocarcinoma treated with long-course neoadjuvant CRT (54 Gy, 5-fluouracil-based) were prospectively studied ( (ClinicalTrials.org) identifier (NCT00254683)). All patients underwent 3 PET/CT studies (at baseline and 6 and 12 weeks from CRT completion). Clinical assessment was at 12 weeks. Maximal standard uptake value (SUVmax) of the primary tumor was measured and recorded at each PET/CT study aftermore » 1 h (early) and 3 h (late) from {sup 18}FDG injection. Patients with an increase in early SUVmax between 6 and 12 weeks were considered 'bad' responders and the others as 'good' responders. Results: Ninety-one patients were included; 46 patients (51%) were 'bad' responders, whereas 45 (49%) patients were 'good' responders. 'Bad' responders were less likely to develop complete clinical response (6.5% vs. 37.8%, respectively; P=.001), less likely to develop significant histological tumor regression (complete or near-complete pathological response; 16% vs. 45%, respectively; P=.008) and exhibited greater final tumor dimension (4.3 cm vs. 3.3 cm; P=.03). Decrease between early (1 h) and late (3 h) SUVmax at 6-week PET/CT was a significant predictor of 'good' response (accuracy of 67%). Conclusions: Patients who developed an increase in SUVmax after 6 weeks were less likely to develop significant tumor downstaging. Early-late SUVmax variation at 6-week PET/CT may help identify these patients and allow tailored selection of CRT-surgery intervals for individual patients.« less

Childhood cancer survivor care: development of the Passport for Care.

PubMed

Poplack, David G; Fordis, Michael; Landier, Wendy; Bhatia, Smita; Hudson, Melissa M; Horowitz, Marc E

2014-12-01

Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed.

Childhood cancer survivor care: development of the Passport for Care

PubMed Central

Poplack, David G.; Fordis, Michael; Landier, Wendy; Bhatia, Smita; Hudson, Melissa M.; Horowitz, Marc E.

2016-01-01

Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed. PMID:25348788

Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia.

PubMed

Mourani, Peter M; Sontag, Marci K; Younoszai, Adel; Miller, Joshua I; Kinsella, John P; Baker, Christopher D; Poindexter, Brenda B; Ingram, David A; Abman, Steven H

2015-01-01

Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.

Dosimetric and clinical predictors for radiation-induced esophageal injury.

PubMed

Ahn, Sung-Ja; Kahn, Daniel; Zhou, Sumin; Yu, Xiaoli; Hollis, Donna; Shafman, Timothy D; Marks, Lawrence B

2005-02-01

To evaluate the clinical and three-dimensional dosimetric parameters associated with esophageal injury after radiotherapy (RT) for non-small-cell lung cancer. The records of 254 patients treated for non-small-cell lung cancer between 1992 and 2001 were reviewed. A variety of metrics describing the esophageal dose were extracted. The Radiation Therapy Oncology Group toxicity criteria for grading of esophageal injury were used. The median follow-up time for all patients was 43 months (range, 0.5-120 months). Logistic regression analysis, contingency table analyses, and Fisher's exact tests were used for statistical analysis. Acute toxicity occurred in 199 (78%) of 254 patients. For acute toxicity of Grade 2 or worse, twice-daily RT, age, nodal stage of N2 or worse, and most dosimetric parameters were predictive. Late toxicity occurred in 17 (7%) of 238 patients. The median and maximal time to the onset of late toxicity was 5 and 40 months after RT, respectively. Late toxicity occurred in 2%, 3%, 17%, 26%, and 100% of patients with acute Grade 0, 1, 2, 3, and 4 toxicity, respectively. For late toxicity, the severity of acute toxicity was most predictive. A variety of dosimetric parameters are predictive of acute and late esophageal injury. A strong correlation between the dosimetric parameters prevented a comparison between the predictive abilities of these metrics. The presence of acute injury was the most predictive factor for the development of late injury. Additional studies to define better the predictors of RT-induced esophageal injury are needed.

Nonsyndromic tooth agenesis patterns and associated developmental dental anomalies: a literature review with radiographic illustrations.

PubMed

Agarwal, P; Vinuth, D P; Dube, G; Dube, P

2013-01-01

Tooth agenesis is one of the most intriguing phenomena, because it is frequently associated with other oral anomalies, structural variations and malformations of other teeth, late eruption, transposition and crowding. The diagnosis can be quite challenging as radiographic examination is critical for the diagnosis but not always possible and the late developing teeth may be sometimes scored developmentally missing. Accurate diagnosis therefore requires radiographic, clinical, and dental cast examinations. It is an important clinical and public health problem. Patients with missing permanent teeth may suffer from a reduced chewing ability, inarticulate pronunciation, and an unfavorable aesthetic appearance. Clinically, early diagnosis of a dental anomaly can alert the clinician to the possible development of other associated dental anomalies in the same patient or family, and avoid the possible sequelae. Understanding of tooth agenesis patterns and their impact on diagnosis, prevention, and eventually therapeutics are becoming integral parts of comprehensive dental care. Dental examination with radiographic screening of hypodontia in early childhood should be emphasized as part of public oral health policy to allow early diagnosis and timely intervention.

Impact of Survivorship-Based Research on Defining Clinical Care Guidelines

PubMed Central

Hudson, Melissa M.; Landier, Wendy; Ganz, Patricia A.

2011-01-01

The growing number of individuals living 5 or more years from cancer diagnosis underscores the importance of providing guidance about potential late treatment effects to clinicians caring for long-term cancer survivors. Late treatment effects are commonly experienced by cancer survivors, increase in prevalence with aging, produce substantial morbidity, and predispose to early mortality. Findings from survivorship research permit providers to anticipate health risks among predisposed survivors and facilitate their access to interventions to prevent, detect, or rehabilitate cancer-related morbidity. This manuscript reviews the impact that survivorship research has made in defining clinical care guidelines and the challenges that remain in developing and translating research findings into health screening recommendations that can optimize the quality and duration of survival after cancer. PMID:21980016

Proton Radiotherapy for Solid Tumors of Childhood

PubMed Central

Cotter, Shane E.; McBride, Sean M.; Yock, Torunn I.

2012-01-01

The increasing efficacy of pediatric cancer therapy over the past four decades has produced many long-term survivors that now struggle with serious treatment related morbidities affecting their quality of life. Radiation therapy is responsible for a significant proportion of these late effects, but a relatively new and emerging modality, proton radiotherapy hold great promise to drastically reduce these treatment related late effects in long term survivors by sparing dose to normal tissues. Dosimetric studies of proton radiotherapy compared with best available photon based treatment show significant dose sparing to developing normal tissues. Furthermore, clinical data are now emerging that begin to quantify the benefit in decreased late treatment effects while maintaining excellent cancer control rates. PMID:22417062

A critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease

PubMed Central

Wormser, Gary P.; Strle, Franc; Shapiro, Eugene D.; Dattwyler, Raymond J.; Auwaerter, Paul G.

2018-01-01

In older studies, a chronic distal symmetric sensory neuropathy was reported as a relatively common manifestation of late Lyme disease in the United States. However, the original papers describing this entity had notable inconsistencies and certain inexplicable findings, such as reports that this condition developed in patients despite prior antibiotic treatment known to be highly effective for other manifestations of Lyme disease. More recent literature suggests that this entity is seen rarely, if at all. A chronic distal symmetric sensory neuropathy as a manifestation of late Lyme disease in North America should be regarded as controversial and in need of rigorous validation studies before acceptance as a documented clinical entity. PMID:27914746

[Final height in symptomatic boys with late-onset adrenal hyperplasia (LOCAH), treated with glucocorticoids. Clinical cases].

PubMed

Pasqualini, Titania; Alonso, Guillermo; Fernández, Cecilia; Buzzalino, Noemí; Dain, Liliana

2013-04-01

Although corticoid replacement is recommended for those late-onset adrenal hyperplasia with clinical manifestations, asymptomatic patients do not need treatment. We describe clinical features at diagnosis, treatment, and growth till adult- height, in 4 boys. At diagnosis, age ranged from 9.2-11.6 years. The initial symptoms/signs were: precocious pubarche (n = 2), accelerated bone age (n = 1) and precocious puberty (n = 1). All of them presented elevated 17 hydroxyprogesterone levels and were compound heterozygotes carrying p.V281L mutation. Since, at diagnosis, bone age was significantly advanced for chronological age (13.1 ± 0.5 vs. 10.2 ± 1.1 p = 0.008), hydrocortisone therapy was initiated. During follow-up, mean height Z score decreased 1.4 ± 0.4 SDS (p = 0.007), though adult mean height was not different from target height (-0.39 ± 0.7 vs. -0.04 ± 0.5 SDS, p = 0.054). In conclusion, in 4 symptomatic patients, accurate treatment of late-onset adrenal hyperplasia led to an adult mean height not different from target height. Advanced bone age at diagnosis and the loss of height during pubertal development suggest the need of therapy.

The Identification and Assessment of Late-Life ADHD in Memory Clinics

ERIC Educational Resources Information Center

Fischer, Barbara L.; Gunter-Hunt, Gail; Steinhafel, Courtney Holm; Howell, Timothy

2012-01-01

Objective: Little data exist about ADHD in late life. While evaluating patients' memory problems, the memory clinic staff has periodically identified ADHD in previously undiagnosed older adults. The authors conducted a survey to assess the extent to which other memory clinics view ADHD as a relevant clinical issue. Method: The authors developed…

77 FR 7166 - Draft Guidance for Industry on Determining the Extent of Safety Data Collection Needed in Late...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-10

... clinical investigations in determining the amounts and types of safety data to collect in trials conducted... types of safety data that should be collected during late-stage premarket and postmarket clinical...] Draft Guidance for Industry on Determining the Extent of Safety Data Collection Needed in Late Stage...

Are former late-preterm children at risk for child vulnerability and overprotection?

PubMed

Samra, Haifa A; McGrath, Jacqueline M; Wey, Howard

2010-09-01

Parent perception of child vulnerability (PPCV) and parent overprotection (POP) are believed to have serious implications for age appropriate cognitive and psychosocial development in very low birth weight preterm children. With recent concerns about suboptimal developmental outcomes in late-preterm children, this study was aimed at examining the relationship between history of late-preterm birth (34-36 6/7 weeks gestation), and PPCV, POP, and healthcare utilization (HCU). This was a cross-sectional observational design. Study participants were mothers of 54 healthy singleton children recruited from community centers including Women and Children Clinics (WIC), primary care clinics and daycare centers in the upper Midwest region. Outcome measures included Forsyth Child Vulnerability Scale (CVS), Thomasgard Parent Protection Scale (PPS) scores, and healthcare utilization (HCU). Potential covariates included history of life-threatening illness, child and maternal demographics, and maternal stress and depression using the Center for Epidemiologic Studies Depression Scale (CESD). HCU (p=0.02) and the PPS subscales of supervision (p=0.003) and separation (p=0.03) were significant predictors of PPCV in mothers of 3-8 years old children with late-preterm history. Age of the child (p=0.008) and CVS scores (p=0.005) were significant predictors of POP. Maternal age (p=0.04), stress (p=0.04), and CVS scores (p=0.003) were significant predictors of HCU. Dependence, a subscale of the PPS, correlated with the child's age and gender even after controlling for age. History of late-preterm did not predict MPCV, MOP, or HCU in healthy children. Future research is needed in larger more diverse samples to better understand causal relationships and develop strategies to lessen risks of MPCV and MOP. Published by Elsevier Ireland Ltd.

Paving the critical path: how can clinical pharmacology help achieve the vision?

PubMed

Lesko, L J

2007-02-01

It has been almost 3 years since the launch of the FDA critical path initiative following the publication of the paper "Innovation or Stagnation: Challenges and Opportunities on the Critical Path of New Medical Product Development." The initiative was intended to create an urgency with the drug development enterprise to address the so-called "productivity problem" in modern drug development. Clinical pharmacologists are strategically aligned with solutions designed to reduce late phase clinical trial failures to show adequate efficacy and/or safety. This article reviews some of the ways that clinical pharmacologists can lead and implement change in the drug development process. It includes a discussion of model-based, semi-mechanistic drug development, drug/disease models that facilitate informed clinical trial designs and optimal dosing, the qualification process and criteria for new biomarkers and surrogate endpoints, approaches to streamlining clinical trials and new types of interaction between industry and FDA such as the end-of-phase 2A and voluntary genomic data submission meetings respectively.

Late-onset Epstein-Barr virus-related disease in acute leukemia patients after haploidentical hematopoietic stem cell transplantation is associated with impaired early recovery of T and B lymphocytes.

PubMed

Liu, Jiangying; Yan, Chenhua; Zhang, Chunli; Xu, Lanping; Liu, Yanrong; Huang, Xiaojun

2015-10-01

Epstein-Barr virus-related disease (EBVD) is a serious clinical complication in patients who have undergone haploidentical hematopoietic stem cell transplantation (haploHSCT). Some recipients develop EBVD relatively late after haploHSCT, and most of these patients suffer a poor outcome. This retrospective cohort study characterized the early adaptive immune recovery of patients with acute leukemia presenting with EBVD more than 100 d after haploHSCT. Patients with acute leukemia who received haploHSCT and developed EBVD 100 d later (n = 8) were compared with a matched control group without EBVD (n = 24) with regard to peripheral WBC, lymphocytes, and neutrophils (at 30, 60, and 90 d) and recoveries of B and T lymphocytes (at 30 and 90 d, via immunophenotyping/flow cytometry). Ninety days after haploHSCT, the median values of WBCs and lymphocytes, and the recoveries of CD19(+) B cells and CD4(+) , CD8(+) , and CD4(+) CD45RO(+) T cells, were significantly lower in patients who developed EBVD, relative to the control group. These results suggest a significant association between deficient early recovery of B and T lymphocytes and the development of late-onset EBVD after haploHSCT. Our observation could facilitate clinical intervention and the improvement of overall survival of patients undergoing haploHSCT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diagnostic accuracy of ultrasonic histogram features to evaluate radiation toxicity of the parotid glands: a clinical study of xerostomia following head-and-neck cancer radiotherapy.

PubMed

Yang, Xiaofeng; Tridandapani, Srini; Beitler, Jonathan J; Yu, David S; Chen, Zhengjia; Kim, Sungjin; Bruner, Deborah W; Curran, Walter J; Liu, Tian

2014-10-01

To investigate the diagnostic accuracy of ultrasound histogram features in the quantitative assessment of radiation-induced parotid gland injury and to identify potential imaging biomarkers for radiation-induced xerostomia (dry mouth)-the most common and debilitating side effect after head-and-neck radiotherapy (RT). Thirty-four patients, who have developed xerostomia after RT for head-and-neck cancer, were enrolled. Radiation-induced xerostomia was defined by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer morbidity scale. Ultrasound scans were performed on each patient's parotids bilaterally. The 34 patients were stratified into the acute-toxicity groups (16 patients, ≤ 3 months after treatment) and the late-toxicity group (18 patients, > 3 months after treatment). A separate control group of 13 healthy volunteers underwent similar ultrasound scans of their parotid glands. Six sonographic features were derived from the echo-intensity histograms to assess acute and late toxicity of the parotid glands. The quantitative assessments were compared to a radiologist's clinical evaluations. The diagnostic accuracy of these ultrasonic histogram features was evaluated with the receiver operating characteristic (ROC) curve. With an area under the ROC curve greater than 0.90, several histogram features demonstrated excellent diagnostic accuracy for evaluation of acute and late toxicity of parotid glands. Significant differences (P < .05) in all six sonographic features were demonstrated between the control, acute-toxicity, and late-toxicity groups. However, subjective radiologic evaluation cannot distinguish between acute and late toxicity of parotid glands. We demonstrated that ultrasound histogram features could be used to measure acute and late toxicity of the parotid glands after head-and-neck cancer RT, which may be developed into a low-cost imaging method for xerostomia monitoring and assessment. Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.

Medical informatics in medical research - the Severe Malaria in African Children (SMAC) Network's experience.

PubMed

Olola, C H O; Missinou, M A; Issifou, S; Anane-Sarpong, E; Abubakar, I; Gandi, J N; Chagomerana, M; Pinder, M; Agbenyega, T; Kremsner, P G; Newton, C R J C; Wypij, D; Taylor, T E

2006-01-01

Computers are widely used for data management in clinical trials in the developed countries, unlike in developing countries. Dependable systems are vital for data management, and medical decision making in clinical research. Monitoring and evaluation of data management is critical. In this paper we describe database structures and procedures of systems used to implement, coordinate, and sustain data management in Africa. We outline major lessons, challenges and successes achieved, and recommendations to improve medical informatics application in biomedical research in sub-Saharan Africa. A consortium of experienced research units at five sites in Africa in studying children with disease formed a new clinical trials network, Severe Malaria in African Children. In December 2000, the network introduced an observational study involving these hospital-based sites. After prototyping, relational database management systems were implemented for data entry and verification, data submission and quality assurance monitoring. Between 2000 and 2005, 25,858 patients were enrolled. Failure to meet data submission deadline and data entry errors correlated positively (correlation coefficient, r = 0.82), with more errors occurring when data was submitted late. Data submission lateness correlated inversely with hospital admissions (r = -0.62). Developing and sustaining dependable DBMS, ongoing modifications to optimize data management is crucial for clinical studies. Monitoring and communication systems are vital in multi-center networks for good data management. Data timeliness is associated with data quality and hospital admissions.

Noninvasive beat-by-beat registration of ventricular late potentials using high resolution electrocardiography.

PubMed

Hombach, V; Kebbel, U; Höpp, H W; Winter, U; Hirche, H

1984-08-01

We have developed a new high resolution ECG equipment for recording cardiac microvolt potentials from the body surface. Noise reduction has been achieved by specially designed suction electrodes, by spatial averaging of the electrocardiograms from four electrode pairs, using extremely low noise amplifiers, by performing registrations within a Faraday cage, and by teaching the patient to relax during end expiratory breath holding. Fourteen young males (controls) and 30 patients with various cardiac diseases (27 with CHD) were studied. In normals ventricular late potentials were not seen, but in 12/30 patients clearcut diastolic potentials were found. In 7/12 patients with positive findings, late potentials appeared beat-by-beat, in 5/12 patients those signals occurred intermittently, in 11/30 patients questionably, and in the remaining 5/30 patients no late potentials were recorded. One patient with the Romano-Ward syndrome revealed phases with stable beat-by-beat and intermittently occurring ventricular late potentials. These results demonstrate the feasibility of continuous non-invasive recording of ventricular late potentials, whose clinical and prognostic significance remains to be established.

Advanced Disease at Enrollment in HIV Care in Four Sub-Saharan African Countries: Change from 2006-2011 and Multi-Level Predictors in 2011

PubMed Central

Hoffman, Susie; Wu, Yingfeng; Lahuerta, Maria; Kulkarni, Sarah Gorrell; Nuwagaba-Biribonwoha, Harriet; Sadr, Wafaa El; Remien, Robert H.; Mugisha, Veronicah; Hawken, Mark; Chuva, Ema; Nash, Denis; Elul, Batya

2015-01-01

Objectives To examine changes between 2006 and 2011 in the proportion of HIV-positive patients newly-enrolled in HIV care with advanced disease and the median CD4+ cell count at enrollment; and identify patient-, facility-, and contextual-level factors associated with late enrollment in care in 2011. Design Cross sectional over time. Methods For time trends analyses, routinely-collected patient-level data (307,110 adults newly-enrolled in 138 HIV clinical care facilities) in Kenya, Mozambique, Rwanda and Tanzania; and for analyses of correlates, patient-level data (46,201 in 195 facilities), and facility- and population-level survey data were used. Late enrollment was defined as CD4+ count ≤350 cells/μl and/or WHO clinical stage 3/4. Results Late enrollment declined from 69.9% to 57.2%, (p<0.0001); median CD4+ count increased from 242 to 292 cells/μL (ptrend<0.0001). In 2011, risk of late enrollment was significantly higher for men and non-pregnant women vs. pregnant women; patients aged >25 vs. 15-25 years; non-married vs. married; and those entering from sites other than prevention of mother to child transmission (PMTCT). More extensive HIV testing coverage in the region of a facility was significantly associated with lower risk of late enrollment. Conclusions Despite improvement, in 2011, 57% of patients entered HIV care already ART-eligible. The lower risk of late enrollment among those referred from PMTCT and in regions where HIV testing coverage was higher suggests that innovative approaches to rapidly increase testing uptake among people living with HIV prior to the development of symptoms have the potential to reduce late enrollment in care. PMID:25136842

Impact of Growing Up with a Chronically Ill Sibling on Well Siblings' Late Adolescent Functioning

PubMed Central

Fleary, Sasha A.; Heffer, Robert W.

2013-01-01

The purpose of this study was to explore the continuing impact of growing up with an ill sibling on well siblings' late adolescent functioning. Forty late adolescents (M age = 18.78, SD = 0.83), who identified themselves as growing up with an ill sibling, completed a semistructured interview, demographic questionnaire, Personality Assessment Screener, and My Feelings and Concerns Sibling Questionnaire. Participants reported clinically significant problems on some PAS scales, and gender differences were found for acting out and alienation. Significant relationships were reported for communication and social withdrawal and alienation. Both positive and negative themes about the experience were elicited from the responses in the semistructured interview. This study provides evidence for some lingering negative effects of growing up with an ill sibling on well siblings' late adolescent functioning. Additionally, evidence for siblings' development of positive characteristics that may act as protective variables as they face the stressors of late adolescence was also highlighted. PMID:24959574

A possible new approach in the prediction of late gestational hypertension: The role of the fetal aortic intima-media thickness.

PubMed

Visentin, Silvia; Londero, Ambrogio P; Camerin, Martina; Grisan, Enrico; Cosmi, Erich

2017-01-01

The aim was to determine the predictive role of combined screening for late-onset gestational hypertension by fetal ultrasound measurements, third trimester uterine arteries (UtAs) Doppler imaging, and maternal history. This prospective study on singleton pregnancies was conducted at the tertiary center of Maternal and Fetal Medicine of the University of Padua during the period between January 2012 and December 2014. Ultrasound examination (fetal biometry, fetal wellbeing, maternal Doppler study, fetal abdominal aorta intima-media thickness [aIMT], and fetal kidney volumes), clinical data (mother age, prepregnancy body mass index [BMI], and parity), and pregnancy outcomes were collected. The P value <0.05 was defined significant considering a 2-sided alternative hypothesis. The distribution normality of variables were assessed using Kolmogorov-Smirnoff test. Data were presented by mean (±standard deviation), median and interquartile range, or percentage and absolute values. We considered data from 1381 ultrasound examinations at 29 to 32 weeks' gestation, and in 73 cases late gestational hypertension developed after 34 weeks' gestation. The final multivariate model found that fetal aIMT as well as fetal umbilical artery pulsatility index (PI), maternal age, maternal prepregnacy BMI, parity, and mean PI of maternal UtAs, assessed at ultrasound examination of 29 to 32 weeks' gestation, were significant and independent predictors for the development of gestational hypertension after 34 weeks' gestation. The area under the curve of the model was 81.07% (95% confidence interval, 75.83%-86.32%). A nomogram was developed starting from multivariate logistic regression coefficients. Late-gestational hypertension could be independently predicted by fetal aIMT assessment at 29 to 32 weeks' gestation, ultrasound Doppler waveforms, and maternal clinical parameters.

A possible new approach in the prediction of late gestational hypertension

PubMed Central

Visentin, Silvia; Londero, Ambrogio P.; Camerin, Martina; Grisan, Enrico; Cosmi, Erich

2017-01-01

Abstract The aim was to determine the predictive role of combined screening for late-onset gestational hypertension by fetal ultrasound measurements, third trimester uterine arteries (UtAs) Doppler imaging, and maternal history. This prospective study on singleton pregnancies was conducted at the tertiary center of Maternal and Fetal Medicine of the University of Padua during the period between January 2012 and December 2014. Ultrasound examination (fetal biometry, fetal wellbeing, maternal Doppler study, fetal abdominal aorta intima-media thickness [aIMT], and fetal kidney volumes), clinical data (mother age, prepregnancy body mass index [BMI], and parity), and pregnancy outcomes were collected. The P value <0.05 was defined significant considering a 2-sided alternative hypothesis. The distribution normality of variables were assessed using Kolmogorov–Smirnoff test. Data were presented by mean (±standard deviation), median and interquartile range, or percentage and absolute values. We considered data from 1381 ultrasound examinations at 29 to 32 weeks’ gestation, and in 73 cases late gestational hypertension developed after 34 weeks’ gestation. The final multivariate model found that fetal aIMT as well as fetal umbilical artery pulsatility index (PI), maternal age, maternal prepregnacy BMI, parity, and mean PI of maternal UtAs, assessed at ultrasound examination of 29 to 32 weeks’ gestation, were significant and independent predictors for the development of gestational hypertension after 34 weeks’ gestation. The area under the curve of the model was 81.07% (95% confidence interval, 75.83%–86.32%). A nomogram was developed starting from multivariate logistic regression coefficients. Late-gestational hypertension could be independently predicted by fetal aIMT assessment at 29 to 32 weeks’ gestation, ultrasound Doppler waveforms, and maternal clinical parameters. PMID:28079791

Phenotypic similarities between late-onset autosomal dominant and sporadic Alzheimer disease: A single-family case-control study

PubMed Central

Day, Gregory S; Musiek, Erik S; Roe, Catherine M; Norton, Joanne; Goate, Alison M; Cruchaga, Carlos; Cairns, Nigel J; Morris, John C

2016-01-01

Importance The “amyloid hypothesis” posits that disrupted amyloid-beta (Aβ) homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant Alzheimer disease (ADAD) has an early symptomatic onset and is caused by single gene mutations that result in overproduction of Aβ42. To the extent that “sporadic” late-onset Alzheimer disease (LOAD) also results from dysregulated Aβ42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. Objective To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) mutation to mitigate the potential confound of age when comparing ADAD and LOAD. Design Case-control study of a family with late-onset ADAD and individuals with histopathologically-proven LOAD. Setting The Knight Alzheimer Disease Research Center, Washington University, St Louis, and other National Institutes of Aging-funded Alzheimer Disease Centers in the United States. Participants Ten PSEN1 A79V mutation carriers from multiple generations of a family with late-onset ADAD (median age-at-onset, 75.0 [63–77] years) and 12 noncarrier family members, followed at the Knight Alzheimer Disease Research Center (1985–2015); and 1115 individuals with neuropathologically confirmed LOAD (median age-at-onset, 74.0 [60–101] years) from the National Alzheimer Coordinating Center database (09/2005-12/14). Main Outcome and Measure Planned comparison of clinical characteristics between cohorts, including age at symptomatic onset, associated symptoms and signs, rates of progression, and disease duration. Results Seven (70%) mutation carriers developed AD dementia, while three are yet asymptomatic in their 7th and 8th decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptomatic onset, presenting symptoms and duration, and rate of progression of dementia. Early emergence of comorbid hallucinations and delusions were observed in 57% of individuals with ADAD versus 19% of individuals with LOAD (p=.03). Three of twelve (25%) noncarriers from the PSEN1 A79V family are potential phenocopies as they also developed AD dementia (median age at onset=76.0 years). Conclusions and Relevance In this family, the amyloidogenic PSEN1 A79V mutation recapitulates the clinical attributes of LOAD. Previously reported clinical phenotypic differences between individuals with ADAD and LOAD may reflect age- or mutation-dependent effects. PMID:27454811

Narrative Skills, Cognitive Profiles and Neuropsychiatric Disorders in 7-8-Year-Old Children with Late Developing Language

ERIC Educational Resources Information Center

Miniscalco, Carmela; Hagberg, Bibbi; Kadesjo, Bjorn; Westerlund, Monica; Gillberg, Christopher

2007-01-01

Background: A community-representative sample of screened and clinically examined children with language delay at 2.5 years of age was followed up at school age when their language development was again examined and the occurrence of neuropsychiatric/neurodevelopmental disorder (attention deficit/hyperactivity disorder (ADHD) and/or autism…

Patients with late-adult-onset ulcerative colitis have better outcomes than those with early onset disease.

PubMed

Ha, Christina Y; Newberry, Rodney D; Stone, Christian D; Ciorba, Matthew A

2010-08-01

The influence of age on the presentation, clinical course, and therapeutic response of patients with adult-onset ulcerative colitis (UC) is understudied. Given potential age-related differences in risk factors and immune function, we sought to determine if disease behavior or clinical outcomes differed between patients diagnosed with UC in later versus earlier stages of adulthood. We performed a retrospective cohort study of 295 patients with UC seen at a tertiary care center from 2001 to 2008. Adult subjects newly diagnosed with UC between the ages of 18 and 30 years were defined as early onset, those newly diagnosed at age 50 or older were defined as late onset. The 2 groups were analyzed for differences in medication use and clinical end points, including disease extent, severity at the time of diagnosis, and steroid-free clinical remission at 1 year after disease onset. Disease extent and symptom severity were similar between groups at the time of diagnosis. One year after diagnosis, more patients in the late-onset group achieved steroid-free clinical remission (64% vs 49%; P = .01). Among those who required systemic steroid therapy, more late-onset patients achieved steroid-free remission by 1 year (50% vs 32%; P = .01). Former smoking status was a more common risk factor in the late-onset cohort (P < .001), whereas more early onset patients had a positive family history (P = .008). Patients with early and late-adult-onset UC have similar initial clinical presentations, but differ in disease risk factors. Late-onset patients have better responses to therapy 1 year after diagnosis. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Diabetes mellitus is associated with late-onset post-stroke depression.

PubMed

Zhang, Yu; He, Ji-Rong; Liang, Huai-Bin; Lu, Wen-Jing; Yang, Guo-Yuan; Liu, Jian-Rong; Zeng, Li-Li

2017-10-15

To explore the associated factors of late-onset post-stroke depression (PSD). A total of 251 patients with acute ischemic stroke were recruited. The evaluation of depression was performed 2 weeks after ischemia. 206 patients showing no depression in 2 weeks were followed up. They were divided into late-onset PSD group and non-depressed group by clinical interview with Hamilton depression scale score 3 months after stroke. On the first day following hospitalization, the clinical data including age, gender, educational level and vascular risk factors were recorded. The severity, etiological subtype and location of stroke were evaluated. The inflammatory mediators, glucose and lipid levels were recorded on the day of admission. The association between clinical factors and late-onset PSD was explored by logistic regression analysis. The ROC analysis was performed to evaluate the predicting power of the clinical factors. 187 of 206 patients completed the assessment 3 months after stroke. 19 (10.16%) patients were diagnosed as late onset PSD. Diabetes mellitus was an independent risk factor for late-onset PSD (OR 2.675, p = 0.047). ROC analysis demonstrated that glucose and HbA1C could predict late-onset PSD with specificity of 84.4%. The sample of our study was small. The results should be further confirmed in a larger cohort of patients with acute ischemic stroke. The acute ischemic stroke patients with diabetes mellitus were more tendered to suffer late-onset PSD. Copyright © 2017 Elsevier B.V. All rights reserved.

Subdural empyema: Clinical presentations and management options for an uncommon neurosurgical emergency in a developing country.

PubMed

Chikani, M C; Mezue, W; Okorie, E; Mbachu, C; Ndubisi, C; Chikani, U N

2017-10-01

Controversy regarding the best management strategy for subdural empyema (SDE) attests to the persisting poor outcomes for this uncommon life threatening intracranial suppurative process. Late presentation confounds the problem in developed countries. While craniotomy is commonly recommended, it is not always possible in late presentation with advanced morbidity. The aim of this study was to identify the pattern of clinical presentation and explore the outcomes following management of SDE using burr hole, aspiration, and drainage (BAAD) in resource poor settings. This is a retrospective review of prospectively collected data of 18 patients presenting with SDE over a period of 10 years from two neurosurgical centers. Data was abstracted on patients' demographic characteristics, sources of SDE, clinical presentation and site of infection, methods of diagnosis, organisms isolated, treatments received, and outcome. Collected data was entered into the Statistical Package for the Social Sciences version 17 software and subjected to descriptive analysis for all variables. Majority of the patients presented late with Glasgow Coma Scale score GCS of 9/15. Altered sensorium was noted in 14 (77.8%) of the patients, 11 (61.1%) out of the 14 patients had ≤ grade 3 of Bannister and Williams level of consciousness. The mainstay of treatment for all patients was BAAD of abscess and administration of appropriate antibiotics. Fourteen patients (77.8%) were discharged on grade A of H.W. Mauser's grading system. Three mortalities were recorded only in patients who had grade 4 Bannister and Williams grading. BAAD is the near approximated option to standard craniotomy management in a limited resource facility and it has a very good clinical outcome. However, more studies are required to draw the final conclusion.

Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases.

PubMed

Zhang, Xiaoying; Luo, Qiong

2017-02-01

The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late-onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis.

Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases

PubMed Central

Zhang, Xiaoying; Luo, Qiong

2017-01-01

The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late-onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis. PMID:28352331

Why Do SGLT2 Inhibitors Inhibit Only 30–50% of Renal Glucose Reabsorption in Humans?

PubMed Central

Liu, Jiwen (Jim); Lee, TaeWeon; DeFronzo, Ralph A.

2012-01-01

Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30–50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible. PMID:22923645

Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans?

PubMed

Liu, Jiwen Jim; Lee, TaeWeon; DeFronzo, Ralph A

2012-09-01

Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30-50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible.

Predictors of clinic satisfaction among adult survivors of childhood cancer.

PubMed

Absolom, Kate; Greenfield, Diana; Ross, Richard; Horne, Beverly; Davies, Helena; Glaser, Adam; Simpson, Adrian; Waite, Heather; Eiser, Christine

2006-07-01

Childhood cancer survivors experience a wide range of late-effects. As survival rates improve, follow-up in paediatric clinics becomes less feasible, and alternative models of care have been proposed. In this study, satisfaction among those attending a traditional paediatric late-effects clinic was compared with a multi-disciplinary clinic in an adult setting. Survivors (adult clinic n=93, paediatric clinic n=105, age 16-39 years) completed measures of symptoms, understanding of vulnerability to late-effects, purpose of follow-up, satisfaction and number of topics discussed. Predictors of satisfaction were: number of topics discussed, greater understanding of the purpose of follow-up and sex. Females, and those reporting longer waiting time were less satisfied. Aspects of clinic organisation, including shorter waiting times and opportunities to discuss health concerns, are more important in determining patient satisfaction than clinic type. Survivors' understanding of the purpose of follow-up is also integral in determining satisfaction.

Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop.

PubMed

Cricchi, F; Di Lorenzo, C; Grieco, G S; Rengo, C; Cardinale, A; Racaniello, M; Santorelli, F M; Nappi, G; Pierelli, F; Casali, C

2007-03-15

Familial hemiplegic migraine type 1, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) are allelic disorders associated with mutations in the CACNA1A gene, which encodes the alpha1 subunit of the P/Q-type calcium channel (Ca(V)2.1). SCA6 and EA2 share a number of clinical features, such as prominent cerebellar involvement and good response to acetazolamide therapy. However, while SCA6 develops as a late-onset, progressive ataxia, EA2 has an earlier, and episodic, onset. We report on two sisters with a heterogeneous clinical phenotype. The first developed progressive cerebellar ataxia after age 30, without noticeable episodes of vertigo or headache. A 1 year trial with acetazolamide did not produce significant results. The other reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia. Brain MRI showed cerebellar atrophy, especially in the vermis, in both patients. Direct sequencing of CACNA1A identified a heterozygous 1360G>A mutation in exon 11 resulting in the substitution of alanine for threonine at residue 454 (p.Ala454Thr). This is the first description of a change residing in the cytoplasmic I-II loop associated with a clinical phenotype.

Degenerative jargon aphasia: unusual progression of logopenic/phonological progressive aphasia?

PubMed

Caffarra, Paolo; Gardini, Simona; Cappa, Stefano; Dieci, Francesca; Concari, Letizia; Barocco, Federica; Ghetti, Caterina; Ruffini, Livia; Prati, Guido Dalla Rosa

2013-01-01

Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction.

[Risk-adjusted assessment: late-onset infection in neonates].

PubMed

Gmyrek, Dieter; Koch, Rainer; Vogtmann, Christoph; Kaiser, Annette; Friedrich, Annette

2011-01-01

The weak point of the countrywide perinatal/neonatal quality surveillance is the ignorance of interhospital differences in the case mix of patients. As a result, this approach does not produce reliable benchmarking. The objective of this study was to adjust the result of the late-onset infection incidence of different hospitals according to their risk profile of patients by multivariate analysis. The perinatal/neonatal database of 41,055 newborns of the Saxonian quality surveillance from 1998 to 2004 was analysed. Based on 18 possible risk factors, a logistic regression model was used to develop a specific risk predictor for the quality indicator "late-onset infection". The developed risk predictor for the incidence of late-onset infection could be described by 4 of the 18 analysed risk factors, namely gestational age, admission from home, hypoxic ischemic encephalopathy and B-streptococcal infection. The AUC(ROC) value of this quality indicator was 83.3%, which demonstrates its reliability. The hospital ranking based on the adjusted risk assessment was very different from hospital rankings before this adjustment. The average correction of ranking position was 4.96 for 35 clinics. The application of the risk adjustment method proposed here allows for a more objective comparison of the incidence of the quality indicator "late onset infection" among different hospitals. Copyright © 2011. Published by Elsevier GmbH.

The development of phonological skills in late and early talkers

PubMed Central

KEHOE, Margaret; CHAPLIN, Elisa; MUDRY, Pauline; FRIEND, Margaret

2016-01-01

This study examined the relationship between phonological and lexical development in a group of French-speaking children (n=30), aged 29 months. The participants were divided into three sub-groups based on the number of words in their expressive vocabulary : low vocabulary (below the 15th percentile) (<< late-talkers >>) ; average-sized vocabulary (40-60th percentile) (<< middle group >>) and advanced vocabulary (above the 90th percentile) (<< precocious >> or “early talkers”). The phonological abilities (e.g., phonemic inventory, percentage of correct consonants, and phonological processes) of the three groups were compared. The comparison was based on analyses of spontaneous language samples. Most findings were consistent with previous results found in English-speaking children, indicating that the phonological abilities of late talkers are less well developed than those of children with average-sized vocabularies which in turn are less well-developed than those of children with advanced vocabularies. Nevertheless, several phonological measures were not related to vocabulary size, in particular those concerning syllable-final position. These findings differ from those obtained in English. The article finally discusses the clinical implications of the findings for children with delayed language development. PMID:26924855

Early- and Late-Onset Depression in Late Life: A Prospective Study on Clinical and Structural Brain Characteristics and Response to Electroconvulsive Therapy.

PubMed

Dols, Annemiek; Bouckaert, Filip; Sienaert, Pascal; Rhebergen, Didi; Vansteelandt, Kristof; Ten Kate, Mara; de Winter, Francois-Laurent; Comijs, Hannie C; Emsell, Louise; Oudega, Mardien L; van Exel, Eric; Schouws, Sigfried; Obbels, Jasmien; Wattjes, Mike; Barkhof, Frederik; Eikelenboom, Piet; Vandenbulcke, Mathieu; Stek, Max L

2017-02-01

The clinical profile of late-life depression (LLD) is frequently associated with cognitive impairment, aging-related brain changes, and somatic comorbidity. This two-site naturalistic longitudinal study aimed to explore differences in clinical and brain characteristics and response to electroconvulsive therapy (ECT) in early- (EOD) versus late-onset (LOD) late-life depression (respectively onset <55 and ≥55 years). Between January 2011 and December 2013, 110 patients aged 55 years and older with ECT-treated unipolar depression were included in The Mood Disorders in Elderly treated with ECT study. Clinical profile and somatic health were assessed. Magnetic resonance imaging (MRI) scans were performed before the first ECT and visually rated. Response rate was 78.2% and similar between the two sites but significantly higher in LOD compared with EOD (86.9 versus 67.3%). Clinical, somatic, and brain characteristics were not different between EOD and LOD. Response to ECT was associated with late age at onset and presence of psychotic symptoms and not with structural MRI characteristics. In EOD only, the odds for a higher response were associated with a shorter index episode. The clinical profile, somatic comorbidities, and brain characteristics in LLD were similar in EOD and LOD. Nevertheless, patients with LOD showed a superior response to ECT compared with patients with EOD. Our results indicate that ECT is very effective in LLD, even in vascular burdened patients. Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Biliary Stenosis and Gastric Outlet Obstruction: Late Complications After Acute Pancreatitis With Pancreatic Duct Disruption.

PubMed

Sugimoto, Motokazu; Sonntag, David P; Flint, Greggory S; Boyce, Cody J; Kirkham, John C; Harris, Tyler J; Carr, Sean M; Nelson, Brent D; Bell, Don A; Barton, Joshua G; Traverso, L William

2018-07-01

Pancreatic duct disruption (PDD) after acute pancreatitis can cause pancreatic collections in the early phase and biliary stenosis (BS) or gastric outlet obstruction (GOO) in the late phase. We aimed to document those late complications after moderate or severe acute pancreatitis. Between September 2010 and August 2014, 141 patients showed pancreatic collections on computed tomography. Percutaneous drainage was primarily performed for patients with signs or symptoms of uncontrolled pancreatic juice leakage. Pancreatic duct disruption was defined as persistent amylase-rich drain fluid or a pancreatic duct cut-off on imaging. Clinical course of the patients who developed BS or GOO was investigated. Among the 141 patients with collections, 33 patients showed PDD in the pancreatic head/neck area. Among them, 9 patients (27%) developed BS 65 days after onset and required stenting for 150 days, and 5 patients (15%) developed GOO 92 days after onset and required gastric decompression and jejunal tube feeding for 147 days (days shown in median). All 33 patients recovered successfully without requiring surgical intervention. Anatomic proximity of the bile duct or duodenum to the site of PDD and severe inflammation seemed to contribute to the late onset of BS or GOO. Conservative management successfully reversed these complications.

Pelvic girdle pain--associations between risk factors in early pregnancy and disability or pain intensity in late pregnancy: a prospective cohort study.

PubMed

Robinson, Hilde Stendal; Veierød, Marit B; Mengshoel, Anne Marit; Vøllestad, Nina K

2010-05-13

Recent studies have shown high prevalence rates for pelvic girdle pain (PGP) in pregnancy. Some risk factors for developing PGP have been suggested, but the evidence is weak. Furthermore there is almost no data on how findings from clinical examinations are related to subsequent PGP. The main purpose for this study was to study the associations between socio-demographical, psychological and clinical factors measured at inclusion in early pregnancy and disability or pain intensity in gestation week 30. This is a prospective cohort study following women from early to late pregnancy. Eligible women were recruited at their first attendance at the maternity care unit. 268 pregnant women answered questionnaires and underwent clinical examinations in early pregnancy and in gestation week 30. We used scores on disability and pain intensity in gestation week 30 as outcome measures to capture the affliction level of PGP. Multiple linear regression analysis was used to study the associations between potential risk factors measured in early pregnancy and disability or pain intensity in gestation week 30. Self-reported pain locations in the pelvis, positive posterior pelvic pain provocation (P4) test and a sum of pain provocation tests in early pregnancy were significantly associated with disability and pain intensity in gestation week 30 in a multivariable statistic model. In addition, distress was significantly associated with disability. The functional active straight leg raise (ASLR) test, fear avoidance beliefs and the number of pain sites were not significantly associated with either disability or pain intensity. The results suggest that a clinical examination, including a few tests, performed in early pregnancy may identify women at risk of a more severe PGP late in pregnancy. The identification of clinical risk factors may provide a foundation for development of targeted prevention strategies.

The clinical spectrum of late-onset Alexander disease: a systematic literature review.

PubMed

Balbi, Pietro; Salvini, Silvana; Fundarò, Cira; Frazzitta, Giuseppe; Maestri, Roberto; Mosah, Dibo; Uggetti, Carla; Sechi, GianPietro

2010-12-01

Following the discovery of glial fibrillary acidic protein (GFAP) mutations as the causative factor of Alexander disease (AxD), new case reports have recently increased, prompting a more detailed comprehension of the clinical features of the three disease subtypes (infantile, juvenile and adult). While the clinical pattern of the infantile form has been substantially confirmed, the late-onset subtypes (i.e., juvenile and adult), once considered rare manifestations of AxD, have displayed a wider clinical spectrum. Our aim was to evaluate the clinical phenotype of the adult and juvenile forms by reviewing the previously reported cases. Data were collected from previously published reports on 112 subjects affected by neuropathologically or genetically proven adult and juvenile Alexander disease. Although the late-onset forms of AxD show a wide clinical variability, a common pattern emerges from comparing previously reported cases, characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Late-onset AxD cases can no longer be considered as rare manifestations of the disease. The clinical pattern usually reflects the topographic localization of the lesions, with adult cases displaying a predominant infratentorial localization of the lesions. Juvenile cases show clinical and radiological features which are intermediate between adult and infantile forms.

Excess of non-verbal cases of autism spectrum disorders presenting to orthodox clinical practice in Africa – a trend possibly resulting from late diagnosis and intervention

PubMed Central

Bakare, Muideen O; Munir, Kerim M

2012-01-01

Objectives Characteristics of children with autism spectrum disorders (ASDs) in Africa are not known because of unavailability of large-scale epidemiological studies in this region. This review explored the age at first presentation to orthodox clinical practice of African children with ASDs and their expressive language ability at presentation. Methods A literature search of case series and case reports of ASDs from Africa was done through PubMed/MEDLINE, Google Scholar, African Journals Online (AJOL), and archives of the Nigerian Journal of Psychiatry. Six articles included content relating to age of the child at first presentation to orthodox clinical practice and symptoms at presentation related to expressive language ability and therefore fulfilled the inclusion criteria. Suggestions are made to explain the observations emanating from the review. Results An excess of non-verbal over verbal cases of ASDs have been presenting to orthodox clinical practice and there is a common denominator of late presentation/diagnosis and in turn late intervention, with most cases presenting for the first time well above 8 years of age. Attempts to explain these observations included low levels of knowledge and awareness about ASDs in Africa; problems with help-seeking behaviour; and lack of mental healthcare facilities and trained personnel. Conclusions Enhancement of processes directed at ensuring early diagnosis and interventions, especially interventions aimed at improving speech and language development well and sufficiently early, may bring about a shift in the trend of excess non-verbal cases of ASDs over verbal cases presenting to orthodox clinical practice. PMID:22229024

Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration.

PubMed

Sarks, Shirley; Cherepanoff, Svetlana; Killingsworth, Murray; Sarks, John

2007-03-01

To correlate basal laminar deposit (BLamD) and membranous debris, including basal linear deposit (BLinD), with the evolution of early age-related macular degeneration (AMD). A clinicopathologic collection of 132 eyes with a continuous layer of BLamD was reviewed. The thickness and type of BLamD and the sites of membranous debris deposition were correlated with the clinical progression of the disease. Two types of BLamD, termed early and late, were identified based on light microscopic appearance by using the picro-Mallory stain. The progressive accumulation of late type BLamD correlated well with increasing BLamD thickness, advancing RPE degeneration, poorer vision, increasing age, and clinically evident pigment changes. Membranous debris initially accumulated diffusely as BLinD, most eyes with BLinD and early BLamD remaining funduscopically normal. However, membranous debris also formed focal collections as basal mounds internal to the RPE basement membrane and as soft drusen external to the basement membrane. Eyes in which membranous debris remained confined to basal mounds belonged to older patients with poorer vision, whereas patients with soft drusen were younger and had better vision. The presence of BLinD and early BLamD define threshold AMD, which manifests clinically as a normal fundus. Although late BLamD correlates most closely with clinical pigment abnormalities, it is the quantity and sites of membranous debris accumulation that appear to determine whether the disease develops pigment changes only or follows the alternative pathway of soft drusen formation with its attendant greater risk of choroidal neovascularization (CNV).

Functional development in clinical high risk youth: Prediction of schizophrenia versus other psychotic disorders

PubMed Central

Tarbox, Sarah I.; Addington, Jean; Cadenhead, Kristin S.; Cannon, Tyrone D.; Cornblatt, Barbara A.; Perkins, Diana O.; Seidman, Larry J.; Tsuang, Ming T.; Walker, Elaine F.; Heinssen, Robert; McGlashan, Thomas H.; Woods, Scott W.

2013-01-01

This study evaluates premorbid social and academic functioning in clinical high-risk individuals as predictors of transition to schizophrenia versus another psychotic disorder. Participants were 54 individuals enrolled in phase one of the North American Prodrome Longitudinal Study who over two and a half years of follow-up met criteria for schizophrenia/schizophreniform disorder (n = 28) or another psychotic disorder (n = 26). Social and academic functioning in childhood, early adolescence, and late adolescence was assessed at baseline using the Cannon-Spoor Premorbid Adjustment Scale. Social maladjustment in late adolescence predicted significantly higher odds of transition to schizophrenia versus another psychotic disorder independent of childhood and early adolescent adjustment (OR = 4.02) and conveyed unique risk over academic maladjustment (OR = 5.64). Premorbid academic maladjustment was not associated with psychotic disorder diagnosis. Results support diagnostic specificity of premorbid social dysfunction to schizophrenia in clinical high-risk youth and underscore an important role for social maladjustment in the developmental pathology of schizophrenia and its prediction. PMID:24200216

Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease

PubMed Central

Brickell, Kiri L; Leverenz, James B; Steinbart, Ellen J; Rumbaugh, Malia; Schellenberg, Gerard D; Nochlin, David; Lampe, Thomas H; Holm, Ida E; Van Deerlin, Vivianna; Yuan, Wuxing; Bird, Thomas D

2007-01-01

Aim Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD. Methods The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP). Results Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin‐1 (PS1) (A79V) with remarkably late onset in a family member. Conclusions MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia. PMID:17615170

The first case series of Chinese patients in Hong Kong with familial Alzheimer's disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer's disease.

PubMed

Shea, Y F; Chu, L W; Lee, S C; Chan, A Ok

2017-12-01

Patients with familial Alzheimer's disease are being increasingly reported in Hong Kong. The objectives of this study were to report the clinical features of these patients, and to compare them with those with biomarker-confirmed sporadic late-onset Alzheimer's disease. All symptomatic Chinese patients with familial Alzheimer's disease who attended Queen Mary Hospital, Memory Clinic between January 1998 and December 2016 were included. Information about clinical features, baseline Mini-Mental State Examination score, and presenting cognitive symptoms or atypical clinical features were collected. Their clinical features were compared with those of 12 patients with sporadic late-onset Alzheimer's disease with cerebrospinal fluid biomarker evidence of Alzheimer's disease and 14 patients with late-onset Alzheimer's disease and positive amyloid loading on Pittsburgh compound B imaging. There were three families with familial Alzheimer's disease among whom eight family members were affected. The mean (± standard deviation) age of onset and the Mini-Mental State Examination score were 48.4 ± 7.7 years and 7.9 ± 9.2, respectively. Compared with the sporadic late-onset Alzheimer's disease patients, those with familial Alzheimer's disease had an earlier age of onset and presentation (both P<0.001) and received the correct diagnosis later (median [interquartile range], 7.5 [5.3-14.5] vs 2 [1.0-3.3] years; P<0.001). Patients with familial disease had a lower Mini-Mental State Examination score at presentation than those having late-onset Alzheimer's disease (mean, 7.9 ± 9.2 vs 17.6 ± 7.2; P=0.01). They also had fewer delusions, and less dysphoria and irritability (0% vs 41.7%, 0% vs 50% and 0% vs 54.2%; P=0.04, 0.01 and 0.01, respectively). There was a trend of less frequent amnesia among patients with familial Alzheimer's disease compared with those having late-onset Alzheimer's disease (75% vs 100%; P=0.05). Clinical features differ for patients with familial Alzheimer's disease compared with those with late-onset Alzheimer's disease. There is a delay in diagnosis. Promotion of public awareness of familial Alzheimer's disease is much needed.

Clinical, serologic, and immunogenetic characterization (HLA-DRB1) of late-onset lupus erythematosus in a Colombian population.

PubMed

Peñaranda-Parada, E; Quintana, G; Yunis, J J; Mantilla, R; Rojas, W; Panqueva, U; Caminos, J E; Garces, M F; Sanchez, E; Rondón-Herrera, F; de Jesús Iglesias-Gamarra, A

2015-10-01

Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup that is defined as onset after 50 years of age. Late-onset lupus may have a different clinical course and serological findings, which may delay diagnosis and timely treatment. The objective of this paper is to determine the clinical, serologic, and immunogenetic differences among Colombian patients with late-onset SLE versus conventional SLE patients. This was a cross-sectional study in a Colombian population. Patients and their medical records were analyzed from the services of Rheumatology in Bogotá and met the criteria for SLE, according to the American College of Rheumatology (ACR) revised criteria for the classification of SLE.In a reference group of late-onset SLE patients (98 participants, with an onset after 50 years of age) and a group of conventional SLE patients (72 participants, with an onset of age of 49 years or less), multiple clinical variables (age, clinical criteria for lupus, alopecia, weight loss, fever, Raynaud's phenomenon) and multiple serological variables (blood count, blood chemistry profile, autoantibodies) were analyzed. Additionally, the HLA class II (DRB1) of all the patients was genotyped, including an additional group of patients without the autoimmune disease. Statistical analysis was performed using the STATA 10.0 package. In the group of late-onset lupus, there was a higher frequency of pleurisy (p = 0.002), pericarditis (p = 0.026), dry symptoms (p = 0.029), lymphopenia (p = 0.007), and higher titers of rheumatoid factor (p = 0.001) compared with the group of conventional SLE. Late-onset SLE patients had a lower seizure frequency (p = 0.019), weight loss (p = 0.009), alopecia (p < 0.001), and Raynaud's phenomenon (p = 0.013) compared to the conventional SLE group. In late-onset SLE, HLA DR17 (DR3) was found more frequently compared with individuals without autoimmune disease (OR 3.81, 95% CI 1.47 to 10.59) (p = 0.0016). In the Colombian SLE population analyzed, there may be a probable association of several clinical and serologic variants, which would allow the differentiation of variables in the presentation of the disease among patients with late-onset SLE vs. conventional SLE. © The Author(s) 2015.

Effect of gestational age on the epidemiology of late-onset sepsis in neonatal intensive care units - a review.

PubMed

Afonso, Elsa Da Palma; Blot, Stijn

2017-10-01

Neonatal sepsis is a major cause of morbidity and mortality. Late-onset sepsis affects a significant percentage of infants admitted to the neonatal intensive care unit (NICU). Most affected newborns are preterm or low birth weight, but late-onset sepsis also affects late preterm and term infants. Understanding how gestational age affects the epidemiology of late-onset sepsis can be of use when defining strategies for its prevention and clinical management in NICU. Areas covered: Available evidence suggests the incidence and mortality of late-onset sepsis is higher in preterm and VLBW infants, but pathogen distribution and risk exposure is similar across all infants admitted to NICU. More research is required for late-onset sepsis in late preterm and term infants admitted to NICU. There is some research insight on the impact of gut bacteria in the epidemiology of Gram-negative sepsis, which could benefit from further dedicated studies. Expert commentary: Understanding the manner in which some infants develop severe sepsis and others don't and what the long-term outcomes are is fundamental to guide management strategies. Further research should focus both on infants' characteristics and on pathogenic processes. The ultimate goal is to be able to design guidelines for prevention and management of sepsis that are adapted to a varied neonatal population.

Revisiting the concept of late catatonia.

PubMed

Kocha, Hiroki; Moriguchi, Sho; Mimura, Masaru

2014-10-01

The objective of this paper is to introduce the concept of late catatonia to foreign readers for the first time in English. The original study was conducted about 20 years ago. The subjects were 16 persons who first visited our institutions between 1990 and 1996. They fulfilled the following criteria: 1) late-onset psychosis, with the initial mental changes occurring after 40 years of age; 2) more than one catatonic symptom observed during the clinical course; 3) a total clinical course lasting more than 2 years; and 4) no evidence of apparent organic brain disease. The medical records of individual patients were retrospectively reviewed to summarize the clinical features of this diagnosis. The crucial feature was the evolution or longitudinal change in the clinical picture over time, with the clinical course being divided into five stages: stage I (prodromal depression), stage II (anxiety and agitation), stage III (hallucination and delusion), stage IV (catatonia syndrome), and residual state. As for treatment, the effect of psychotropic agents was very limited. The electroconvulsive treatment was the most effective treatment option. Apart from the current diagnostic dichotomy of schizophrenia and mood disorder, the concept of late catatonia is useful in clinical settings and may provide clinically important knowledge. Copyright © 2014 Elsevier Inc. All rights reserved.

Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study.

PubMed

Tran, Thach D; Tran, Tuan; Simpson, Julie A; Tran, Ha T; Nguyen, Trang T; Hanieh, Sarah; Dwyer, Terence; Biggs, Beverley-Ann; Fisher, Jane

2014-01-08

Antenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development. A cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score ≥ 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants' motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis. In total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy. Antenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. These findings highlight the need to improve the quality of antenatal care when developing interventions for pregnant women that aim to optimise early childhood development in low- and middle-income countries.

Relationship between season, lactation number and incidence of clinical mastitis in different stages of lactation in a Holstein dairy farm.

PubMed

Moosavi, Maede; Mirzaei, Abdolah; Ghavami, Mohsen; Tamadon, Amin

2014-01-01

The aim of the present study was to compare the occurrence and duration of clinical mastitis in different seasons, stages of lactation period and parities in a Holstein dairy farm in Iran. A retrospective epidemiological survey from April 2005 to March 2008 was conducted on 884 clinical mastitis cases of 7437 lactations. Data of each case including calendar-date of mastitis onset, days in milk (DIM) of mastitis onset (early: 0-74 DIM; middle: 75-150 DIM, and late ≥ 150 DIM), duration of mastitis, and parity (1, 2, and ≥ 3) were recorded. Based on date of mastitis onset, cases were classified into stages of lactation. Moreover, beginning of mastitis was seasonally categorized. Duration of clinical mastitis after treatment in early lactation was less than late lactation in the first-parity cows (p = 0.005). In early lactation period, the first-parity cows suffered clinical mastitis in days earlier than two other parity groups (p < 0.001). Moreover, in late lactation period, the first-parity cows had clinical mastitis in days later than cows in the third and more parities (p = 0.002). Occurrence of clinical mastitis in summer increased in late lactation period but in winter increased in early lactation period (p = 0.001). In addition, occurrence time of clinical mastitis in summer were in days later than in spring (p = 0.02) and winter (p = 0.03) in early lactation period. In conclusion, occurrence of mastitis in winter and spring during early lactation and in summer during late lactation period were more prevalent especially in lower parities.

Relationship between season, lactation number and incidence of clinical mastitis in different stages of lactation in a Holstein dairy farm

PubMed Central

Moosavi, Maede; Mirzaei, Abdolah; Ghavami, Mohsen; Tamadon, Amin

2014-01-01

The aim of the present study was to compare the occurrence and duration of clinical mastitis in different seasons, stages of lactation period and parities in a Holstein dairy farm in Iran. A retrospective epidemiological survey from April 2005 to March 2008 was conducted on 884 clinical mastitis cases of 7437 lactations. Data of each case including calendar-date of mastitis onset, days in milk (DIM) of mastitis onset (early: 0-74 DIM; middle: 75-150 DIM, and late ≥ 150 DIM), duration of mastitis, and parity (1, 2, and ≥ 3) were recorded. Based on date of mastitis onset, cases were classified into stages of lactation. Moreover, beginning of mastitis was seasonally categorized. Duration of clinical mastitis after treatment in early lactation was less than late lactation in the first-parity cows (p = 0.005). In early lactation period, the first-parity cows suffered clinical mastitis in days earlier than two other parity groups (p < 0.001). Moreover, in late lactation period, the first-parity cows had clinical mastitis in days later than cows in the third and more parities (p = 0.002). Occurrence of clinical mastitis in summer increased in late lactation period but in winter increased in early lactation period (p = 0.001). In addition, occurrence time of clinical mastitis in summer were in days later than in spring (p = 0.02) and winter (p = 0.03) in early lactation period. In conclusion, occurrence of mastitis in winter and spring during early lactation and in summer during late lactation period were more prevalent especially in lower parities. PMID:25568687

Preventing group B streptococcal infections in newborns.

PubMed

Porta, Kelly; Rizzolo, Denise

2015-03-01

Despite advances in intrapartum antibiotic prophylaxis (IAP), group B streptococcal infection continues to be a predominant cause of early-onset disease in neonates. About 2% of neonates exposed to group B Streptococcus develop clinical manifestations including sepsis, pneumonia, and meningitis. Screening in late pregnancy reduces the incidence of early-onset sepsis by more than 80%. Clinicians must be able to identify the risk factors and clinical manifestations of group B streptococcal infection and to understand management and prevention guidelines.

From the RNA world to the clinic.

PubMed

Sullenger, Bruce A; Nair, Smita

2016-06-17

The study of RNA has continually emphasized the structural and functional versatility of RNA molecules. This versatility has inspired translational and clinical researchers to explore the utility of RNA-based therapeutic agents for a wide variety of medical applications. Several RNA therapeutics, with diverse modes of action, are being evaluated in large late-stage clinical trials, and many more are in early clinical development. Hundreds of patients are enrolled in large trials testing messenger RNAs to combat cancer, small interfering RNAs to treat renal and hepatic disorders, and aptamers to combat ocular and cardiovascular disease. Results from these studies are generating considerable interest among the biomedical community and the public and will be important for the future development of this emerging class of therapeutic agents. Copyright © 2016, American Association for the Advancement of Science.

Two-year follow-up after intracoronary gamma radiation therapy.

PubMed

Condado, J A; Waksman, R; Calderas, C; Saucedo, J; Lansky, A

1999-01-01

Neointimal hyperplasia and unfavorable remodeling have been demonstrated to be the major limitation to endovascular revascularization procedures. Intracoronary gamma radiation therapy has been shown to reduce the restenosis index. However, the late effects of these novel procedures are unknown. To evaluate the long-term effects on clinical and angiographic outcome of endovascular gamma radiation therapy following percutaneous transluminal coronary angioplasty (PTCA), serial angiography over a 2-year period was performed in 21 patients (22 lesions) who were treated with 192Ir in doses of 20-25 Gy after PTCA. Angiograms were analyzed using quantitative methods (QCA). The mean late loss between PTCA and 6 months was 0.20 +/- 0.59 and 0.13 +/- 0.84 between 6 months and 2 years. At 6 months, angiographic binary restenosis was present in six arteries (27.2%). At 2 years, binary restenosis was observed in six arteries (27.2%), including one patient who had developed restenosis and excluding one patient with spontaneous regression. Two early pseudoaneurysms and two late aneurysms were observed at 6 months, with little increase at 2 years. No other angiographic complication was observed. None of the patients or medical staff developed complications or illnesses that could be related to the effects of the radiation procedure. Gamma radiation therapy decreases late luminal loss, is safe and free of unexpected complications at 6 months follow-up, with no significant changes or late complications at 2-years' follow-up.

Development of InCVAX as a novel in situ autologous vaccine for metastatic cancers (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hode, Tomas; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel Siu Kit; Nordquist, Robert E.; Chen, Wei R.

2016-03-01

A novel method, an in situ autologous whole-cell cancer vaccine (inCVAX), is being developed by Immunophotonics, Inc., for the treatment of metastatic cancers. inCVAX combines phototherapy and immunotherapy to potentially induce a systemic anti-tumor immune response in the hosts. Immunophotonics and its academic partners have spent years conducting nonclinical research, developing CMC techniques and conducting clinical research. In 2015 the company initiated a late-stage (II/III) clinical trial in South America for advanced breast cancer patients. The process of developing the inCVAX approach from a laboratory setting into clinical trials requires significant efforts from a group of dedicated engineers, scientists, and physicians. The growth of the company and its business advances demonstrated the determination of a group of visionary investors, entrepreneurs, and business leaders. This talk will chronicle the milestones of the scientific achievement, medical progress, and business development of Immunophotonics.

An analysis of the differences between early and late preeclampsia with severe hypertension.

PubMed

Li, X L; Guo, P L; Xue, Y; Gou, W L; Tong, M; Chen, Q

2016-01-01

Preeclampsia is clinically divided into early onset and late onset preeclampsia based on the gestational age at delivery. Although the diagnostic criteria are the same in each subgroup of preeclampsia, it has been suggested that the maternal and perinatal mortalities of early onset and late onset preeclampsia are different. However, studies that compare clinical parameters or laboratory biomarkers between early onset and late onset preeclampsia are limited. Data on 177 women with early or late preeclampsia with severe hypertension were collected from a University Teaching Hospital from January 2010 to January 2011 and analysed. Data included all the clinical parameters and laboratory biomarkers of liver and renal function. 63 women and 114 women were diagnosed with early and late preeclampsia with severe hypertension, respectively. There was no difference in the maternal age and the incidence of clinical symptoms including edema, vision disturbance, severe headache and stillbirth between two groups. There was a decrease in alkaline phosphatase levels in early preeclampsia with severe hypertension but other markers of liver function were not altered. However, renal function including blood urea nitrogen, creatinine and uric acid were significantly higher in early preeclampsia with severe hypertension. Umbilical artery systolic velocity/diastolic velocity ratio was significantly higher in early preeclampsia with severe hypertension. Our data demonstrates that the laboratory biomarkers of renal function differ between early and late preeclampsia with severe hypertension. The severity of renal dysfunction correlated with the time of delivery in preeclampsia with severe hypertension. Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

Redefining late acute graft pancreatitis: clinical presentation, radiologic findings, principles of management, and prognosis.

PubMed

Small, Risa M; Shetzigovski, Ilanit; Blachar, Arye; Sosna, Jacob; Klausner, Joseph M; Nakache, Richard; Ben-Haim, Menahem

2008-06-01

To define the incidence, clinical presentation, radiologic findings and principles of diagnosis, and management of acute graft pancreatitis occurring more than 3 months after transplantation. Acute graft pancreatitis is a frequent late complication after simultaneous pancreas-kidney transplantation (SPKT) with enteric drainage that is not well understood. We performed a retrospective analysis of data from patients who underwent SPKT with enteric drainage at our institution. All recipients who experienced episodes that met the clinical criteria for late graft pancreatitis were included. We excluded events proven to be anastomotic or duodenal stump leaks. Clinical presentation, laboratory findings, radiologic imaging, course of management, and graft and patient outcome were evaluated and analyzed. Of 79 SPKTs (1995-2007), 11 (14%) recipients experienced 31 episodes of late graft pancreatitis (average number per patient, 3; range, 1-13), occurring an average of 28 months after transplantation (range, 3 months to 8 years). All patients presented with right lower quadrant abdominal peritonitis, fever, and findings compatible with pancreas graft inflammation on computed tomography or ultrasound imaging. Mild hyperamylasemia (>110 IU/L) was found in 82% of cases. Treatment was conservative, including bowel rest, antibiotics, and percutaneous sampling and drainage of abscesses as necessary. Excellent graft and patient survival were achieved. The diagnosis of late acute graft pancreatitis is clinical, with confirmatory computed tomography or ultrasound imaging. Conservative treatment yields excellent graft and patient survival.

Is It Time to Tailor the Prediction of Radio-Induced Toxicity in Prostate Cancer Patients? Building the First Set of Nomograms for Late Rectal Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valdagni, Riccardo; Radiotherapy, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan; Kattan, Michael W.

Purpose: Development of user-friendly tools for the prediction of single-patient probability of late rectal toxicity after conformal radiotherapy for prostate cancer. Methods and Materials: This multicenter protocol was characterized by the prospective evaluation of rectal toxicity through self-assessed questionnaires (minimum follow-up, 36 months) by 718 adult men in the AIROPROS 0102 trial. Doses were between 70 and 80 Gy. Nomograms were created based on multivariable logistic regression analysis. Three endpoints were considered: G2 to G3 late rectal bleeding (52/718 events), G3 late rectal bleeding (24/718 events), and G2 to G3 late fecal incontinence (LINC, 19/718 events). Results: Inputs for themore » nomogram for G2 to G3 late rectal bleeding estimation were as follows: presence of abdominal surgery before RT, percentage volume of rectum receiving >75 Gy (V75Gy), and nomogram-based estimation of the probability of G2 to G3 acute gastrointestinal toxicity (continuous variable, which was estimated using a previously published nomogram). G3 late rectal bleeding estimation was based on abdominal surgery before RT, V75Gy, and NOMACU. Prediction of G2 to G3 late fecal incontinence was based on abdominal surgery before RT, presence of hemorrhoids, use of antihypertensive medications (protective factor), and percentage volume of rectum receiving >40 Gy. Conclusions: We developed and internally validated the first set of nomograms available in the literature for the prediction of radio-induced toxicity in prostate cancer patients. Calculations included dosimetric as well as clinical variables to help radiation oncologists predict late rectal morbidity, thus introducing the possibility of RT plan corrections to better tailor treatment to the patient's characteristics, to avoid unnecessary worsening of quality of life, and to provide support to the patient in selecting the best therapeutic approach.« less

Usefulness of Tricuspid Annular Diameter to Predict Late Right Sided Heart Failure in Patients With Left Ventricular Assist Device.

PubMed

Nakanishi, Koki; Homma, Shunichi; Han, Jiho; Takayama, Hiroo; Colombo, Paolo C; Yuzefpolskaya, Melana; Garan, Arthur R; Farr, Maryjane A; Kurlansky, Paul; Di Tullio, Marco R; Naka, Yoshifumi; Takeda, Koji

2018-07-01

Although late-onset right-sided heart failure is recognized as a clinical problem in the treatment of patients with left ventricular assist devices (LVADs), the mechanism and predictors are unknown. Tricuspid valve (TV) deformation leads to the restriction of the leaflet motion and decreased coaptation, resulting in a functional tricuspid regurgitation that may act as a surrogate marker of late right-sided heart failure. This study aimed to investigate the association of preoperative TV deformation (annulus dilatation and leaflet tethering) with late right-sided heart failure development after continuous-flow LVAD implantation. The study cohort consisted of 274 patients who underwent 2-dimensional echocardiography before LVAD implantation. TV annulus diameter and tethering distance were measured in an apical 4-chamber view. Late right-sided heart failure was defined as right-sided heart failure requiring readmission and medical and/or surgical treatment after initial LVAD implantation. During a mean follow-up of 25.1 ± 19.0 months after LVAD implantation, late right-sided heart failure occurred in 33 patients (12.0%). Multivariate Cox proportional hazard analysis demonstrated that TV annulus diameter (hazard ratio 1.221 per 1 mm, p <0.001) was significantly associated with late right-sided heart failure development, whereas leaflet tethering distance was not. The best cut-off value of the TV annular diameter was 41 mm (area under the curve 0.787). Kaplan-Meier analysis showed that patients with dilated TV annulus (TV annular diameter ≥41 mm) exhibited a significantly higher late right-sided heart failure occurrence than those without TV annular enlargement (log-rank p <0.001). In conclusion, preoperative TV annulus diameter, but not leaflet tethering distance, predicted the occurrence of late right-sided heart failure after LVAD implantation. Copyright © 2018 Elsevier Inc. All rights reserved.

[Dropout behavior during inpatient psychotherapy ].

PubMed

Martens, Ute; Rempel, Irene; Zipfel, Stephan; Enck, Paul; Teufel, Martin

2014-01-01

Dropouts result in far-reaching consequences for the individual patient, fellow patients, therapists, and the clinic. This study was aimed at early identification of patients with a dropout risk. Data from patients of the Department of Psychosomatic Medicine and Psychotherapy of the Medical University Clinic of Tübingen (Germany) were analyzed retrospectively in a case-control study (matched). Differences in the results of various questionnaires (SCL-90-R, IIP-D, SF-36) regarding reasons for dropout and sociodemographic data were analyzed. A total of 59 dropouts, 50 females and 9 males, were included. They were split into 28 early dropouts and 31 late dropouts. The data were compared between early and late dropouts and control group. Early dropouts were significantly younger than late dropouts; they tended to live with their parents or on their own, and suffered more frequently from eating disorders. Late dropouts lived together with partners and suffered from somatoform disorders more frequently than early dropouts. The reasons given for dropout did not differ between the groups. No differences between dropouts and the controls were found with respect to psychopathology (SCL- 90-R) and quality of life (SF-36). Late dropouts did show significantly lower scores on the scale "autocracy/dominance" than the controls (IIP). Therapy dropout is a multifactorial occurrence. It is generally not predictable, though it may be predicted with different instruments on the basis of a diagnosis, especially with respect to interpersonal behavior patterns. In further studies, targeted interventions should be developed and tested which enable procedures to minimize the risk of dropout and to achieve complete treatment according to patients' intentions.

Dose-volume effects for pelvic bone marrow in predicting hematological toxicity in prostate cancer radiotherapy with pelvic node irradiation.

PubMed

Sini, Carla; Fiorino, Claudio; Perna, Lucia; Noris Chiorda, Barbara; Deantoni, Chiara Lucrezia; Bianchi, Marco; Sacco, Vincenzo; Briganti, Alberto; Montorsi, Francesco; Calandrino, Riccardo; Di Muzio, Nadia; Cozzarini, Cesare

2016-01-01

To prospectively identify clinical/dosimetric predictors of acute/late hematologic toxicity (HT) in chemo-naÏve patients treated with whole-pelvis radiotherapy (WPRT) for prostate cancer. Data of 121 patients treated with adjuvant/salvage WPRT were analyzed (static-field IMRT n=19; VMAT/Rapidarc n=57; Tomotherapy n=45). Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral, lower and whole pelvis (WP), and the relative DVHs were calculated. HT was graded both according to CTCAE v4.03 and as variation in percentage relative to baseline. Logistic regression was used to analyze association between HT and clinical/DVHs factors. Significant differences (p<0.005) in the DVH of BM volumes between different techniques were found: Tomotherapy was associated with larger volumes receiving low doses (3-20 Gy) and smaller receiving 40-50 Gy. Lower baseline absolute values of WBC, neutrophils and lymphocytes (ALC) predicted acute/late HT (p ⩽ 0.001). Higher BM V40 was associated with higher risk of acute Grade3 (OR=1.018) or late Grade2 lymphopenia (OR=1.005). Two models predicting lymphopenia were developed, both including baseline ALC, and BM WP-V40 (AUC=0.73) and IL-V40+smoking (AUC=0.904) for acute/late respectively. Specific regions of pelvic BM predicting acute/late lymphopenia, a risk factor for viral infections, were identified. The 2-variable models including specific constraints to BM may help reduce HT. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Late-onset Bartter syndrome type II.

PubMed

Gollasch, Benjamin; Anistan, Yoland-Marie; Canaan-Kühl, Sima; Gollasch, Maik

2017-10-01

Mutations in the ROMK1 potassium channel gene ( KCNJ1 ) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero , accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities.

Infection after anterior spinal fusion for idiopathic scoliosis using the Cotrel-Dubousset-Hopf system: A clinical case series of three patients.

PubMed

Tolk, Jaap J; Willems, Paul C; Punt, Ilona M; van Rhijn, Lodewijk W; van Ooij, André

2016-01-01

Three patients with late-onset infection after multilevel instrumented anterior spinal fusion for idiopathic scoliosis, using the Cotrel-Dubousset-Hopf (CDH) system, are presented. The CDH-system is an anterior instrumentation with high biomechanical stability and rigidity, ensuring a stable primary fixation. Unlike after posterior spinal fusion, infection after anterior spinal fusion (ASF) for idiopathic scoliosis has rarely been reported. The files of three patients who developed an infection after ASF for scoliosis using the CDH-system, were reviewed. The clinical presentation and diagnostic and therapeutic options are discussed. All three patients had a late-onset infection of the CDH-system, which was difficult to diagnose because of nonspecific symptoms. Radiographs and technetium bone scan appeared to be of low value. When an abscess was present, this could accurately be diagnosed with MRI or CT imaging. Operative treatment with implant removal and antibiotic therapy was successful in all cases. Late onset infections after ASF using the CDH-system presented with few and nonspecific symptoms. The clinical presentation was mainly characterized by vague abdominal- or back-pain after an interval of normal postoperative recovery, moderately raised infection parameters and inconclusive findings with imaging modalities. As treatment, implant removal, debridement and parenteral antibiotics are recommended. It should be noted though that implant removal poses serious risks for vascular and visceral structures.

Genetic testing for the risk of developing late effects among survivors of childhood cancer: Consumer understanding, acceptance, and willingness to pay.

PubMed

Georgiou, Gabrielle; Wakefield, Claire E; McGill, Brittany C; Fardell, Joanna E; Signorelli, Christina; Hanlon, Lucy; Tucker, Kathy; Patenaude, Andrea F; Cohn, Richard J

2016-09-15

Genetic testing to determine cancer survivors' risk of developing late effects from their cancer treatment will be increasingly used in survivorship care. This 2-stage study with 64 survivors of childhood cancer and their parents investigated the preferences and acceptability of testing among those who may be at risk of developing late effects. The first stage (Stage 1) identified the most commonly perceived benefits and concerns regarding genetic testing for the risk of late effects among 24 participants. In Stage 2, during interviews, 20 survivors (55% of whom were female; mean age, 26.0 years [range, 18-39 years]; standard deviation [SD], 0.80) and 20 parents (55% of whom were male; mean age of child survivor, 14.2 years [range, 10-19 years]; SD, 0.79) rated the 7 most common benefits and concerns from those identified in Stage 1. Interviews were transcribed verbatim and analyzed. Decisional balance ratios were calculated by dividing the participants' average concerns scores with the average benefits scores. Genetic testing for late effects was highly acceptable: 95% of participants leaned toward testing, and the majority (65.9%) would pay up to Australian $5000. The majority (97.2%) reported it was acceptable to wait for up to 6 months to receive results, and to be offered testing immediately after treatment or when the survivor reached adulthood (62.9%). Survivors and parents had a highly positive decisional balance (Mean (M), 0.5 [SD, 0.38] and M, 0.5 [SD, 0.39], respectively), indicating that perceived benefits outweighed concerns. Although to our knowledge clinical efficacy has yet to be clearly demonstrated, survivors and parents described positive interest in genetic testing for the risk of developing late effects. Perceived benefits outweighed harms, and the majority of participants would be willing to pay, and wait, for testing. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2876-2885. © 2016 American Cancer Society. © 2016 American Cancer Society.

Validation of transcutaneous bilirubin nomogram for identifying neonatal hyperbilirubinemia in healthy Chinese term and late-preterm infants: a multicenter study.

PubMed

Yu, Zhangbin; Han, Shuping; Wu, Jinxia; Li, Mingxia; Wang, Huaiyan; Wang, Jimei; Liu, Jiebo; Pan, Xinnian; Yang, Jie; Chen, Chao

2014-01-01

to prospectively validate a previously constructed transcutaneous bilirubin (TcB) nomogram for identifying severe hyperbilirubinemia in healthy Chinese term and late-preterm infants. this was a multicenter study that included 9,174 healthy term and late-preterm infants in eight hospitals of China. TcB measurements were performed using a JM-103 bilirubinometer. TcB values were plotted on a previously developed TcB nomogram, to identify the predictive ability for subsequent significant hyperbilirubinemia. in the present study, 972 neonates (10.6%) developed significant hyperbilirubinemia. The 40(th) percentile of the nomogram could identify all neonates who were at risk of significant hyperbilirubinemia, but with a low positive predictive value (PPV) (18.9%). Of the 453 neonates above the 95(th) percentile, 275 subsequently developed significant hyperbilirubinemia, with a high PPV (60.7%), but with low sensitivity (28.3%). The 75(th) percentile was highly specific (81.9%) and moderately sensitive (79.8%). The area under the curve (AUC) for the TcB nomogram was 0.875. this study validated the previously developed TcB nomogram, which could be used to predict subsequent significant hyperbilirubinemia in healthy Chinese term and late-preterm infants. However, combining TcB nomogram and clinical risk factors could improve the predictive accuracy for severe hyperbilirubinemia, which was not assessed in the study. Further studies are necessary to confirm this combination. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

[Late-onset depression and a new psychometric scale for its clinical evaluation].

PubMed

Ivanets, N N; Kinkul'kina, M A; Avdeeva, T I

2012-01-01

The most of existed psychometric scales for depression have some shortcomings hampering their use in old patients. The authors worked out the original scale for clinical evaluation of symptoms of late-onset depression. The list of symptoms was made up basing on literature data. The most significant symptoms that characterized the structure and severity of depression in old patients were singled out. According to results of factor analyses they were combined in the groups forming the corresponding items of the scale. In addition, some symptoms with particular clinical significance for late-onset depression (suicidal thoughts, senesto-hypochondriac symptoms, insight) were singled out. The scale comprises 13 items with scores from -6 to +6. It can be implemented for symptom screening, clinical diagnosis and rating, including dynamics of depression in elderly patients.

Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.

PubMed

Rubino, Elisa; Vacca, Alessandro; Gallone, Salvatore; Govone, Flora; Zucca, Milena; Gai, Annalisa; Ferrero, Patrizia; Fenoglio, Pierpaola; Giordana, Maria Teresa; Rainero, Innocenzo

2017-11-01

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

Translating Research for Professional Development and Effective Clinical Practice with Older Adults

ERIC Educational Resources Information Center

Steffen, Ann M.

2012-01-01

This paper offers a commentary on the articles in the special series on cognitive behavior therapy with older adults (Carmin, 2012-this issue), noting the commonalities found across discussions of diagnostic interviewing and cognitive-behavioral assessment and treatment for late-life insomnia, depression and suicide risk, PTSD, and OCD. These case…

[Randomized, controlled clinical trials with observational follow-up investigations for evaluating efficacy of antihyperglycaemic treatment. I. Main results of the studies].

PubMed

Jermendy, György

2018-04-01

The effect of antihyperglycaemic (antidiabetic) treatment on the late diabetic complications is one of the most important research areas in clinical diabetology. The relationship between glycaemic control and late micro- and macrovascular complications was highlighted by the results of the DCCT (Diabetes Control and Complications Trial) with type 1 and by the UKPDS (United Kingdom Prospective Diabetes Study) with type 2 diabetic patients. In these studies, observational follow-up investigations were also performed after the close-out of the randomized phase of the trial. In addition to these landmark studies, other randomized, controlled efficacy trials were also performed with observational follow-up investigations resulting in the development of the concept of metabolic memory or metabolic legacy. In this article, the main results of the studies are summarized. Orv Hetil. 2018; 159(15): 575-582.

Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

NASA Astrophysics Data System (ADS)

Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

2011-02-01

Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

Mutiple keratocystic odontogenic tumors (KCOT) in a patient with Gorlin syndrome: a case report with late presentation and absence of skin manifestations.

PubMed

Hashmi, Atif Ali; Edhi, Muhammad Muzzammil; Faridi, Naveen; Hosein, Mervyn; Khan, Mehmood

2016-07-22

Gorlin syndrome is a rare autosomal dominant syndrome characterized by multiple basal cell carcinomas, keratocystic odontogenic tumors (KOT) and falx cerebral calcifications, which occur due to mutation in PTCH gene. A 36 year old Asian patient presented with jaw swelling and pain. Radiographic examination revealed six cysts in maxilla and mandible which were excised and histologically were compatable with keratocystic odontogenic tumors. CT scan also revealed falx cerebral calcification which led to the diagnosis of Gorlin syndrome confirmed on genetic testing. There was no evidence of basal cell carcinoma and other manifestations of Gorlin syndrome were absent. Multiple KCOT are hallmark of Gorlin syndrome and should always leads to its suspicion even in the absence of other manifestations and late presentation. Moreover, keratocystic odontogenic tumors have a particularly higher risk of recurrence and patients with Gorlin syndrome are prone to develop additional keratocystic odontogenic tumors from basal cells of oral epithelium. Therefore we suggest a stepwise approach to manage such patients which include a preoperative biopsy to establish a definitive diagnosis and complete removal of all keratocystic odontogenic tumors to prevent recurrence followed by close clinical follow up and early removal of any newly developed or recurrent cyst. Additionally thorough clinical examination is necessary to rule out the possibility of Gorlin syndrome in any patient with keratocystic odontogenic tumors as there are only subtle differences in histology of those cysts with a syndromic association and clinical features of Gorlin syndrome are markedly variable. Hence late occurrence of keratocystic odontogenic tumors and absence of skin manifestations like basal cell carcinoma should not preclude a diagnosis of Gorlin syndrome.

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity.

PubMed

Kent, D

2015-11-01

This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complement-mediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR.

Late complication after tropic storm accident: subcutaneous and intracranial actinomycetoma.

PubMed

Verma, Shyam B; Nayak, Suresh; Pasale, Ravindra K; Kittner, Thomas; Wollina, Uwe

2008-12-01

We report a 53-year-old farmer who developed subcutaneous and cerebral masses 24 years after penetrating trauma during a tropic storm. Computed tomography scans, magnetic resonance imaging and histopathology disclosed actinomycetoma, a disease that rarely develops after trauma and is only occasionally seen with intracranial manifestation. Clinically, the cutaneous manifestation resembled acne keloidalis nuchae or dissecting folliculitis of the scalp. He was treated by neurosurgery and antibiosis.

Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma.

PubMed

Bethge, Anja; Schumacher, Udo; Wree, Andreas; Wedemann, Gero

2012-01-01

Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient's death. The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e., metastases from metastases, are irrelevant in terms of total tumour mass. Hence metastases seeded from metastases are clinically irrelevant in our model system. Only the first metastases seeded from the primary tumour contribute significantly to the tumour burden and thus cause the patient's death.

Nailfold capillaroscopy for prediction of novel future severe organ involvement in systemic sclerosis.

PubMed

Smith, Vanessa; Riccieri, Valeria; Pizzorni, Carmen; Decuman, Saskia; Deschepper, Ellen; Bonroy, Carolien; Sulli, Alberto; Piette, Yves; De Keyser, Filip; Cutolo, Maurizio

2013-12-01

Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma (systemic sclerosis; SSc) ("early," "active," and "late") with novel future severe clinical involvement in 2 independent cohorts. Sixty-six consecutive Belgian and 82 Italian patients with SSc underwent NVC at baseline. Images were blindly assessed and classified into normal, early, active, or late NVC pattern. Clinical evaluation was performed for 9 organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart, and kidney) according to the Medsger disease severity scale (DSS) at baseline and in the future (18-24 months of followup). Severe clinical involvement was defined as category 2 to 4 per organ of the DSS. Logistic regression analysis (continuous NVC predictor variable) was performed. The OR to develop novel future severe organ involvement was stronger according to more severe NVC patterns and similar in both cohorts. In simple logistic regression analysis the OR in the Belgian/Italian cohort was 2.16 (95% CI 1.19-4.47, p = 0.010)/2.33 (95% CI 1.36-4.22, p = 0.002) for the early NVC SSc pattern, 4.68/5.42 for the active pattern, and 10.14/12.63 for the late pattern versus the normal pattern. In multiple logistic regression analysis, adjusting for disease duration, subset, and vasoactive medication, the OR was 2.99 (95% CI 1.31-8.82, p = 0.007)/1.88 (95% CI 1.00-3.71, p = 0.050) for the early NVC SSc pattern, 8.93/3.54 for the active pattern, and 26.69/6.66 for the late pattern versus the normal pattern. Capillaroscopy may be predictive of novel future severe organ involvement in SSc, as attested by 2 independent cohorts.

Perspective on the pipeline of drugs being developed with modulation of DNA damage as a target.

PubMed

Plummer, Ruth

2010-09-15

Inhibitors of various elements of the DNA repair pathways have entered clinical development or are in late preclinical stages of drug development. It was initially considered that agents targeting DNA repair would act to overcome tumor resistance to chemotherapy and radiotherapy. More recent data have shown that targeting DNA repair pathways can be effective in selected tumors via a synthetically lethal route, with single agent activity having been shown with poly-ADP ribose polymerase (PARP) inhibitors. An increased understanding of the biology and interaction of the DNA repair pathways also means that rational combination of DNA repair inhibitors may also give great benefit in the clinic. ©2010 AACR.

The longitudinal development of social and executive functions in late adolescence and early adulthood

PubMed Central

Taylor, Sophie J.; Barker, Lynne A.; Heavey, Lisa; McHale, Sue

2015-01-01

Our earlier work suggests that, executive functions and social cognition show protracted development into late adolescence and early adulthood (Taylor et al., 2013). However, it remains unknown whether these functions develop linearly or non-linearly corresponding to dynamic changes to white matter density at these age ranges. Executive functions are particularly in demand during the transition to independence and autonomy associated with this age range (Ahmed and Miller, 2011). Previous research examining executive function (Romine and Reynolds, 2005) and social cognition (Dumontheil et al., 2010a) in late adolescence has utilized a cross sectional design. The current study employed a longitudinal design with 58 participants aged 17, 18, and 19 years completing social cognition and executive function tasks, Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), Positive and Negative Affect Schedule (Watson et al., 1988), and Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983) at Time 1 with follow up testing 12–16 months later. Inhibition, rule detection, strategy generation and planning executive functions and emotion recognition with dynamic stimuli showed longitudinal development between time points. Self-report empathy and emotion recognition functions using visual static and auditory stimuli were stable by age 17 whereas concept formation declined between time points. The protracted development of some functions may reflect continued brain maturation into late adolescence and early adulthood including synaptic pruning (Sowell et al., 2001) and changes to functional connectivity (Stevens et al., 2007) and/or environmental change. Clinical implications, such as assessing the effectiveness of rehabilitation following Head Injury, are discussed. PMID:26441579

ABM Clinical Protocol #1: Guidelines for Blood Glucose Monitoring and Treatment of Hypoglycemia in Term and Late-Preterm Neonates, Revised 2014

PubMed Central

Wight, Nancy

2014-01-01

A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID:24823918

Late-life depression in the primary care setting: Challenges, collaborative care, and prevention

PubMed Central

Hall, Charles A.; Reynolds, Charles F.

2014-01-01

Late-life depression is highly prevalent worldwide. In addition to being a debilitating illness, it is a risk factor for excess morbidity and mortality. Older adults with depression are at risk for dementia, coronary heart disease, stroke, cancer and suicide. Individuals with late-life depression often have significant medical comorbidity and, poor treatment adherence. Furthermore, psychosocial considerations such as gender, ethnicity, stigma and bereavement are necessary to understand the full context of late-life depression. The fact that most older adults seek treatment for depression in primary care settings led to the development of collaborative care interventions for depression. These interventions have consistently demonstrated clinically meaningful effectiveness in the treatment of late-life depression. We describe three pivotal studies detailing the management of depression in primary care settings in both high and low-income countries. Beyond effectively treating depression, collaborative care models address additional challenges associated with late-life depression. Although depression treatment interventions are effective compared to usual care, they exhibit relatively low remission rates and small to medium effect sizes. Several studies have demonstrated that depression prevention is possible and most effective in at-risk older adults. Given the relatively modest effects of treatment in averting years lived with disability, preventing late-life depression at the primary care level should be highly prioritized as a matter of health policy. PMID:24996484

[History of clinical pharmacology in France: adaptation, evaluation, defense and illustration of drug in France 1978-1981].

PubMed

Montastruc, Paul

2014-01-01

This text illustrates some unknown aspects of the history and beginnings of clinical pharmacology in France in the late 1970s and early 1980s From the current situation, development and objectives of clinical pharmacology are recalled as well as obstacles necessary to overcome to change the paradigm in the field of drug evaluation and appropriate use in France. The text recalls this important moment where French medicine and medical pharmacology entered the modern era. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Late recurrences of germ cell malignancies: a population-based experience over three decades

PubMed Central

Oldenburg, J; Alfsen, G C; Wæhre, H; Fosså, S D

2006-01-01

The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them. PMID:16508636

Innovative financing for late-stage global health research and development: the Global Health Investment Fund.

PubMed

Fitchett, Joseph Robert; Fan Li, Julia; Atun, Rifat

2016-01-01

Innovative financing strategies for global health are urgently needed to reinvigorate investment and new tools for impact. Bottleneck areas along the research and development (R&D) pipeline require particular attention, such as the transitions from preclinical discovery to clinical study, and product development to implementation and delivery. Successful organizations mobilizing and disbursing resources through innovating financing mechanisms include UNITAID, the Global Fund, and Gavi, the Vaccine Alliance. Although precise numbers are poorly documented, estimated investment in low-income settings falls seriously short of local need. This commentary discusses the newly established Global Health Investment Fund as a case study to support late-stage global health R&D. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Factors Associated with Late Engagement to HIV Care in Western Kenya: A Cross-Sectional Study.

PubMed

Kwobah, Charles Meja; Braitstein, Paula; Koech, Julius K; Simiyu, Gilbert; Mwangi, Ann W; Wools-Kaloustian, Kara; Siika, Abraham M

2016-11-01

Late presentation of patients contributes significantly to the high mortality reported in HIV -care and treatment programs in sub-Saharan Africa. A cross-sectional study was conducted to assess factors associated with late engagement to HIV care at the Academic Model Providing Access to Healthcare in western Kenya. Late engagement was defined as baseline CD4 ≤100 cells/mm 3 . Of the 10 533 participants included in the analysis, 67% were female and mean age was 36.7 years. Overall, 23% of the participants presented late. Factors associated with late engagement included male gender (adjusted odds ratio [AOR]: 1.54, 95% confidence interval [CI]: 1.35-1.75), older age (AOR: 1.62, 95% CI: 1.02-2.56), and longer travel time to clinic (AOR: 1.18, 95% CI: 1.04-1.34). Nearly one-quarter of HIV-infected patients in our setting present with advanced immune suppression at initial encounter. Being male, older age, and living further away from clinic are associated with late engagement to care. © The Author(s) 2015.

Neural Correlates of Response Inhibition and Cigarette Smoking in Late Adolescence

PubMed Central

Galván, Adriana; Poldrack, Russell A; Baker, Christine M; McGlennen, Kristine M; London, Edythe D

2011-01-01

Smoking is usually initiated in adolescence, and is the leading preventable cause of death in the United States. Little is known, however, about the links between smoking and neurobiological function in adolescent smokers. This study aimed to probe prefrontal cortical function in late adolescent smokers, using a response inhibition task, and to assess possible relationships between inhibition-related brain activity, clinical features of smoking behavior, and exposure to cigarette smoking. Participants in this study were otherwise healthy late adolescent smokers (15–21 years of age; n=25), who reported daily smoking for at least the 6 months before testing, and age- and education-matched nonsmokers (16–21 years of age; n=25), who each reported smoking fewer than five cigarettes in their lifetimes. The subjects performed the Stop-signal Task, while undergoing functional magnetic resonance imaging. There were no significant group differences in prefrontal cortical activity during response inhibition, but the Heaviness of Smoking Index, a measure of smoking behavior and dependence, was negatively related to neural function in cortical regions of the smokers. These findings suggest that smoking can modulate prefrontal cortical function. Given the late development of the prefrontal cortex, which continues through adolescence, it is possible that smoking may influence the trajectory of brain development during this critical developmental period. PMID:21270772

Sexual behavior of gender-dysphoric individuals before gender-confirming interventions: a European multicenter study.

PubMed

Cerwenka, Susanne; Nieder, Timo O; Cohen-Kettenis, Peggy; De Cuypere, Griet; Haraldsen, Ira R Hebold; Kreukels, Baudewijntje P C; Richter-Appelt, Hertha

2014-01-01

A transsexual course of development that starts before puberty (early onset) or during or after puberty, respectively (late onset), may lead to diverse challenges in coping with sexual activity. The authors explored the sexual behavior of 380 adult male-to-female and female-to-male individuals diagnosed according to DSM-IV-TR criteria who had not yet undergone gender-confirming interventions. Data originated from the European Network for the Investigation of Gender Incongruence Initiative, conducted in Belgium, Germany, The Netherlands, and Norway. Information on outcome variables was collected using self-administered questionnaires at first clinical presentation. Compared with late-onset male-to-females, early-onset individuals tended to show sexual attraction toward males more frequently (50.5%), involve genitals less frequently in partner-related sexual activity, and consider penile sensations and orgasm as more negative. Early-onset female-to-males predominantly reported sexual attraction toward females (84.0%), whereas those with a late-onset more frequently showed other sexual attractions (41.7%). The study (a) shows that early- and late-onset male-to-females differ considerably with regard to coping strategies involving their body during sexual relations and (b) reveals initial insights into developmental pathways of late-onset female-to-males.

Clinical chemistry through Clinical Chemistry: a journal timeline.

PubMed

Rej, Robert

2004-12-01

The establishment of the modern discipline of clinical chemistry was concurrent with the foundation of the journal Clinical Chemistry and that of the American Association for Clinical Chemistry in the late 1940s and early 1950s. To mark the 50th volume of this Journal, I chronicle and highlight scientific milestones, and those within the discipline, as documented in the pages of Clinical Chemistry. Amazing progress has been made in the field of laboratory diagnostics over these five decades, in many cases paralleling-as well as being bolstered by-the rapid pace in the development of computer technologies. Specific areas of laboratory medicine particularly well represented in Clinical Chemistry include lipids, endocrinology, protein markers, quality of laboratory measurements, molecular diagnostics, and general advances in methodology and instrumentation.

Late-onset Huntington's disease: diagnostic and prognostic considerations.

PubMed

Koutsis, Georgios; Karadima, Georgia; Kladi, Athina; Panas, Marios

2014-07-01

To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD). We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical and microbiologic aspects of penems, a distinct class of beta-lactams: focus on faropenem.

PubMed

Hamilton-Miller, Jeremy M T

2003-11-01

Many beta-lactam antimicrobials were developed between the 1960s and 1980s, with continuing development driven by the emergence of microbial resistance. Penems form a discrete class of beta-lactams that comprises structural hybrids of penicillins (penams) and cephalosporins (cephems). The chemistry and microbiology of the representative penems MEN 10700, ritipenem, CGP 31608, sulopenem, BRL 42715, and faropenem are reviewed. Particular emphasis is placed on faropenem, which is in late clinical development.

Social networking between cells of the foetal skeleton: the importance of thyroid hormones.

PubMed

Farquharson, Colin

2011-08-01

In this issue of Journal of Endocrinology, Lanham et al. investigated the effects of hypothyroidism on the developing skeleton of the ovine foetus in utero. Their analyses indicated that, following thyroidectomy, bone growth, structure and mechanical properties were all altered at late gestation or at term. Adrenalectomy, whilst preventing the prepartum rise in triiodothyronine, did not modify skeletal development. The hypothyroid-mediated skeletal defects of the developing foetus described in this study may have clinical implications for bone health in later life.

Age-related physical and psychological vulnerability as pathways to problem gambling in older adults.

PubMed

Parke, Adrian; Griffiths, Mark; Pattinson, Julie; Keatley, David

2018-03-01

Background To inform clinical treatment and preventative efforts, there is an important need to understand the pathways to late-life gambling disorder. Aims This study assesses the association between age-related physical health, social networks, and problem gambling in adults aged over 65 years and assesses the mediating role of affective disorders in this association. Methods The sample comprised 595 older adults (mean age: 74.4 years, range: 65-94 years; 77.1% female) who were interviewed using a structured questionnaire to assess physical frailty, geriatric pain, loneliness, geriatric depression, geriatric anxiety, and problem gambling. Results Pathway analysis demonstrated associations between these variables and gambling problems, providing a good fit for the data, but that critically these relationships were mediated by both anxiety and depression symptoms. Conclusions This study indicates that late-life problem gambling may develop as vulnerable individuals gamble to escape anxiety and depression consequent to deteriorating physical well-being and social support. When individuals develop late-life problem gambling, it is recommended that the treatment primarily focuses upon targeting and replacing avoidant coping approaches.

[The clinical and microbiological characteristics of oropharyngeal candidiasis in the HIV-infected patients at the late stages of the disease].

PubMed

Charushin, A O; Elovikov, A M; Charushina, I P; Vorob'eva, N N; Katretskaya, G G

Oropharyngeal candidiasis in 512 HIV-infected patients at the late stages of the disease was studied with special reference to the clinical and microbiological characteristics of this condition. The diagnosis was established based on the results of the clinical and microbiological examination of the patients including investigation of the tissue samples taken from the oral cavity and the throat with the use of the device specially developed for this purpose. It was shown that the disease existed in various clinical forms the most common of which were monocomponent pathology represented by pseudomembranous candidiasis in 37.5±2.14% of the patients, the two-component mixed form (pseudomembranous candidiasis with concomitant angular chelitis) diagnosed in 27.5±1.97% cases, and the ternary form (the combination of pseudomembranous candidiasis, acute atrophic process, and angular chelitis) documented in 11.9±1.43% patients. The main clinical features of the disease included the combination of its various forms, multiple localization of the pathological process, and its polymorphous manifestations. Changes in the clinical course of oropharyngeal candidiasis associated with the progression of HIV from the 4A to the 4B stage were detected for the first time. They were shown to be accompanied by variations in the species composition and concentration of fungal flora in the crypts of the palatine tonsils and its sensitivity to fluconazole therapy.

Clinical Trials in Late Life: New Science in Old Paradigms

ERIC Educational Resources Information Center

Lebowitz, Barry D.

2004-01-01

This article, based on a Lawton Award Lecture, addresses the subject of the need to enhance the evidence base in our field in order to influence processes of policy development. Four issues are identified as critical to this: theory-driven targets of public health significance, use of appropriate and sophisticated approaches to research design and…

Functional asymmetry of pelvic floor innervation--myth or fact?

PubMed

Enck, Paul

2004-01-01

Neurophysiology of the pelvic floor is not completely understood yet. The importance of its symmetry and asymmetry of innervation has been pointed out lately. These facts have the clinical relevance in case of pelvic floor trauma or incontinence surgery. New techniques of EMG are necessary to confirm correlations between symptoms development and asymmetry of sphincter innervation.

Poster - 34: Clinical Implementation of Prone Breast Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Runqing; Fleming, Katrina; Kobeleva, Sofya

2016-08-15

Purpose: Prone breast treatment is used to reduce acute and late toxicities for large or pendulous breast patients. This study developed and implemented the clinical workflow of prone breast radiotherapy treatment. Methods: Varian kVue Access360™ Prone Breast Couchtop was used as prone breast board. The treatment planning (TP)is performed in Eclipse TP system. TP comparisons between supine deep inspiration breathing hold (DIBH) and prone breast; prone forward field-in-field (FinF) planning and inverse IMRT planning were performed and discussed. For the daily setup, breast coverage was assessed in the room using light field and MV imaging was used at day 1more » and weekly. Results: The first ten patients are CT scanned and planned both supine and prone. The coverage was all excellent for supine DIBH plan and prone breast plan. The plan in the prone position demonstrated improvements in lung sparing comparing to the DIBH plan. Both forward FinF plan and inverse IMRT plan achieved acceptable coverage of the breast, and heart dose is comparable. Considering the daily setup variations and MLC leakage, forward FinF plan was recommended for routine clinical use. The procedure has been tested in phantom and patients were treated clinically. Conclusions: Prone breast irradiation has been advocated for women with large pendulous breasts in order to decrease acute and late toxicities. The workflow for prone breast radiation therapy has been developed and the technique is ready to treat patients.« less

[Comparative efficiency of nootropic drugs in complex treatment of patients with remote consequences of closed craniocereberal trauma].

PubMed

Hliebova, O S; Tkachenko, O V

2008-01-01

Main data of the research were data obtained after a complex treatment of 120 persons with late consequences of closed craniocereberal trauma (CCRCT). The treatment included administration of one of nootropic agents (noophen, aminolon or entropil), magnesium sulfate, group B vitamins. All patients have passed a complex examination: specially developed questionnaire, anamnesis gathering, neurologic status, neuropsychological status with the use of multiple-aspect scales and questionnaires, examination of fundus of eye, rheoencephalography, echoencephalography, brain MRT. Results of a complex examination proved positive effect of the use of nootropic agents, in particular noophen, entropil and aminolon in complex treatment of late consequences of closed craniocereberal trauma. For optimisation of the use of nootropic agents in the treatment of late consequences of closed craniocereberal trauma it is recommended to consider features of influence of nootropic agents on certain clinical aspects of the disease.

Late myocardial ischemia with ST-segment elevation after negative dobutamine stress echocardiography in a patient with normal coronary arteries.

PubMed

Cabani, Enrico; Lattanzi, Fabio; Paci, Anna Maria; Pieroni, Andrea; Baria, Luca; Tommasi, Salvatore Mario De

2009-04-01

Late complications after pharmacological stress echocardiography are infrequent but potentially dreadful events. We report the case of a 80-year-old woman admitted to hospital for rest chest pain with trivial troponin increase, normal left ventricular function and no significant ECG changes. A dobutamine stress echocardiography was performed for diagnostic purpose, with a negative result. About 30 min after the end of dobutamine infusion, she developed ST-segment elevation in inferior leads associated with chest pain and left ventricular dyssynergy, promptly resolved by sublingual nitrates. Subsequently, angiography documented the absence of significant coronary stenoses. The following clinical course was uneventful. Transient myocardial ischemia was likely due to dobutamine-induced coronary spasm. The case emphasizes the utility of routine, long-lasting monitoring of patients after stress echocardiography, even if negative, to counteract possible late life-threatening complications.

Drug-eluting stent thrombosis: results from the multicenter Spanish registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivos).

PubMed

de la Torre-Hernández, José M; Alfonso, Fernando; Hernández, Felipe; Elizaga, Jaime; Sanmartin, Marcelo; Pinar, Eduardo; Lozano, Iñigo; Vazquez, Jose M; Botas, Javier; Perez de Prado, Armando; Hernández, Jose M; Sanchis, Juan; Nodar, Juan M Ruiz; Gomez-Jaume, Alfredo; Larman, Mariano; Diarte, Jose A; Rodríguez-Collado, Javier; Rumoroso, Jose R; Lopez-Minguez, Jose R; Mauri, Josepa

2008-03-11

This study sought to assess the incidence, predictors, and outcome of drug-eluting stent(DES) thrombosis in real-world clinical practice. The DES thromboses in randomized trials could not be comparable to those observed in clinical practice, frequently including off-label indications. We designed a large-scale, nonindustry-linked multicentered registry, with 20 centers in Spain. The participant centers provided follow-up data for their patients treated with DES, reporting a detailed standardized form in the event of any angiography-documented DES-associated thrombosis occurring. Of 23,500 patients treated with DES, definite stent thrombosis(ST) developed in 301: 24 acute, 125 subacute, and 152 late. Of the late, 62 occurred >1 year(very late ST). The cumulative incidence was 2% at 3 years. Antiplatelet treatment had been discontinued in 95 cases(31.6%). No differences in incidences were found among stent types. Independent predictors for subacute ST analyzed in a subgroup of 14,120 cases were diabetes, renal failure, acute coronary syndrome, ST-segment elevation myocardial infarction, stent length, and left anterior descending artery stenting, and for late ST were ST-segment elevation myocardial infarction, stenting in left anterior descending artery, and stent length. Mortality at 1-year follow-up was 16% and ST recurrence 4.6%. Older age, left ventricular ejection fraction <45%, nonrestoration of Thrombolysis In Myocardial Infarction flow grade 3, and additional stenting were independent predictors for mortality. The cumulative incidence of ST after DES implantation was 2% at 3 years. No differences were found among stent types. Patient profiles differed between early and late ST. Short-term prognosis is poor, especially when restoration of normal flow fails.

Products resulting from cleavage of the interglobular domain of aggrecan in samples of synovial fluid collected from dogs with early- and late-stage osteoarthritis.

PubMed

Innes, John F; Little, Chris B; Hughes, Clare E; Caterson, Bruce

2005-10-01

To investigate interglobular domain (IGD) cleavage of aggrecan in dogs with naturally developing osteoarthritis (OA). Samples of synovial fluid (SF) obtained from 3 cubital (elbow) joints and 3 stifle joints of 4 clinically normal dogs, 24 elbow joints of 12 dogs with early-stage OA, 8 stifle joints of 5 dogs with early-stage OA, and 10 stifle joints of 9 dogs with late-stage OA. Fractions of SF were assayed for total glycosaminoglycan (GAG) content and also subjected to Western blot analysis by use of monoclonal antibodies against neoepitopes generated by cleavage of the IGD of the aggrecan protein core by matrix metalloproteinase (MMP; BC-14) and aggrecanase (BC-3). Total GAG content of SF from joints of clinically normal dogs did not differ from that of dogs with early-stage OA. The GAG content of SF from joints of dogs with late-stage OA was significantly lower, compared with GAG content for other SF samples. Aggrecanase-generated fragments were detected in SF from all groups but not in all samples. Matrix metalloproteinase-generated fragments were not detected in any SF samples. In early-stage OA, high-molecular-weight aggrecanase-generated aggrecan catabolites were evident. GAG content of SF obtained from dogs with late-stage OA is significantly decreased, suggesting proteoglycan depletion of cartilage. Aggrecanases, but not MMPs, are the major proteolytic enzymes responsible for IGD cleavage of aggrecan in canine joints. Analyses of SF samples to detect aggrecanase-generated catabolites may provide an early biomarker for discriminating early- and late-stage OA in dogs.

Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis.

PubMed

Romi, Fredrik; Gilhus, Nils E; Varhaug, Jan E; Myking, Andreas; Skeie, Geir O; Aarli, Johan A

2003-09-01

The clinical effect of thymectomy in early- and late-onset myasthenia gravis (MG) and the correlation to MG severity, pharmacological treatment, and antimuscle antibodies were examined in two series of consecutive acetylcholine receptor (AChR) antibody-positive nonthymoma MG patients. The results indicate a benefit of thymectomy in early-onset MG, but no obvious clinical benefit in late-onset MG. The presence of muscle autoantibodies did not influence the outcome of thymectomy in early-onset MG. In late-onset MG, improvement is least likely in patients with titin and/or RyR antibodies. Thymectomy should always be considered shortly after MG onset in early-onset MG patients and might only be considered in late-onset patients who have early-onset-like immunological characteristics.

Remune trial will stop; new trials planned.

PubMed

James, J S

1999-05-21

A clinical trial using remune, the anti-HIV vaccine developed by the late Dr. Jonas Salk, has been ended. The study is a clinical-endpoint trial which looks for statistically significant differences in AIDS sickness or death between patients who add remune to their treatment regimens versus those who use a placebo. Agouron Pharmaceuticals and the Immune Response Corporation who were conducting the trial announced their decision to stop it after an analysis by the Data Safety Monitoring Board. No differences in clinical endpoints were found and it was projected that continuing the trial would likely not find any. The companies are now planning two new Phase III trials using viral load testing rather than clinical endpoints as study criteria.

Predictors of study completion and withdrawal in a randomized clinical trial of a pediatric diabetes adherence intervention.

PubMed

Driscoll, Kimberly A; Killian, Michael; Johnson, Suzanne Bennett; Silverstein, Janet H; Deeb, Larry C

2009-05-01

Loss of participants in randomized clinical trials threatens the validity of study findings. The purpose of this study was to determine pre-randomization predictors of study completion status throughout the course of a randomized clinical trial involving young children with type 1 diabetes and their primary caregivers. An intervention to improve adherence to the diabetes treatment regimen was delivered as part of the child's regular 3-month diabetes clinic visit. The study protocol involved 7 clinic visits across 18 months for the Immediate Treatment group and 9 clinic visits across 24 months for the Delayed Treatment group. Among those who completed the study and regardless of treatment group, participants were categorized into two groups: On-Time Completers (n=41) and Late Completers (n=39). Demographic, disease, and psychosocial characteristics of children and their primary caregivers measured prior to study randomization were tested for their association with the participants' completion status (i.e., On-Time Completers, Late Completers, or Withdrawals). Of the 108 participants, 28 (25.9%) withdrew and 80 (74.1%) completed the study. On-Time Completers (i.e., study completed within 4 months of expected date) were more likely to have private insurance and primary caregivers with some college education. Late Completers (i.e., study completion took longer than 4 months) were more likely to be boys and to have primary caregivers who reported mild to moderate levels of depression. Children who subsequently withdrew from the study reported poorer diabetes-related quality of life and poorer school-related quality of life at study inception and were more likely to have primary caregivers who did not work outside the home. Pre-randomization screening of participants on both demographic and psychological variables may help identify those at greatest risk for study withdrawal or poor study protocol adherence, permitting the investigators to develop retention strategies aimed at this high-risk group.

Visceral predictors of cardiovascular deconditioning in late middle-aged men

NASA Technical Reports Server (NTRS)

Goldwater, D. J.; De Roshia, C.; Natelson, B. H.; Levin, B. E.

1985-01-01

A number of visceral and behavioral factors connected with cardiovascular deconditioning were investigated, in order to identify a method for predicting the degree of orthostatic intolerance to spaceflight in several late-middle-aged men (55-65 years). Preliminary measurements were made of: mean arterial blood pressure plasma cortisol levels; and norepinephrine levels. Measurements of core temperature; plasma epinephrine level and subjective arousal from sleep were also obtained. Pairwise correlations were found for each of the variables and the time-to-blackout due centrifugal acceleration of up to +3 Gz. It is shown that the men with relatively low resting blood pressure were at greater risk of developing the clinical signs of cardiovascular deconditioning than were the men with higher basal blood pressure. Some applications of the experimental results to the development of selection criteria for Shuttle crews are discussed.

Effect of pregnancy on experimental allergic encephalomyelitis in guinea pigs and rats.

PubMed

Keith, A B

1978-10-01

Pregnancy in guinea pigs and rats exerted a suppressive influence on the development of experimental allergic encephalomyelitis (EAE). Early or late stages in pregnancy had a similar effect in delaying the onset of EAE, a greater delay being observed in pregnant guinea pigs with full term pregnancies. However, the suppressive effect in the majority of animals was only temporary and when they developed the disease the clinical severity was then similar to that in the controls. Clinical symptoms of EAE, in guinea pigs that did not maintain their pregnancy, developed soon after abortion or resorption and these animals deteriorated rapidly. Histologic lesions were markedly enhanced with prominent demyelination in the majority of guinea pigs that were sensitised when pregnant.

Lymphoedema of the lower limbs: management problems in a developing country.

PubMed

Adigun, A I; Ogundipe, O K

2008-01-01

Lymphoedema is a clinical condition involving the extremities that is characterized by accumulation of protein rich fluid within the intercellular space of the skin and the subcutaneous tissue. It most frequently occurs in the extremities. Developing countries are mostly faced with cases of secondary lymphoedema where patients present lately. In addition to swollen limbs, there are lot of skin changes on the affected limb, these create a lot of problems to the managing clinician. We hereby present five cases out of several patients managed to highlight the challenges. We review the case notes of three patients managed by our unit and present the summary of each patient. Majority of our patients present late to the hospital, mainly because of the socio-cultural and spiritual beliefs concerning the aetiology of the condition. Most of them have visited the spiritualist, herbalist and the clergymen for solution. Clinicians in the developing countries are seriously handicapped by lack of modern equipment for both diagnostic and therapeutic management of these clinical conditions. Chronic lymphoedema is a major cause of permanent disability. Excisional surgery such as Charles procedure even though old is still very much relevant in our environment. Patients need to be enlightened on the need for early presentation, adequate post-operative care and prolonged follow-up.

Late onset dysthymic disorder and major depression differ from early onset dysthymic disorder and major depression in elderly outpatients.

PubMed

Devanand, D P; Adorno, Elizabeth; Cheng, Jocelyn; Burt, Tal; Pelton, G H Gregory H; Roose, S P Steven P; Sackeim, H A Harold A

2004-03-01

Age of onset may affect clinical features and prognosis in elderly patients with major depression (MDD), but there is a lack of such data in elderly patients with dysthymic disorder (DD) and systematic comparisons of late onset MDD and DD have not been conducted. In a Late Life Depression Clinic, patients > or = 60 years old who met DSM-III-R or DSM-IV criteria for MDD or DD were studied. The 24-item Hamilton Rating Scale for Depression (HRSD) and SCID-P were completed, family history was obtained, and medical illnesses were assessed. In the total sample (n=370; 211 MDD and 159 DD), compared to early onset patients, late onset (onset > or =60 years) patients had a higher rate of cardiovascular disease (chi(2)=4.12, df=1, P<0.05), lower rate of anxiety disorder (chi(2)=4.19, df=1, P<0.05), and a lower rate of family history of affective disorder (chi(2)=9.37, df=1, P<0.002). Late onset DD patients were more likely to have cardiovascular disease than early onset DD patients (chi(2)=5.63, df=1, P<0.02), but the rate of cardiovascular disease did not differ between late and early onset MDD patients (chi(2)=0.35, df=1, P<0.6). Late onset MDD patients were less likely to have a family history of affective disorder than early onset MDD patients (chi(2)=10.71, df=1, P<0.001). Prevalence of anxiety disorders did not differ between the early and late onset MDD patients (chi(2)=0.07, df=1, P<0.79), but was more common in the early onset DD compared to the late onset DD patients (17.98% versus 4.29%, chi(2)=6.98, df=1, P<0.01). Late onset DD did not differ from late onset MDD in the rates of cardiovascular disease, anxiety disorders, and family history of affective disorder. Excluding patients with double depression (n=32) did not alter the cardiovascular or family history findings, but the difference in anxiety disorders between early and late onset DD patients was no longer significant. Academic clinic sample results may not generalize to community populations. In the elderly, late-onset DD is typically different from early onset DD. Cerebrovascular disease appears to play a role in the etiology of late onset DD. The similarities between late onset DD and late onset MDD suggest a single condition along a continuum.

The challenge of detecting herds sub-clinically infected with Actinobacillus pleuropneumoniae.

PubMed

Gottschalk, Marcelo

2015-10-01

The introduction into a naïve herd of animals sub-clinically infected with Actinobacillus pleuropneumoniae (App) is frequently the cause of clinical pleuropneumonia and the identification of such infected herds is a priority in the control of disease. Different serological tests for App have been developed and a number of these are routinely used. Some are species-specific whereas others identify more specifically the serotype/serogroup involved which requires updated information about important serotypes recovered from diseased pigs in a given area/country. Serotyping methods based on molecular techniques have been developed lately and are ready to be used by most diagnostic laboratories. When non-conclusive serological results are obtained, direct detection of App from tonsils is sometimes attempted. This review addresses different techniques and approaches used to monitor herds sub-clinically infected by this important pathogen. Copyright © 2015 Elsevier Ltd. All rights reserved.

Late-Onset Asthma Predicts Cardiovascular Disease Events: The Wisconsin Sleep Cohort.

PubMed

Tattersall, Matthew C; Barnet, Jodi H; Korcarz, Claudia E; Hagen, Erika W; Peppard, Paul E; Stein, James H

2016-08-24

Asthma is a heterogeneous syndrome with different clinical subtypes that is associated with an increased risk for cardiovascular disease (CVD). We hypothesized that the late-onset subtype of asthma is associated with a higher risk of incident CVD. Participants from the Wisconsin Sleep Cohort free of CVD at baseline were followed for a mean (SD) of 13.9 (5.9) years for development of CVD (myocardial infarction, angina, stroke, coronary revascularization, heart failure, or CVD death). Late-onset asthma was defined as physician-diagnosed asthma at age ≥18 years. Multivariable Cox regression models adjusted for age, sex, and CVD risk factors were used to assess associations of late-onset asthma and incident CVD. The 1269 participants were 47.3 (8.0) years old; 166 participants had asthma (111 late-onset, 55 early-onset). Participants with late-onset asthma compared to nonasthmatics were more likely to be female (67% versus 44%) and to have a higher body-mass index (32.2 versus 29.4 kg/m(2)) (P<0.05). Mean age of asthma diagnosis in the late-onset group was 39.5 (9.6) years versus 8.9 (5.7) years in the early-onset group (P<0.0001). Late-onset asthmatics had a higher adjusted risk of incident CVD than nonasthmatics (hazard ratio 1.57, 95% CI 1.01-2.45, P=0.045). There was no interaction between body-mass index and age of asthma diagnosis on incident CVD (P=0.83). In a large cohort study of adults followed prospectively for over a decade, late-onset asthmatics had an increased risk of incident CVD events that persisted after adjustment for age, sex, and CVD risk factors. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

A Study to Develop a Model for the Allocation of Medical Supply Funds to the Various Clinical Services at Keller Army Community Hospital Based Upon Inpatient Weighted Units and Ambulatory Weighted Units

DTIC Science & Technology

1989-05-11

zDiagnosis Related Groups (DRGs), as developed by ther Mz researchers at Yale University in the late 1960s, were a m mmeans of classifying patients by...the group’s recalibration of the Rickard 19 ambulatory portion of the HCU was most important. This was because it resulted in, "an ambulatory

Pancreatic Reference Set Application: Kazufumi Honda-National Cancer Center (2014) — EDRN Public Portal

Cancer.gov

Among human malignancies, invasive ductal adenocarcinoma of the pancreas has the worst prognosis,with a 5-year survival rate of less than 10%. Most patients with early stage pancreatic cancer have no clinical symptoms; therefore, many of them develop progressive disease that is not detected until the late stage. To improve the survival rate of pancreatic cancer, non-invasive diagnostic methods that detect the disease in its early stage must be developed.

[Medical empiricism from one myth to another. A critical reading of Foucault's Birth of Clinic].

PubMed

de Calan, Ronan

2013-01-01

The new history of the clinic, developed mainly after the publication of Othmar Keel's L'avènement de la médecine clinique moderne en Europe, 1750-1815 in 2001, invites the scholars to turn upside down the chronology adopted by Michel Foucault in his classic Birth of the Clinic. This paper investigates the philosophical consequences of this chronological displacement, showing that the medical empiricism of the clinic cannot have the characteristics attributed by Foucault. If the myth of the purity of such empiricism cannot be taken seriously anymore thanks to Foucault, is has been substituted by the myth of the creation of the clinic on the basis of enlightened empiricism. The clinic is, however, older than empiricism à la Condillac. It refers to an earlier medical empiricism developed in the 17th century which in its turn allowed for Condillac's philosophy. The clinic had in fact to choose between an elder medical empiricism and a new chemical empirism that appeared in the late 17th century. But the clinic was not a creation of the Enlightenment.

Risk factors for adverse events after vaccinations performed during the initial hospitalization of infants born prematurely.

PubMed

Wilińska, Maria; Warakomska, Małgorzata; Głuszczak-Idziakowska, Ewa; Jackowska, Teresa

There are significant delays in implementing vaccination among preterm infants. Description of the frequency and kinds of adverse events following immunization in preterms. Establishment of the group of preterms who will distinctively be susceptible to adverse events. Demographical, clinical data and the occurrence of adverse events after DTaP, HIB and pneumococcal vaccination among preterms during their initial hospitalization were prospectively collected with the use of an electronic data form between 1st June 2011 and 31st May 2015. The analysis was conducted on 138 patients. The groups were divided according to maturity (I: ≤ GA 28w n=73 and GA 29-36 w n=65). There were no statistically significant differences between the groups in the occurrence of adverse events. Out of the total group, following vaccination apnoea developed in 6 newborns (4%) and activity dysfunctions were observed in 13 newborns (10%). The occurrence of apnoea after vaccination positively correlated with the time of non-invasive ventilation and the occurrence of late infection. There were no statistically significant demographical or clinical risk factors for the development of activity dysfunctions following vaccination. Term vaccination in clinically stable preterm infants is a safe medical procedure. However, long-term non-invasive respiratory support and late infections are risk factors for apnea following vaccinations. In these patients vaccinations should be considered during hospitalization.

Characteristics and outcomes of older adults with long-standing versus late-onset asthma.

PubMed

Herscher, Michael L; Wisnivesky, Juan P; Busse, Paula J; Hanania, Nicola A; Sheng, Tianyun; Wolf, Michael S; Federman, Alex D

2017-04-01

To examine the effect of age of onset on clinical characteristics and outcomes in a cohort of older patients with long-standing (LSA) and late-onset asthma (LOA). In all, 452 patients 60 years of age and older with persistent asthma were recruited. We defined LOA as asthma developing at age 40 or later and LSA as developing before age 40. We compared airway obstruction as assessed by spirometry, as well as asthma control using the Asthma Control Questionnaire (ACQ), quality of life using the Mini Asthma Quality of Life Questionnaire (AQLQ), and asthma-related emergency department visits and hospitalizations among patients with LSA vs. LOA. Patients with LOA, were less likely to have FEV 1 <70% of predicted (23% vs. 40%, p = 0.0002), to have FEV 1 /FVC<0.7 (27% vs. 38%, p = 0.01), or to have been intubated in the past (5% vs. 14%, p = 0.0007), and were also less likely to report a history of allergic conditions (64% vs 76%, p = 0.007). There was no significant difference in the level of asthma control, quality of life, or health care utilization. Older adults with LOA have different clinical and physiological characteristics and outcomes compared to those with LSA. Some of these differences may represent sequelae of longstanding disease, however LOA may also represent a different clinical phenotype that could influence management approaches.

Brain Development in Autism: Early Overgrowth Followed by Premature Arrest of Growth

ERIC Educational Resources Information Center

Courchesne, Eric

2004-01-01

Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies…

‘Miscarriage or abortion?’ Understanding the medical language of pregnancy loss in Britain; a historical perspective

PubMed Central

Moscrop, Andrew

2013-01-01

Clinical language applied to early pregnancy loss changed in late twentieth century Britain when doctors consciously began using the term ‘miscarriage’ instead of ‘abortion’ to refer to this subject. Medical professionals at the time and since have claimed this change as an intuitive empathic response to women's experiences. However, a reading of medical journals and textbooks from the era reveals how the change in clinical language reflected legal, technological, professional and social developments. The shift in language is better understood in the context of these historical developments, rather than as the consequence of more empathic medical care for women who experience miscarriage. PMID:23429567

Delayed Antitoxin Treatment of Two Adult Patients with Botulism after Cosmetic Injection of Botulinum Type A Toxin.

PubMed

Fan, Kit-Ling; Wang, Yan-Li; Chu, Gary; Leung, Ling-Pong

2016-12-01

Injection of botulinum toxin type A for cosmetic purposes is common. It is believed to be safe, but adverse reactions have been reported, including dysphagia, generalized paralysis, respiratory depression, and death caused by focal injection of the toxin. Early administration of antitoxin in patients with adverse reactions is the mainstay of management, but the time window for its clinical efficacy is not well defined. Two female adult patients with clinical botulism after botulinum toxin type A injection are described. Both patients had received intramuscular injection of botulinum toxin type A in their calves at beauty shops for cosmetic reasons. They developed clinical botulism about 3 days postinjection. They presented late to the emergency department. Monovalent type A botulinum antitoxin was administered 7 and 9 days from symptom onset, respectively. Both patients showed clinical improvement after the antitoxin treatment. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients may present to the emergency department with systemic effects of botulinum toxin type A after cosmetic injection. Clinical efficacy of botulinum antitoxin treatment was observed in two patients who were given the drug 7 and 9 days after the occurrence of symptoms of botulism after cosmetic injection of botulinum toxin type A. It may be worthwhile to commence antitoxin treatment even if patients present late. Copyright © 2016 Elsevier Inc. All rights reserved.

Late-developing infection following posterior fusion for adolescent idiopathic scoliosis.

PubMed

Di Silvestre, Mario; Bakaloudis, Georgios; Lolli, Francesco; Giacomini, Stefano

2011-05-01

This study is a retrospective case series review of patients with adolescent idiopathic scoliosis (AIS) who were revised more than 1 year after the index procedure, due to a late-developing deep wound infection, to determine onset, bacteriology, possible influence of implant alloy (titanium vs. stainless-steel) and treatment outcome of patients. From a total of 540 patients who underwent posterior-only fusion for AIS from 1993 through 2005 at our institution, 15 cases (2.77%) were revised due to a late-developing post-operative infection: there were six males and nine females, with an average age at initial surgery of 15.8 years (range 12-18). Late infections occurred at a mean of 70 months (15-95) after the index procedure. The implant alloy used was a stainless-steel instrumentation in 11 patients (4.56% of 241) and a titanium one in 4 patients (1.33% of 299): there was an higher incidence of late infections in stainless-steel alloy group of patients (P < 0.0001). Complete removal of instrumentation was performed in nine patients, obtaining in all cases wound healing and no symptoms of infection, at a minimum 3 years follow-up. In the other six patients, presenting less severe clinical signs of infections, an attempt to save/replace the previous instrumentation was performed, but a complete instrumentation removal had to be performed 11.6 months later (range 3-24) for the persistence or recurrence of infection: all patients healed uneventfully at a minimum 3 years follow-up. Intraoperative cultures were obtained in all 15 cases, being positive in 13 cases (S. epidermidis in 5 patients, S. aureus in 3, Propionibacterium acnes in 1, Serratia marcescens in 1, Propionibacterium acnes + S. epidermidis in 1, S. aureus + S. epidermidis in 1 and coagulase-negative Staphylococci in 1). None presented at latest follow-up scoliosis progression: there was no statistically significant difference between final and pre-operative revision surgery values (P = 0.17). In conclusion, treatment of late-developing post-operative infection in AIS surgery required complete removal of the implant, continuous drain and adequate antibiotic therapy based on intraoperative swab antibiogram. Titanium alloy instrumentations resulted less subject to late post-operative infections, when compared to stainless-steel ones (P < 0.0001).

Tuberculosis-associated Fibrosing Mediastinitis: Case Report and Literature Review.

PubMed

Tan, Ronald; Martires, Joanne; Kamangar, Nader

2016-01-01

Fibrosing mediastinitis is a rare condition defined by the presence of fibrotic mediastinal infiltrates that obliterate normal fat planes. It is a late complication of a previous granulomatous infection, such as histoplasmosis or tuberculosis (TB). Due to its rarity, fibrosing mediastinitis is often under-recognized, and the clinical presentation is variable and dependent on the extent of infiltration or encasement of structures within the mediastinum. We present a case of fibrosing mediastinitis in a man with a prior history of TB, who presented with progressive dyspnea and was found to have chronic mediastinal soft tissue opacities and pulmonary hypertension. His diagnosis was delayed due to the lack of recognition of this clinical/radiographic entity. Fibrosing mediastinitis is a rare entity usually caused by granulomatous disease. Most cases develop as a late complication of histoplasmosis or TB. The presence of calcified mediastinal soft tissue infiltrates on advanced chest imaging can be diagnostic of fibrosing mediastinitis in patients with a prior history of a granulomatous infection once active processes such as malignancy are excluded.

Cardiorenal benefits of early versus late cyclosporine to sirolimus conversion in a rat model

PubMed Central

Sereno, José; Romão, Ana M.; Parada, Belmiro; Lopes, Patrícia; Carvalho, Eugénia; Teixeira, Frederico; Reis, Flávio

2012-01-01

Objective: To compare the cardiorenal effects of early versus late cyclosporine (CsA) to sirolimus (SRL) conversion, using a novel animal model that mimics these protocols used in the clinical practice, and focusing on blood pressure, heart rate (HR), biochemical data and heart and kidney lipid peroxidation. Materials and Methods: The study had five groups. Six male Wistar rats in each group were used during a 9-week study protocol: control, CsA (5 mg/kg/day), SRL (1 mg/kg/day); early conversion and late conversion. Cardiorenal evaluation was assessed by biochemical data, blood pressure, HR, and heart and kidney lipid peroxidation. Results: As expected, CsA promoted cardiorenal impairment, viewed by development of hypertension, tachycardia, increased urea, creatine kinase, and glucose levels, as well as heart and kidney oxidative stress. SRL, as expected, promoted less cardiorenal side effects, namely those related with nephrotoxicity. In agreement, both early and late conversions from CsA to SRL produced less side-effects, namely those related to the CsA-induced nephrotoxicity. Conclusions: In our model, both early and late CsA to SRL conversion promoted amelioration of the CsA -induced cardiorenal damage. However, early substitution seems to produce more benefits, in particular due to higher improvement of the cardiac profile. PMID:22629089

Effect of total body irradiation on late lung effects: hidden dangers.

PubMed

Johnston, Carl J; Manning, Casey; Hernady, Eric; Reed, Christina; Thurston, Sally W; Finkelstein, Jacob N; Williams, Jacqueline P

2011-08-01

In our ongoing investigation into the consequences of a radiological terrorism or nuclear dispersion event, we assessed whether a dose range that is believed to be sub-threshold for the development of lung endpoints results in late pathological changes and, secondarily, whether those late changes affect the lung's ability to respond to subsequent challenge. C57BL/6J mice received total body irradiation (0.5-10 Gy) and were followed for 6-18 months after irradiation. At 12 and 15 months, a subset of mice was exposed to a second challenge (aerosolised lipopolysaccharide [LPS]). Cytokines shown to be upregulated early (hours) following irradiation (interleukin [IL]6, keratinocyte chemoattractant [KC], IL1B, and IL1R2) demonstrated increases in messenger ribose nucleic acid (mRNA) expression at late time points, beginning at nine months. Although persistent, dose-dependent increases in T cell counts were seen, no other overt changes in pathophysiology were observed. Nonetheless, animals that were exposed to a secondary challenge at late time points demonstrated an increased inflammatory cell recruitment and persistence in response relative to controls. We propose that, following doses that elicit little change in pathophysiology, sub-clinical radiation-induced injury increases the lungs' susceptibility to a secondary challenge, possibly through a radiation-induced alteration in the immune defense system.

Chronic radiation-induced dermatitis: challenges and solutions.

PubMed

Spałek, Mateusz

2016-01-01

Chronic radiation dermatitis is a late side effect of skin irradiation, which may deteriorate patients' quality of life. There is a lack of precise data about its incidence; however, several risk factors may predispose to the development of this condition. It includes radiotherapy dose, fractionation, technique, concurrent systemic therapy, comorbidities, and personal and genetic factors. Chronic radiation dermatitis is mostly caused by the imbalance of proinflammatory and profibrotic cytokines. Clinical manifestation includes changes in skin appearance, wounds, ulcerations, necrosis, fibrosis, and secondary cancers. The most severe complication of irradiation is extensive radiation-induced fibrosis (RIF). RIF can manifest in many ways, such as skin induration and retraction, lymphedema or restriction of joint motion. Diagnosis of chronic radiation dermatitis is usually made by clinical examination. In case of unclear clinical manifestation, a biopsy and histopathological examination are recommended to exclude secondary malignancy. The most effective prophylaxis of chronic radiation dermatitis is the use of proper radiation therapy techniques to avoid unnecessary irradiation of healthy skin. Treatment of chronic radiation dermatitis is demanding. The majority of the interventions are based only on clinical practice. Telangiectasia may be treated with pulse dye laser therapy. Chronic postirradiation wounds need special dressings. In case of necrosis or severe ulceration, surgical intervention may be considered. Management of RIF should be complex. Available methods are rehabilitative care, pharmacotherapy, hyperbaric oxygen therapy, and laser therapy. Future challenges include the assessment of late skin toxicity in modern irradiation techniques. Special attention should be paid on genomics and radiomics that allow scientists and clinicians to select patients who are at risk of the development of chronic radiation dermatitis. Novel treatment methods and clinical trials are strongly needed to provide more efficacious therapies.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013)

PubMed Central

Brahim, Lucia Regina; Valete-Rosalino, Cláudia Maria; Antônio, Liliane de Fátima; Pimentel, Maria Inês Fernandes; Lyra, Marcelo Rosandiski; Paes, Luiz Eduardo de Carvalho; da Costa, Ananda Dutra; Vieira, Iracema Forni; Dias, Cristina Maria Giordano; Duque, Maria Cristina de Oliveira; Marzochi, Mauro Celio de Almeida; Schubach, Armando de Oliveira

2017-01-01

BACKGROUND American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence. PMID:29211245

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

PubMed

Brahim, Lucia Regina; Valete-Rosalino, Cláudia Maria; Antônio, Liliane de Fátima; Pimentel, Maria Inês Fernandes; Lyra, Marcelo Rosandiski; Paes, Luiz Eduardo de Carvalho; Costa, Ananda Dutra da; Vieira, Iracema Forni; Dias, Cristina Maria Giordano; Duque, Maria Cristina de Oliveira; Marzochi, Mauro Celio de Almeida; Schubach, Armando de Oliveira

2017-12-01

American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. Data were recovered from records of all ATL patients diagnosed during that period. Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Clinical characteristics and treatment outcomes of patients with colorectal cancer who develop brain metastasis: a single institution experience.

PubMed

Fountzilas, Christos; Chang, Katherine; Hernandez, Brian; Michalek, Joel; Crownover, Richard; Floyd, John; Mahalingam, Devalingam

2017-02-01

The development of brain metastasis (BM) in patients with colorectal cancer (CRC) is a rare and late event. We sought to investigate the clinical characteristics, disease course and safety using biologic agents in our patients with CRC who develop brain metastases. A retrospective review of patients with CRC with brain metastases treated at our institution from 01/2005-01/2015 was performed. Survival analysis was performed using the Kaplan-Meier method. Forty patients were included in the analysis. Median age was 55.5 years, 67.5% were males, and 28% had a KRAS mutation. Twenty-four percent were treatment-naive at the time of BM diagnosis. Patients had a median of two brain lesions. Sixty-five percent of the patients were treated with radiotherapy alone, 22.5% had both surgical resection and brain radiotherapy. Median overall survival was 3.2 months after development of BM. Overall survival was longer in patients who received combined modality local therapy compared to patients treated with surgical resection or radiotherapy alone. Patients who received systemic treatment incorporating biologics following development of BM had a median overall survival of 18.6 months. Overall, the administration of biologic agents was safe and well tolerated. In summary, BM is an uncommon and late event in the natural history of metastatic CRC. The ability to deliver combined-modality local brain therapy as well as availability of more systemic therapy options appear to lead to improved outcomes.

Training mid- to late-career health professionals for clinical work in low-income regions abroad.

PubMed

Harris, W Andrew; Spencer, Peter; Winthrop, Kevin; Kravitz, Jay

2014-01-01

Oregon Health & Science University (OHSU) Global Health Center has developed a unique training program-Professionals' Training in Global Health (PTGH)--for mid- and late-career health professionals wanting to perform clinical services overseas in low-income countries. A multidisciplinary, multifaceted, structured curriculum underpins the clinical retraining, with classes aimed to be practical for clinical settings in resource-poor regions of the world. Preceptorships in family medicine and emergency medicine offer specialists the opportunity to observe primary care physicians one-on-one. In addition, PTGH trainees volunteer at free medical clinics where they work under the guidance and supervision of a family physician. For those individuals who live at some distance from Portland, Oregon, the course offers live videoconferencing, as well as archived streaming for later review. As of November 2013, 79 health professionals have completed the course, with 45 graduates having subsequently volunteered on one or more overseas medical missions, for a total of 109 medical service visits to 36 countries. Pre- and post-course testing shows improvements in clinical skills and knowledge base. Professionals' Training in Global Health has a 6-year record of interprofessional training and service both overseas and at home. The course has trained physicians, nurses, nurse practitioners, physician assistants, midwives, paramedics and other health professionals. © 2014 The Alliance for Continuing Education in the Health Professions, the Society for Academic Continuing Medical Education, and the Council on Continuing Medical Education, Association for Hospital Medical Education.

Healthy late preterm infants and supplementary artificial milk feeds: effects on breast feeding and associated clinical parameters.

PubMed

Mattsson, Elisabet; Funkquist, Eva-Lotta; Wickström, Maria; Nyqvist, Kerstin H; Volgsten, Helena

2015-04-01

to compare the influence of supplementary artificial milk feeds on breast feeding and certain clinical parameters among healthy late preterm infants given regular supplementary artificial milk feeds versus being exclusively breast fed from birth. a comparative study using quantitative methods. Data were collected via a parental diary and medical records. parents of 77 late preterm infants (34 5/7-36 6/7 weeks), whose mothers intended to breast feed, completed a diary during the infants׳ hospital stay. infants who received regular supplementary artificial milk feeds experienced a longer delay before initiation of breast feeding, were breast fed less frequently and had longer hospital stays than infants exclusively breast fed from birth. Exclusively breast-fed infants had a greater weight loss than infants with regular artificial milk supplementation. A majority of the mothers (65%) with an infant prescribed artificial milk never expressed their milk and among the mothers who used a breast-pump, milk expression commenced late (10-84 hours after birth). At discharge, all infants were breast fed to some extent, 43% were exclusively breast fed. clinical practice and routines influence the initiation of breast feeding among late preterm infants and may act as barriers to the mothers׳ establishment of exclusive breast feeding. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exertional heat stroke and acute liver failure: a late dysfunction

PubMed Central

Carvalho, Ana Sofia; Rodeia, Simão C; Silvestre, Joana; Póvoa, Pedro

2016-01-01

Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year-old man with a history of cognitive enhancers’ intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID:26969359

The development of falling intonation in young children with cochlear implants: a 2-year longitudinal study.

PubMed

Snow, David P; Ertmer, David J

2013-07-01

This article describes the development of intonation in 12 cochlear implant (CI) recipients. In a previously reported study of the first year of CI use, children who were implanted late (after 24 months) acquired intonation more rapidly than the younger participants. The older children's advantage is plausibly owing to their greater maturity. However, children who were implanted early (before 25 months) did not have an advantage over the still younger control group of infants with normal hearing (NH), suggesting that the advantage requires a critical age of about 30 months. The younger CI-users reached this age in the second year of CI use. The results confirmed our expectation that even the younger CI recipients would acquire intonation more rapidly than infants with NH who had the same amount of robust hearing experience. Clinical implications are discussed in relation to the question of early versus late implantation.

Alzheimer's Disease and Exercise: A Literature Review.

PubMed

Cass, Shane P

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment. It is the leading cause of dementia in late adult life and is associated with a significant social burden and increased morbidity and mortality in the elderly. Because of mixed effectiveness of medications, exercise has been considered as a treatment for pre-clinical AD, late stage AD, and as a prevention strategy. Exercise appears to improve brain blood flow, increase hippocampal volume, and improve neurogenesis. Prospective studies indicate that physical inactivity is one of the most common preventable risk factors for developing AD and that higher physical activity levels are associated with a reduced risk of development of disease. Exercise as a treatment for AD shows improvement in cognitive function, decreased neuropsychiatric symptoms, and a slower decline in activities of daily living (ADL). Exercise has been shown to have fewer side effects and better adherence compared to medications.

The role of SCUBE1 in the development of late stent thrombosis presenting with ST-elevation myocardial infarction.

PubMed

Bolayır, Hasan Ata; Kıvrak, Tarık; Güneş, Hakan; Akaslan, Dursun; Şahin, Ömer; Bolayır, Aslı

2018-05-01

There is an important link between platelets and inflammation, thrombosis, and vascular and tissue repair mechanisms. SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) may function as a novel platelet-endothelial adhesion molecule and play pathological roles in cardiovascular biology. Stent thrombosis (ST) following percutaneous coronary intervention is an uncommon and potentially catastrophic event that can manifest as myocardial infarction and sudden death. High platelet reactivity is a risk factor for thrombotic events, including late ST. For this reason, in the current study, we researched the role of SCUBE1 in the development of late coronary ST. We included 40 patients admitted to our hospital with a diagnosis of ST-elevation myocardial infarction (STEMI) and signs of late ST on a coronary angiogram. For the control group, we recruited 50 healthy gender- and age-matched individuals who were seen for health check-ups. We also randomly included 100 patients with a diagnosis of STEMI without ST. There were no significant differences between the groups in terms of baseline and demographic characteristics. The mean SCUBE1 level in patients with STEMI with late ST at admission and the STEMI without ST group was significantly higher than in the control group (p<0.01). The mean SCUBE1 level in the STEMI with late ST group was significantly higher than in the STEMI without ST group (p=0.03). In multivariate regression analysis, serum SCUBE1 (odds ratio [OR]: 1.022; 95% confidence interval [CI]: 1.011-1.033, p<0.001) remained an independent predictor for the presence of late ST. In addition, receiver operating characteristic curve analysis was used to determine the optimal SCUBE1 cut-off value for predicting late ST. The area under the curve was 0.972 (95% CI 0.95-0.98). The SCUBE1 cut-off value was 59.2 ng/ml, with a sensitivity of 95.4% and specificity of 82.9%. The present work is the first clinical study to demonstrate that serum SCUBE1 levels are significantly higher in patients with late ST and serum SCUBE1 was an independent predictor for the presence of late ST in our study population. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES).

PubMed

Ribichini, Flavio; Tomai, Fabrizio; Pesarini, Gabriele; Zivelonghi, Carlo; Rognoni, Andrea; De Luca, Giuseppe; Boccuzzi, Giacomo; Presbitero, Patrizia; Ferrero, Valeria; Ghini, Anna S; Marino, Paolo; Vassanelli, Corrado

2013-06-01

To analyse the clinical outcome at 4 years in patients with coronary artery disease treated with bare metal stents (BMS) vs. BMS and oral prednisone, or drug-eluting stents (DES), all assuming similar adjunctive medical treatment. Five Italian hospitals enrolled 375 non-diabetic, ischaemic patients without contraindications to dual anti-platelet treatment or corticosteroid therapy in a randomized controlled study. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischaemia needing repeated target vessel revascularization at 1 year, and this was significantly lower in the BMS group (80.8%) compared with the prednisone (88.0%) and DES group (88.8%, P = 0.04 and 0.006, respectively). The long-term analysis of the primary endpoint was a pre-specified aim of the trial, and was performed at 1447 days (median, IQ range = 1210-1641). Patients receiving BMS alone had significantly lower event-free survival (75.3%) compared with 84.1% in the prednisone group (HR: 0.447; 95% CI: 0.25-0.80, P = 0.007) and 80.6% in DES patients (HR: 0.519; 95% CI: 0.29-0.93, P = 0.03). Prednisone-treated patients did not develop new treatment-related clinical problems. Drug-eluting stents patients suffered more very late stent thrombosis as a cause of spontaneous myocardial infarction. The need for target vessel revascularization remained lower in the prednisone and DES groups (13.6 and 15.2%, respectively), compared with BMS (23.2%). The clinical benefits of prednisone compared with BMS only persisted almost unchanged at 4 years. Drug-eluting stents performed better than BMS at long-term, although the advantages observed at 1 year were in part attenuated because of the occurrence of very late stent thrombosis and late revascularizations. Clinical Trial NCT 00369356.

Enhanced erythrocyte aggregation in type 2 diabetes with late complications.

PubMed

Demiroglu, H; Gürlek, A; Barişta, I

1999-01-01

We investigated whether erythrocyte aggregation (EA) is enhanced in type 2 diabetic patients who have developed microvascular or macrovascular complications. EA rates at high and low shear rates were analysed in 141 patients with type 2 diabetes who were further divided into 4 subgroups according to the status of diabetic complications and degree of metabolic control. Groups 1 (n = 43) and 2 (n = 23) consisted of well-controlled patients without and with clinically evident late complications, while groups 3 (n = 33) and 4 (n = 42) represented poorly controlled patients without and with these complications, respectively. 124 healthy subjects served as the control group. Mean EA rate was comparable between control subjects and group 1 both at high (2.05 +/- 0.03 vs. 2.14 +/- 0.07, respectively) and low (6.96 +/- 0.02 vs. 7.04 +/- 0.06, respectively) shear rates. Mean EA rate was also comparable between groups 2 and 4 at high (2.76 +/- 0.09 vs. 2.94 +/- 0.07, respectively) and low (8.18 +/- 0.13 vs. 8.41 +/- 0.1, respectively) shear rates. However, EA at both shear rates in groups 2 and 4 were significantly higher than control subjects, group 1 (p < 0.0001) and group 3 (high shear rate EA: 2.76 +/- 0.09 and low shear rate EA: 7.48 +/- 0.07 (p < 0.01). In group 3, EA rates were significantly higher than control subjects and group 1 (p < 0.05) at both shear rates. No significant correlation was found between EA at high and low shear rates and fibrinogen levels in diabetic subgroups and control subjects. The data suggest that patients with type 2 diabetes who had developed clinically evident late complications have enhanced EA regardless of the degree of metabolic control. Whether enhanced EA is a primary phenomenon contributing to the development of these complications or it occurs secondary to their development remains to be clarified.

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

PubMed Central

2012-01-01

Background The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery). Methods A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis. Results A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant GSTP1 (Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, p = 0.047). Conclusions The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity. Trial Registration ClinicalTrials.gov: NCT01316328 PMID:22272830

Executive functions and basic symptoms in adolescent antisocial behavior: a cross-sectional study on an Italian sample of late-onset offenders.

PubMed

Muscatello, Maria Rosaria A; Scimeca, Giuseppe; Pandolfo, Gianluca; Micò, Umberto; Romeo, Vincenzo M; Mallamace, Domenico; Mento, Carmela; Zoccali, Rocco; Bruno, Antonio

2014-04-01

Executive cognitive functions (ECFs) and other cognitive impairments, such as lower IQ and verbal deficits, have been associated with the pattern of antisocial and delinquent behavior starting in childhood (early-onset), but not with late-onset antisocial behavior. Beyond objective measures of ECF, basic symptoms are prodromal, subjectively experienced cognitive, perceptual, affective, and social disturbances, associated with a range of psychiatric disorders, mainly with psychosis. The goal of the present study was to examine ECF and basic symptoms in a sample of late-onset juvenile delinquents. Two-hundred nine male adolescents (aged 15-20 years) characterized by a pattern of late-onset delinquent behavior with no antecedents of Conduct Disorder, were consecutively recruited from the Social Services of the Department of Juvenile Justice of the city of Messina (Italy), and compared with nonantisocial controls matched for age, educational level, and socio-demographic features on measures for ECF dysfunction and basic symptoms. Significant differences between late-onset offenders (completers=147) and control group (n=150) were found on ECF and basic symptoms measures. Chi-square analysis showed that a significantly greater number of late-onset offending participants scored in the clinical range on several ECF measures. Executive cognitive impairment, even subtle and subclinical, along with subjective symptoms of cognitive dysfunction (basic symptom), may be contributing factor in the development and persistence of antisocial behaviors displayed by late-onset adolescent delinquents. The findings also suggest the need for additional research aimed to assess a broader range of cognitive abilities and specific vulnerability and risk factors for late-onset adolescent offenders. Copyright © 2014 Elsevier Inc. All rights reserved.

Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience.

PubMed

Rowczenio, Dorota M; Gomes, Sónia Melo; Aróstegui, Juan I; Mensa-Vilaro, Anna; Omoyinmi, Ebun; Trojer, Hadija; Baginska, Anna; Baroja-Mazo, Alberto; Pelegrin, Pablo; Savic, Sinisa; Lane, Thirusha; Williams, Rene; Brogan, Paul; Lachmann, Helen J; Hawkins, Philip N

2017-01-01

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations.

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.

PubMed

De Antonio, M; Dogan, C; Hamroun, D; Mati, M; Zerrouki, S; Eymard, B; Katsahian, S; Bassez, G

2016-10-01

The broad clinical spectrum of myotonic dystrophy type 1 (DM1) creates particular challenges for both medical care and design of clinical trials. Clinical onset spans a continuum from birth to late adulthood, with symptoms that are highly variable in both severity and nature of the affected organ systems. In the literature, this complex phenotype is divided into three grades (mild, classic, and severe) and four or five main clinical categories (congenital, infantile/juvenile, adult-onset and late-onset forms), according to symptom severity and age of onset, respectively. However, these classifications are still under discussion with no consensus thus far. While some specific clinical features have been primarily reported in some forms of the disease, there are no clear distinctions. As a consequence, no modifications in the management of healthcare or the design of clinical studies have been proposed based on the clinical form of DM1. The present study has used the DM-Scope registry to assess, in a large cohort of DM1 patients, the robustness of a classification divided into five clinical forms. Our main aim was to describe the disease spectrum and investigate features of each clinical form. The five subtypes were compared by distribution of CTG expansion size, and the occurrence and onset of the main symptoms of DM1. Analyses validated the relevance of a five-grade model for DM1 classification. Patients were classified as: congenital (n=93, 4.5%); infantile (n=303, 14.8%); juvenile (n=628, 30.7%); adult (n=694, 34.0%); and late-onset (n=326, 15.9%). Our data show that the assumption of a continuum from congenital to the late-onset form is valid, and also highlights disease features specific to individual clinical forms of DM1 in terms of symptom occurrence and chronology throughout the disease course. These results support the use of the five-grade model for disease classification, and the distinct clinical profiles suggest that age of onset and clinical form may be key criteria in the design of clinical trials when considering DM1 health management and research. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Big data from electronic health records for early and late translational cardiovascular research: challenges and potential.

PubMed

Hemingway, Harry; Asselbergs, Folkert W; Danesh, John; Dobson, Richard; Maniadakis, Nikolaos; Maggioni, Aldo; van Thiel, Ghislaine J M; Cronin, Maureen; Brobert, Gunnar; Vardas, Panos; Anker, Stefan D; Grobbee, Diederick E; Denaxas, Spiros

2018-04-21

Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research. We sought exemplars based on literature reviews and expertise across the BigData@Heart Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health. High volumes of inherently diverse ('big') EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.

Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single-Family Case-Control Study.

PubMed

Day, Gregory S; Musiek, Erik S; Roe, Catherine M; Norton, Joanne; Goate, Alison M; Cruchaga, Carlos; Cairns, Nigel J; Morris, John C

2016-09-01

The amyloid hypothesis posits that disrupted β-amyloid homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant AD (ADAD) has an early symptomatic onset and is caused by single-gene mutations that result in overproduction of β-amyloid 42. To the extent that sporadic late-onset AD (LOAD) also results from dysregulated β-amyloid 42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) gene mutation to mitigate the potential confound of age when comparing ADAD and LOAD. This case-control study was conducted at the Knight Alzheimer Disease Research Center at Washington University, St Louis, Missouri, and other National Institutes of Aging-funded AD centers in the United States. Ten PSEN1 A79V mutation carriers from multiple generations of a family with late-onset ADAD and 12 noncarrier family members were followed up at the Knight Alzheimer Disease Research Center (1985-2015) and 1115 individuals with neuropathologically confirmed LOAD were included from the National Alzheimer Coordinating Center database (September 2005-December 2014). Data analysis was completed in January 2016, including Knight Alzheimer Disease Research Center patient data collected up until the end of 2015. Planned comparison of clinical characteristics between cohorts, including age at symptom onset, associated symptoms and signs, rates of progression, and disease duration. Of the PSEN1 A79V carriers in the family with late-onset ADAD, 4 were female (57%); among those with LOAD, 529 were female (47%). Seven mutation carriers (70%) developed AD dementia, while 3 were yet asymptomatic in their seventh and eighth decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptom onset (mutation carriers: mean, 75 years [range, 63-77 years] vs those with LOAD: mean, 74 years [range, 60-101 years]; P = .29), presenting symptoms (memory loss in 7 of 7 mutation carriers [100%] vs 958 of 1063 individuals with LOAD [90.1%]; P ≥ .99) and duration (mutation carriers: mean, 9.9 years [range, 2.3-12.8 years] vs those with LOAD: 9 years [range, 1-27 years]; P = .73), and rate of progression of dementia (median annualized change in Clinical Dementia Rating-Sum of Boxes score, mutation carriers: 1.2 [range, 0.1-3.3] vs those with LOAD: 1.9 [range, -3.5 to 11.9]; P = .73). Early emergence of comorbid hallucinations and delusions were observed in 57% of individuals with ADAD (4 of 7) vs 19% of individuals with LOAD (137 of 706) (P = .03). Three of 12 noncarriers (25%) from the PSEN1 A79V family are potential phenocopies as they also developed AD dementia (median age at onset, 76.0 years). In this family, the amyloidogenic PSEN1 A79V mutation recapitulates the clinical attributes of LOAD. Previously reported clinical phenotypic differences between individuals with ADAD and LOAD may reflect age- or mutation-dependent effects.

Developmental typologies of serious mental illness and violence: Evidence from a forensic psychiatric setting.

PubMed

Simpson, Alexander I; Grimbos, Teresa; Chan, Christine; Penney, Stephanie R

2015-11-01

To identify subgroups of forensic psychiatric patients based on the age onset of serious mental illness and offending and assess the external validity of the subgroups with theoretically based sociodemographic, clinical, legal and risk-related variables. The age onset of serious mental illness and criminal contact was ascertained for a sample of 232 patients. A range of sociodemographic, clinical, legal and risk-related variables were coded to assess whether age onset subgroups differed in a manner consistent with the literature on typologies of mentally ill offenders. One-quarter of the sample was classified as early starters (patients whose first offense occurred before becoming mentally ill), while two-thirds were late starters (where first offense occurred following illness onset). A small percentage (8%) of patients were deemed late late starters, defined as late starters who had experienced 10+ years of illness and were >37 years upon first arrest. A larger proportion of early starters had a substance use disorder, antisocial personality disorder and a greater number of static/historical risk factors for violence. Early starters were younger upon first arrest and had more previous criminal contacts compared to late starters and late late starters. Mental illness was found to start later in life for late late starters; this group was also more likely to have been married and to have a spouse as victim in the index offense. We found support for distinct subgroups of mentally ill offenders based on the age onset of illness and criminal contact. Compared to late starters, offenses committed by early starters may be motivated more frequently by antisocial lifestyle and attitudes, as well as more instrumental behaviors related to substance abuse. In addition, late late starters may represent a distinct third subgroup within late starters, characterized by relatively higher levels of functioning and social stability; future work should replicate. Findings suggest different rehabilitation needs of the subgroups. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy.

PubMed

Schmied, Julie; Rupa, Prithy; Garvie, Sarah; Wilkie, Bruce

2013-07-15

The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use. Copyright © 2013 Elsevier B.V. All rights reserved.

[Psychosocial factors associated with late HAART initiation in Mexican patients with HIV].

PubMed

Nogueda-Orozco, María José; Caro-Vega, Yanink; Crabtree-Ramírez, Brenda; Vázquez-Pineda, Fernando; Sierra-Madero, Juan G

2015-01-01

To explore the association between psychosocial factors and late highly active antiretroviral therapy (HAART) initiation in a sample of Mexican patients with HIV. We conducted a cross-sectional study at the HIV Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), and applied structured questionnaires to 150 patients who initiated HAART between January 2010 and August 2011. Late HAART initiation (LHI) was considered when patients started HAART with CD4 counts of <200+ cells/mm³. By multivariate analysis, the strongest psychosocial risk factor for LHI observed was self-stigma towards HIV/AIDS. In addition, being tested by medical prescription, not by own initiative, as well as having one or more previous medical contacts, were associated with greater risk for LH. Our findings suggest the need to develop psychosocial interventions to decrease negative self-image and stigmatizing attitudes and behaviors in risk groups for HIV in Mexico.

Bipolar Transfer of Latissimus Dorsi Myocutaneous Flap for Restoration of Elbow Flexion in Late Traumatic Brachial Plexus Injury: Evaluation of 13 Cases.

PubMed

Azab, Ahmed Abo-Hashem; Alsabbahi, Mohammad Salah

2017-02-01

Restoration of elbow flexion following traumatic brachial plexus injury represents a great challenge to the reconstructive surgeons. Functional muscle transfers come next to the sophisticated types of nerve surgery in this area. Many transfers are well known for restoration of elbow flexion; bipolar or unipolar latissimus dorsi, triceps brachii, sternocleidomastoid, pectoralis major, and Steindler flexorplasty. Evaluation of the outcome of bipolar transfer of latissimus dorsi myocutaneous flap when used to restore elbow flexion in late traumatic brachial plexus injury. Thirteen patients were included in this case series with careful evaluation both preoperatively and postoperatively both clinically and using electromyography. Almost 84.6% of patients (11 of 13) developed G3-4 on the Medical Research Council grading with relatively minimal both donor-site and recipient-site morbidity. Bipolar transfer of latissimus dorsi myocutaneous flap is a reliable method for restoration of elbow flexion in patients suffering from late sequelae of traumatic brachial plexus injury.

Percutaneous Repair of Postoperative Mitral Regurgitation After Left Ventricular Assist Device Implant.

PubMed

Cork, David P; Adamson, Robert; Gollapudi, Raghava; Dembitsky, Walter; Jaski, Brian

2018-02-01

Mitral regurgitation commonly improves after implantation of a left ventricular assist device without concomitant valvular repair owing to the mechanical unloading of the left ventricle. However, the development (or persistence) of significant mitral regurgitation after implantation of a left ventricular assist device is associated with adverse clinical events. We present a case of a left ventricular assist device patient who successfully underwent a percutaneous MitraClip procedure for repair of persistent late postoperative mitral insufficiency with demonstrable clinical and hemodynamic improvement. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

[Advances in the research of scar stricture after esophageal burn].

PubMed

Zhao, Shi-lei; Gu, Chun-dong

2013-10-01

Caustic esophageal burn is a common ailment in clinical practice. In some patients, scar stricture was formed in the late stage of injury, and it seriously undermined quality of life of the patients. We adopted various clinical interventions at an early stage in order to relieve and alleviate the formation and development of corrosive esophageal stricture as a result of chemical injury as well as to avoid invasive operations to make it more acceptable for the patients. This article summarized the progress in etiology, pathological changes, identification, early prevention, and surgical management of corrosive esophageal stricture.

Neuropsychiatric manifestations in late-onset urea cycle disorder patients.

PubMed

Serrano, Mercedes; Martins, Cecilia; Pérez-Dueñas, Belén; Gómez-López, Lilian; Murgui, Empar; Fons, Carmen; García-Cazorla, Angels; Artuch, Rafael; Jara, Fernando; Arranz, José A; Häberle, Johannes; Briones, Paz; Campistol, Jaume; Pineda, Mercedes; Vilaseca, Maria A

2010-03-01

Inherited urea cycle disorders represent one of the most common groups of inborn errors of metabolism. Late-onset urea cycle disorders caused by partial enzyme deficiencies may present with unexpected clinical phenotypes. We report 9 patients followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity disorder [ADHD], language disorder, and delirium). Generally, these clinical pictures did not benefit from pharmacological treatment. Conversely, dietary treatment improved the symptoms. Regarding biochemical data, 2 patients showed normal ammonium but high glutamine levels. This study highlights the fact that neuropsychiatric/neurodevelopmental findings are common among the initial symptomatology of late-onset urea cycle disorders. The authors recommend that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.

Multiscale mechanistic modeling in pharmaceutical research and development.

PubMed

Kuepfer, Lars; Lippert, Jörg; Eissing, Thomas

2012-01-01

Discontinuation of drug development projects due to lack of efficacy or adverse events is one of the main cost drivers in pharmaceutical research and development (R&D). Investments have to be written-off and contribute to the total costs of a successful drug candidate receiving marketing authorization and allowing return on invest. A vital risk for pharmaceutical innovator companies is late stage clinical failure since costs for individual clinical trials may exceed the one billion Euro threshold. To guide investment decisions and to safeguard maximum medical benefit and safety for patients recruited in clinical trials, it is therefore essential to understand the clinical consequences of all information and data generated. The complexity of the physiological and pathophysiological processes and the sheer amount of information available overcharge the mental capacity of any human being and prevent a prediction of the success in clinical development. A rigorous integration of knowledge, assumption, and experimental data into computational models promises a significant improvement of the rationalization of decision making in pharmaceutical industry. We here give an overview of the current status of modeling and simulation in pharmaceutical R&D and outline the perspectives of more recent developments in mechanistic modeling. Specific modeling approaches for different biological scales ranging from intracellular processes to whole organism physiology are introduced and an example for integrative multiscale modeling of therapeutic efficiency in clinical oncology trials is showcased.

Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty.

PubMed Central

Tanner, J M; Whitehouse, R H

1976-01-01

New charts for height, weight, height velocity, and weight velocity are presented for clinical (as opposed to population survey) use. They are based on longitudinal-type growth curves, using the same data as in the British 1965 growth standards. In the velocity standards centiles are given for children who are early- and late-maturing as well as for those who mature at the average age (thus extending the use of the previous charts). Limits of normality for the age of occurrence of the adolescent growth spurt are given and also for the successive stages of penis, testes, and pubic hair development in boys, and for stages of breast and pubic hair development in girls. PMID:952550

CURRENT CONCEPTS OF PLYOMETRIC EXERCISE.

PubMed

Davies, George; Riemann, Bryan L; Manske, Robert

2015-11-01

As knowledge regarding rehabilitation science continues to increase, exercise programs following musculoskeletal athletic injury continue to evolve. Rehabilitation programs have drastically changed, especially in the terminal phases of rehabilitation, which include performance enhancement, development of power, and a safe return to activity. Plyometric exercise has become an integral component of late phase rehabilitation as the patient nears return to activity. Among the numerous types of available exercises, plyometrics assist in the development of power, a foundation from which the athlete can refine the skills of their sport. Therefore, the purpose of this clinical commentary is to provide an overview of plyometrics including: definition, phases, the physiological, mechanical and neurophysiological basis of plyometrics, and to describe clinical guidelines and contraindications for implementing plyometric programs.

[Is late-onset schizophrenia related to neurodegenerative processes? A review of literature].

PubMed

Lagodka, A; Robert, P

2009-09-01

Since 1943 when, for the first time, M. Bleuler used the term late-onset schizophrenia (LOS) to refer to diagnostic groups gathering some clinical features of schizophrenia, but with onset after the age of 40, opinions on this entity are divided. The main question is whether LOS and schizophrenia, with onset in early adulthood (early-onset schizophrenia EOS), have the same etiopathogeny. This discussion became more complex with the introduction, in 2000, of a new entity, the "very-late-onset schizophrenia-like psychosis" (VLOSP), which took the place of "late paraphrenia" and grouped together schizophrenia, delusional disorders and paranoid psychosis with age of onset after 60 years. Neuropathological processes underlying these entities have not beed determined. In particular, neurodegenerative processes could be explored. A literature review between 1 January 1995 and 30 April 2008, based on a research on PubMed with the terms "late-onset schizophrenia", "paraphrenia", "late paraphrenia", "VLOSP", and "late psychosis", takes stock of the various studies and hypotheses which have investigated the link between LOS/VLOSP and neurodegenerative processes. Clinical approach: there is no greater family history of dementia disorders in LOS/VLOSP than in the general population. Neuropsychological pattern between LOS and Alzheimer's disease (AD) seems different, with more impairment in delayed recall in AD, and in short-term memory in LOS. Some longitudinal studies, however, have argued that a part of patients with LOS would develop dementia at 10 years. These patients would have a later onset of disorders (> 60 years). Anatomopathological approach: anatomopathological studies show that LOS is not consecutive to AD, and might be related to a restricted limbic tauopathy. Neuroimaging approach: Magnetic Resonance Imaging (MRI) morphological neuroimaging studies show little differences between LOS and EOS. The thalamus volume was significantly smaller, and cortical atrophy was more important in LOS. MRI neuroimaging studies regarding white matter hyperintensities (WMH), which are considered as a macroscopic manifestation of cerebrovascular disease (CD), show inconsistent results. Positive results are observed with LOS subjects with later onset of disease. In addition, WMH were not located on cerebral tracts, which are implicated in EOS, but were periventricular. It is notable that the studies conducted do not differentiate between LOS and VLOSP, since these two groups of patients are generally mixed. Furthermore, an attempt to analyse the data has to take into account only the studies which have included subjects with strict criteria of schizophrenia, independently of the disorders' age of onset. In addition, we found no study comparing LOS and Lewy Bodies Dementia, which is however an important differential diagnosis. The two main hypotheses tested appear to be: (1): is LOS a prodrome of AD? (2): is LOS consecutive to CD? This review permits a partial answer to these questions. First, LOS as a prodrome of AD seems very unlikely, considering anatomopathological studies. However, it is possible that subjects with later age of onset of the disease develop dementia at 10 years. Second, CD seems not to be altered by the cerebral tracts which are implicated in EOS. A hypothesis could be that the tracts implicated in LOS and EOS differ. This might explain the differences found in clinical (less formal thought disorders and negative symptoms in LOS compared with EOS) and electroencephalographical studies (no reduction of P300's amplitude in LOS, which has however been proposed as trait marker of schizophrenia in EOS) between LOS and EOS. These tracts could be related to a limbic tauopathy found in anatomopathological studies. More vulnerable subjects would develop LOS with ageing. Other subjects would develop LOS secondary to CD. This could explain the later age of onset of the disease in these subjects.

Timing of Decompression in Patients With Acute Spinal Cord Injury: A Systematic Review

PubMed Central

Wilson, Jefferson R.; Tetreault, Lindsay A.; Kwon, Brian K.; Arnold, Paul M.; Mroz, Thomas E.; Shaffrey, Christopher; Harrop, James S.; Chapman, Jens R.; Casha, Steve; Skelly, Andrea C.; Holmer, Haley K.; Brodt, Erika D.; Fehlings, Michael G.

2017-01-01

Study Design: Systematic review. Objective: To conduct a systematic review and synthesis of the literature to assess the comparative effectiveness, safety, and cost-effectiveness of early (≤24 hours) versus late decompression (>24 hours) in adults with acute spinal cord injury (SCI). Methods: A systematic search was conducted of Medline, EMBASE, the Cochrane Collaboration Library, and Google Scholar to identify studies published through November 6, 2014. Studies published in any language, in humans, and with an abstract were considered for inclusion. Included studies were critically appraised and the overall strength of evidence was determined using methods proposed by the Grading of Recommendation Assessment, Development and Evaluation working group. Results: The search yielded 449 potentially relevant citations. Sixteen additional primary studies were identified through other sources. Six studies met inclusion criteria. All but 2 studies were considered to have moderately high risk of bias. Across studies and injury levels, the impact of early surgical decompression (≤24 hours) on clinically important improvement in neurological status was variable. Isolated studies reported statistically significant and clinically important improvements at 6 months (cervical injury, low strength of evidence) and following discharge from inpatient rehabilitation (all levels, very low strength of evidence) but not at other time points; another study observed a statistically significant 6 point improvement in ASIA Impairment Scale (AIS) among patients with AIS B, C, or D, but not for those with AIS A (very low strength of evidence). In one study of acute central cord syndrome without instability, a clinically and statistically meaningful improvement in total motor scores was reported at 6 and 12 months in patients treated early (versus late). There were, however, no significant differences in AIS improvement between early and late surgical groups at 6- or 12-months (very low strength of evidence). One of 3 studies found a shorter length of hospital stay associated with early surgical decompression. Of 3 studies reporting on safety, no significant differences in rates of complications (including mortality, neurologic deterioration, pneumonia or pressure ulcers) were noted between early and late decompression groups. Conclusions: Results surrounding the efficacy of early versus late decompressive surgery, as well as the quality of evidence available, were variable depending on the level of SCI, timing of follow-up, and specific outcome considered. Existing evidence supports improved neurological recovery among cervical SCI patients undergoing early surgery; however, evidence regarding remaining SCI populations and clinical outcomes was inconsistent. PMID:29164038

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics.

PubMed

Li, Zhaoyang; Easton, Rachael

2018-01-01

The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field.

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics

PubMed Central

Easton, Rachael

2018-01-01

ABSTRACT The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field. PMID:29035675

Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension

PubMed Central

Foss, Jason D.; Fink, Gregory D.

2015-01-01

Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼170 mmHg. RDNX reduced MAP ∼10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves. PMID:26661098

Rarity of late anastomotic leakage after low anterior resection of the rectum.

PubMed

Maeda, Hiromichi; Okamoto, Ken; Namikawa, Tsutomu; Akimori, Toyokazu; Kamioka, Norihito; Shiga, Mai; Dabanaka, Ken; Hanazaki, Kazuhiro; Kobayashi, Michiya

2015-06-01

Late anastomotic leakage is reported to account for half of all anastomotic leakages after low anterior resection of the rectum. An important clinical question is whether late and early anastomotic leakages are different entities. We retrospectively reviewed the medical records of patients who experienced anastomotic leakage after low anterior resection in two Japanese hospitals. The clinical characteristics were extracted and analyzed. During the study period, 179 patients underwent low anterior resection. A pelvic drainage tube was routinely utilized in all cases and was generally removed 4 to 6 days after the operation. Twenty-six patients had anastomotic leakage; the diagnosis was based on fecal contamination of the drainage in 24 cases. The median interval between operation and detection of anastomotic leakage was 3.5 days. Anastomotic leakage was diagnosed within 7 days of the operation in 25 cases and on postoperative day 20 (after hospital discharge) in one case. There was no instance of anastomotic leakage diagnosed more than 30 days after the operation. There was no relationship between clinical variables and days of leakage diagnosis. The rarity of late anastomotic leakage in our study, compared with previous studies, may relate to the relatively extended period of pelvic drainage tube usage in our institutes, which likely shortens the interval before leakage diagnosis. Our results suggest that late anastomotic leakage is a delayed symptom of subtle early anastomotic leakage rather than a separate entity.

Compound heterozygous mutations in electron transfer flavoprotein dehydrogenase identified in a young Chinese woman with late-onset glutaric aciduria type II.

PubMed

Xue, Ying; Zhou, Yun; Zhang, Keqin; Li, Ling; Kayoumu, Abudurexiti; Chen, Liye; Wang, Yuhui; Lu, Zhiqiang

2017-09-26

Glutaric aciduria type II (GA II) is an autosomal recessive disorder affecting fatty acid and amino acid metabolism. The late-onset form of GA II disorder is almost exclusively associated with mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Till now, the clinical features of late-onset GA II vary widely and pose a great challenge for diagnosis. The aim of the current study is to characterize the clinical phenotypes and genetic basis of a late-onset GAII patient. In this study, we described the clinical and biochemical manifestations of a 23-year-old female Chinese patient with late-onset GA II, and performed genomic DNA-based PCR amplifications and sequence analysis of ETFDH gene of the whole pedigree. We also used in-silicon tools to analyze the mutation and evaluated the pathogenicity of the mutation according to the criteria proposed by American College of Medical Genetics and Genomics (ACMG). The muscle biopsy of this patient revealed lipid storage myopathy. Blood biochemical test and urine organic acid analyses were consistent with GA II. Direct sequence analysis of the ETFDH gene (NM_004453) revealed compound heterozygous mutations: c.250G > A (p.A84T) on exon 3 and c.920C > G (p.S307C) on exon 8. Both mutations were classified as "pathogenic" according to ACMG criteria. In conclusion, our study described the phenotype and genotype of a late-onset GA II patient, reiterating the importance of ETFDH gene screening in these patients.

Reimagining the self at late-career transitions: how identity threat influences academic physicians' retirement considerations.

PubMed

Onyura, Betty; Bohnen, John; Wasylenki, Don; Jarvis, Anna; Giblon, Barney; Hyland, Robert; Silver, Ivan; Leslie, Karen

2015-06-01

There is scant empirical work exploring academic physicians' psychosocial adjustment during late-career transitions or on the factors that influence their retirement decisions. The authors examine these issues through the lens of sociopsychological identity theory, specifically examining how identity threat influences academic physicians' decisions about retirement. Participants were academic physicians at a Canadian medical school and were recruited via e-mail requests for clinical faculty interested in discussing late-career and retirement planning issues. Participants included 15 males and 6 females (N = 21; mean age = 63, standard deviation = 7.54), representing eight specialties (clinical and surgical). Data were collected in October and November 2012 via facilitated focus groups, which were digitally recorded, transcribed verbatim, and anonymized, then analyzed using thematic analysis. Four primary themes were identified: centrality of occupational identity, experiences of identity threat, experiences of aging in an indifferent system, and coping with late-career transitions. Identity threats were manifested in apprehensions about self-esteem after retirement, practice continuity, and clinical competence, as well as in a loss of meaning and belonging. These identity challenges influenced decisions on whether to retire. Organizational and system support was perceived as wanting. Coping strategies included reimagining and revaluing various aspects of the self through assimilating new activities and reprioritizing others. Identity-related struggles are a significant feature of academic physicians' considerations about late-career transitions. Understanding these challenges, their antecedents, and their consequences can prepare faculty, and their institutions, to better manage late-career transitions. Individual- and institution-level implications are discussed.

Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy.

PubMed

Singh, Anurag K; Lockett, Mary Ann; Bradley, Jeffrey D

2003-02-01

To evaluate the incidence and clinical/dosimetric predictors of acute and late Radiation Therapy Oncology Group Grade 3-5 esophageal toxicity in patients with non-small-cell lung cancer (NSCLC) treated with definitive three-dimensional conformal radiotherapy (3D-CRT). We retrospectively reviewed the charts of 207 consecutive patients with NSCLC who were treated with high-dose, definitive 3D-CRT between March 1991 and December 1998. This population consisted of 107 men and 100 women. The median age was 67 years (range 31-90). The following patient and treatment parameters were studied: age, gender, race, performance status, sequential chemotherapy, concurrent chemotherapy, presence of subcarinal nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy. All doses are reported without heterogeneity corrections. The median prescription dose to the isocenter in this population was 70 Gy (range 60-74) delivered in 2-Gy daily fractions. All patients were treated once daily. Acute and late esophageal toxicities were graded by Radiation Therapy Oncology Group criteria. Patient and clinical/dosimetric factors were coded and correlated with acute and late Grade 3-5 esophageal toxicity using univariate and multivariate regression analyses. Of 207 patients, 16 (8%) developed acute (10 patients) or late (13 patients) Grade 3-5 esophageal toxicity. Seven patients had both acute and late Grade 3-5 esophageal toxicity. One patient died (Grade 5 esophageal toxicity) of late esophageal perforation. Concurrent chemotherapy, maximal point dose to the esophagus >58 Gy, and a mean dose to the entire esophagus >34 Gy were significantly associated with a risk of Grade 3-5 esophageal toxicity on univariate analysis. Concurrent chemotherapy and maximal point dose to the esophagus >58 Gy retained significance on multivariate analysis. Of 207 patients, 53 (26%) received concurrent chemotherapy. Fourteen (88%) of the 16 patients who developed Grade 3-5 esophageal toxicity had received concurrent chemotherapy (p = 0.0001, Pearson's chi-square test). No case of Grade 3-5 esophageal toxicity occurred in patients who received a maximal point dose to the esophagus of <58 Gy (p = 0.0001, Fisher's exact test, two-tail). Only 2 patients developed Grade 3-5 esophageal toxicity in the absence of concurrent chemotherapy; both received a maximal esophageal point dose >69 Gy. All assessable patients who developed Grade 3-5 esophageal toxicity had a mean dose to the entire esophagus >34 Gy (p = 0.0351, Pearson's chi-square test). However, the mean dose was not predictive on multivariate analysis. Concurrent chemotherapy and the maximal esophageal point dose were significantly associated with a risk of Grade 3-5 esophageal toxicity in patients with NSCLC treated with high-dose 3D-CRT. In patients who received concurrent chemotherapy, the threshold maximal esophageal point dose for Grade 3-5 esophageal toxicity was 58 Gy. An insufficient number of patients developed Grade 3-5 esophageal toxicity in the absence of chemotherapy to allow a valid statistical analysis of the relationship between the maximal esophageal point dose and esophagitis.

Vascular depression consensus report - a critical update.

PubMed

Aizenstein, Howard J; Baskys, Andrius; Boldrini, Maura; Butters, Meryl A; Diniz, Breno S; Jaiswal, Manoj Kumar; Jellinger, Kurt A; Kruglov, Lev S; Meshandin, Ivan A; Mijajlovic, Milija D; Niklewski, Guenter; Pospos, Sarah; Raju, Keerthy; Richter, Kneginja; Steffens, David C; Taylor, Warren D; Tene, Oren

2016-11-03

Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5 th edition - a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term "MRI-defined vascular depression". This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal-subcortical-limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed. The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.

Preterm or not--an evaluation of estimates of gestational age in a cohort of women from Rural Papua New Guinea.

PubMed

Karl, Stephan; Li Wai Suen, Connie S N; Unger, Holger W; Ome-Kaius, Maria; Mola, Glen; White, Lisa; Wangnapi, Regina A; Rogerson, Stephen J; Mueller, Ivo

2015-01-01

Knowledge of accurate gestational age is required for comprehensive pregnancy care and is an essential component of research evaluating causes of preterm birth. In industrialised countries gestational age is determined with the help of fetal biometry in early pregnancy. Lack of ultrasound and late presentation to antenatal clinic limits this practice in low-resource settings. Instead, clinical estimators of gestational age are used, but their accuracy remains a matter of debate. In a cohort of 688 singleton pregnancies from rural Papua New Guinea, delivery gestational age was calculated from Ballard score, last menstrual period, symphysis-pubis fundal height at first visit and quickening as well as mid- and late pregnancy fetal biometry. Published models using sequential fundal height measurements and corrected last menstrual period to estimate gestational age were also tested. Novel linear models that combined clinical measurements for gestational age estimation were developed. Predictions were compared with the reference early pregnancy ultrasound (<25 gestational weeks) using correlation, regression and Bland-Altman analyses and ranked for their capability to predict preterm birth using the harmonic mean of recall and precision (F-measure). Average bias between reference ultrasound and clinical methods ranged from 0-11 days (95% confidence levels: 14-42 days). Preterm birth was best predicted by mid-pregnancy ultrasound (F-measure: 0.72), and neuromuscular Ballard score provided the least reliable preterm birth prediction (F-measure: 0.17). The best clinical methods to predict gestational age and preterm birth were last menstrual period and fundal height (F-measures 0.35). A linear model combining both measures improved prediction of preterm birth (F-measure: 0.58). Estimation of gestational age without ultrasound is prone to significant error. In the absence of ultrasound facilities, last menstrual period and fundal height are among the more reliable clinical measures. This study underlines the importance of strengthening ultrasound facilities and developing novel ways to estimate gestational age.

Enteric gram-negative bacilli bloodstream infections: 17 years' experience in a neonatal intensive care unit.

PubMed

Cordero, Leandro; Rau, Rachel; Taylor, David; Ayers, Leona W

2004-06-01

To assess the occurrence of enteric gram-negative bacilli (EGNB) bloodstream infections (BSI) in a neonatal intensive care setting during a 17-year period in which a consistent antibiotic treatment program was in place. To document infections, outbreaks, or epidemics, emergence of antibiotic resistance, clinical correlates, and outcomes of the most prevalent EGNB (Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae). This study analyzed demographic, clinical, and bacteriologic information from 360 infants born 1986-2002 who developed 633 blood culture-proven BSI. A total of 121 EGNB were isolated (E coli, K pneumoniae, and E cloacae). Early-onset BSI were discovered within 48 hours from birth, and late-onset BSI were those that occurred thereafter. Suspected early-onset BSI were treated with ampicillin and gentamicin, suspected late-onset BSI with vancomycin and gentamicin. Antibiotics were changed on the basis of organism antimicrobial susceptibility. Early-onset BSI were noted in 52 of 21,336 (244/100,000) live births (1986-1991), 40 of 20,402 (196/100,000) live births (1992-1997), and 25 of 17,926 (139/100,000) live births (1998-2002). Of these cases, 39 were caused by E coli and 4 by K pneumoniae. Antibiograms for E coli isolated during the last 5 years of the study showed an increase in antibiotic resistance that coincided with obstetric group B streptococcus antepartum antibiotic prophylaxis. Group B streptococcus declined from 41 to 4 cases from the first to the last period. Late-onset BSI increased from 111 to 230 cases from the first to the second 6-year study period and declined modestly (171 cases) during the last. Fifteen percent (78 cases) of late-onset BSI were caused by EGNB, 5% by other gram-negative bacilli, 67% primarily by coagulase-negative staphylococcus, and 13% by fungus. Nonspecific clinical and hematologic signs of late-onset BSI were similar across EGNB species, but necrotizing enterocolitis was often associated with E coli, whereas pneumonia and prolonged thrombocytopenia characterized K pneumoniae infections. No outbreaks or epidemics were observed, and strains of EGNB with evidence of extended spectrum beta-lactamase production were never isolated. Antepartum antibiotic prophylaxis may have increased antibiotic resistance in E coli isolates from early-onset BSI but has dramatically decreased group B streptococcus infections. Late-onset BSI caused by EGNB increased, but without changes in antibiotic susceptibility. In spite of medical advances, E coli, K pneumoniae, and E cloacae remain responsible for significant morbidity and mortality, especially in very low birth weight infants.

Novel drugs in clinical development for hepatocellular carcinoma.

PubMed

Waidmann, Oliver; Trojan, Jörg

2015-01-01

Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.

[Allogeneic hematopoietic stem cell transplantation using myeloablative conditioning including total body irradiation for pediatric acute lymphoblastic leukemia: a single-center retrospective analysis].

PubMed

Honda, Mamoru; Arakawa, Yuki; Kawakami, Ryota; Itabashi, Toshikazu; Yanagi, Masato; Sasaki, Koji; Watanabe, Kentaro; Isobe, Kiyotaka; Mori, Makiko; Hanada, Ryoji; Koh, Katsuyoshi

2018-01-01

This study aimed to investigate the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with total body irradiation-based myeloablative conditioning (TBI-MAC) in pediatric patients with acute lymphoblastic leukemia (ALL). We retrospectively examined patients with ALL who underwent HSCT with TBI-MAC from January 2000 to August 2016 at our institute. We enrolled 67 patients with a median follow-up period of 8 years. The 5-year event-free survival (EFS) and overall survival (OS) were 51.2% and 59.6%, respectively. At the first complete remission, HSCT exhibited significantly superior EFS and OS in our patients than that in patients with other diseases. We encountered 57.9% of patients with at least one late complication. Major late complications were short stature (26.3%) and hypogonadism (18.4%). While late complications were observed in several recipients of HSCT, late complication-related deaths occurred in three patients. The TBI-MAC regimen led to favorable clinical outcomes in pediatric patients with ALL who underwent HSCT. Thus, proper evaluation and management of late complications are mandatory.

Late presentation of canine nasal tumours in a UK referral hospital and treatment outcomes.

PubMed

Mason, S L; Maddox, T W; Lillis, S M; Blackwood, L

2013-07-01

To determine the computed tomographic stage of dogs with nasal tumours in a UK referral population, and whether stage, time to referral and treatment correlates with outcome. Retrospective review of clinical records and computed tomography scans of dogs with nasal tumours. Dogs (n=78) presented to a referral practice in the UK with suspected nasal tumours are presented with more late stage tumours than dogs in the USA and Japan. Length of time from initial presentation to referral did not correlate with tumour stage at diagnosis. Median survival times for radiotherapy-treated dogs in this population are equivalent to those previously reported for late stage nasal tumours. Dogs with nasal tumours are presented late in the course of disease in the North West of England. Dogs with clinical signs consistent with a nasal tumour should have timely imaging and biopsy, in order to make prompt treatment decisions. Although survival times are comparable with previous reports and radiotherapy is a valid treatment option for dogs with late stage disease, better outcomes are likely to be achievable with earlier treatment. © 2013 British Small Animal Veterinary Association.

Psychosocial Characteristics of Women with a Delayed Diagnosis of Turner Syndrome.

PubMed

Reimann, Gabrielle E; Bernad Perman, Martha M; Ho, Pei-Shu; Parks, Rebecca A; Comis, Leora E

2018-05-09

To characterize the psychosocial profiles of adult women diagnosed with Turner syndrome before (early diagnosis) and at or after (late diagnosis) 13 years of age. Women with Turner syndrome ages 22 and older at evaluation (n = 110) participated in a cross-sectional study at the National Institutes of Health. Researchers performed nonparametric and logistic regression analyses to assess early and late diagnosis cohorts on measures of depression, substance use, and perceptions of competence and identity. Of study participants, 47% received a Turner syndrome diagnosis at or after age 13 years. Median age at diagnosis was 12.0 years (range, 0-43). Covariate-adjusted models revealed that women with late diagnoses had an increased likelihood of developing mild to severe depressive symptoms (OR,  7.36) and a decreased likelihood of being perceived as competent (OR, 0.26). Women with a late diagnosis also exhibited more frequent substance use compared with women with early diagnoses. These data suggest that Turner syndrome diagnoses received at or after age 13 years may contribute to adverse outcomes related to depression, substance use, and perceptions of competence. Delayed Turner syndrome diagnoses may place women and girls at risk for negative psychosocial development extending into adulthood. These findings indicate it is important for pediatricians to evaluate psychosocial domains in girls with Turner syndrome regularly, particularly among those diagnosed at age 13 years or older. ClinicalTrials.gov: NCT00006334. Published by Elsevier Inc.

(Re)-wiring a brain with light: Clinical and visual processing findings after application of specific coloured glasses in patients with symptoms of a visual processing disorder (CVPD): Challenge of a possible new perspective?

PubMed

Friederichs, Edgar; Wahl, Siegfried

2017-08-01

The present investigation examined whether changes of electrophysiological late event related potential pattern could be used to reflect clinical changes from therapeutic intervention with coloured glasses in a group of patients with symptoms of central visual processing disorder. Subjects consisted of 13 patients with average age 16years (range 6-51years) with attention problems and learning disability, respectively. These patients were provided with specified coloured glasses which were required to be used during day time. Results indicated that specified coloured glasses significantly improved attention performance. Furthermore electrophysiological parameters revealed a significant change in the late event related potential distribution pattern (latency, amplitudes). This reflects a synchronization of together firing wired neural assemblies responsible for visual processing, suggesting an accelerated neuromaturation process when using coloured glasses. Our results suggest that the visual event related potentials measures are sensitive to changes in clinical development of patients with deficits of visual processing wearing appropriate coloured glasses. It will be discussed whether such a device might be useful for a clinical improvement of distraction symptoms caused by visual processing deficits. A model is presented explaining these effects by inducing the respiratory chain of the mitochondria such increasing the low energy levels of ATP of our patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Perspectives on the clinical development of immunotherapy in prostate cancer.

PubMed

Cordes, Lisa M; Gulley, James L; Madan, Ravi A

2018-01-01

Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. Sipuleucel-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.

Basic Reading Skills in Swedish Children with Late Developing Language and with or without Autism Spectrum Disorder or ADHD

ERIC Educational Resources Information Center

Miniscalco, Carmela; Sandberg, Annika Dahlgren

2010-01-01

Reading skills at age 7-8 years were examined in a community-representative sample of 21 screened and clinically examined children with language delay (LD) followed prospectively from 2.5 years of age. The present study aimed to (1) determine whether these children with a history of LD had deficits in basic reading skills, i.e. decoding and…

Fictional father?: Oliver Sacks and the revalidation of pathography.

PubMed

Hull, Andrew John

2013-12-01

This paper is a revalidation of Oliver Sacks's role in the development of medicine's narrative turn and, as such, a reinterpretation of the history of narrative in medicine. It suggests that, from the late 1960s, Sacks pioneered in his 'Romantic Science' a new medical mode that reunited the seemingly incommensurable art and science of medicine while also offering a way for medical humanities to shape clinical reasoning more effectively.

Health care informatics research implementation of the VA-DHCP Spanish version for Latin America.

PubMed Central

Samper, R.; Marin, C. J.; Ospina, J. A.; Varela, C. A.

1992-01-01

The VA DHCP, hospital computer program represents an integral solution to the complex clinical and administrative functions of any hospital world wide. Developed by the Department of Veterans Administration, it has until lately run exclusively in mainframe platforms. The recent implementation in PCs opens the opportunity for use in Latinamerica. Detailed description of the strategy for Spanish, local implementation in Colombia is made. PMID:1482994

Health care informatics research implementation of the VA-DHCP Spanish version for Latin America.

PubMed

Samper, R; Marin, C J; Ospina, J A; Varela, C A

1992-01-01

The VA DHCP, hospital computer program represents an integral solution to the complex clinical and administrative functions of any hospital world wide. Developed by the Department of Veterans Administration, it has until lately run exclusively in mainframe platforms. The recent implementation in PCs opens the opportunity for use in Latinamerica. Detailed description of the strategy for Spanish, local implementation in Colombia is made.

fMRI response during visual motion stimulation in patients with late whiplash syndrome.

PubMed

Freitag, P; Greenlee, M W; Wachter, K; Ettlin, T M; Radue, E W

2001-01-01

After whiplash trauma, up to one fourth of patients develop chronic symptoms including head and neck pain and cognitive disturbances. Resting perfusion single-photon-emission computed tomography (SPECT) found decreased temporoparietooccipital tracer uptake among these long-term symptomatic patients with late whiplash syndrome. As MT/MST (V5/V5a) are located in that area, this study addressed the question whether these patients show impairments in visual motion perception. We examined five symptomatic patients with late whiplash syndrome, five asymptomatic patients after whiplash trauma, and a control group of seven volunteers without the history of trauma. Tests for visual motion perception and functional magnetic resonance imaging (fMRI) measurements during visual motion stimulation were performed. Symptomatic patients showed a significant reduction in their ability to perceive coherent visual motion compared with controls, whereas the asymptomatic patients did not show this effect. fMRI activation was similar during random dot motion in all three groups, but was significantly decreased during coherent dot motion in the symptomatic patients compared with the other two groups. Reduced psychophysical motion performance and reduced fMRI responses in symptomatic patients with late whiplash syndrome both point to a functional impairment in cortical areas sensitive to coherent motion. Larger studies are needed to confirm these clinical and functional imaging results to provide a possible additional diagnostic criterion for the evaluation of patients with late whiplash syndrome.

Brain reserve hypothesis in dementia.

PubMed

Fratiglioni, Laura; Wang, Hui-Xin

2007-08-01

The concept of brain reserve refers to the ability to tolerate the age-related changes and the disease related pathology in the brain without developing clear clinical symptoms or signs. A considerable body of biological research has documented that a number of factors including education, work complexity, social network, and leisure activities may contribute to this reserve allowing cognitive function to be maintained in old ages. Epidemiological studies have also related these factors to the development of dementia, suggesting that intellectual challenges experienced across the whole life span may increase the brain reserve and be crucial for the occurrence of dementia symptoms in late life. This paper is a systematic review of the published epidemiological studies on this topic. The availability of numerous epidemiological and biological data investigating the reserve hypothesis in dementia permits some preliminary conclusions. High education, adult-life occupational work complexity, as well as a mentally and socially integrated lifestyle in late life could postpone the onset of clinical dementia and AD. The relevance of physical activity itself remains in debate, as most physical activities include also social and mental stimulation. Leisure activities with all three components--physical, mental and social--seem to have the most beneficial effect. Delaying dementia onset by five years would halve dementia prevalence and substantially decrease the number of dementia cases in the community.

Recommendations for Premature Ovarian Insufficiency Surveillance for Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Report From the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration With the PanCareSurFup Consortium.

PubMed

van Dorp, Wendy; Mulder, Renée L; Kremer, Leontien C M; Hudson, Melissa M; van den Heuvel-Eibrink, Marry M; van den Berg, Marleen H; Levine, Jennifer M; van Dulmen-den Broeder, Eline; di Iorgi, Natascia; Albanese, Assunta; Armenian, Saro H; Bhatia, Smita; Constine, Louis S; Corrias, Andreas; Deans, Rebecca; Dirksen, Uta; Gracia, Clarisa R; Hjorth, Lars; Kroon, Leah; Lambalk, Cornelis B; Landier, Wendy; Levitt, Gill; Leiper, Alison; Meacham, Lillian; Mussa, Alesandro; Neggers, Sebastian J; Oeffinger, Kevin C; Revelli, Alberto; van Santen, Hanneke M; Skinner, Roderick; Toogood, Andrew; Wallace, William H; Haupt, Riccardo

2016-10-01

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer. © 2016 by American Society of Clinical Oncology.

Nanoparticles for Retinal Gene Therapy

PubMed Central

Conley, Shannon M.; Naash, Muna I.

2010-01-01

Ocular gene therapy is becoming a well-established field. Viral gene therapies for the treatment of Leber’s congentinal amaurosis (LCA) are in clinical trials, and many other gene therapy approaches are being rapidly developed for application to diverse ophthalmic pathologies. Of late, development of non-viral gene therapies has been an area of intense focus and one technology, polymer-compacted DNA nanoparticles, is especially promising. However, development of pharmaceutically and clinically viable therapeutics depends not only on having an effective and safe vector but also on a practical treatment strategy. Inherited retinal pathologies are caused by mutations in over 220 genes, some of which contain over 200 individual disease-causing mutations, which are individually very rare. This review will focus on both the progress and future of nanoparticles and also on what will be required to make them relevant ocular pharmaceutics. PMID:20452457

Retrospective study on the characteristics and treatment of late-onset vitiligo.

PubMed

Kong, Yan Ling; Ching, Vanessa Hui Ling; Chuah, Sai Yee; Thng, Tien Guan

2017-01-01

Late-onset vitiligo, defined as being aged 50 years and above at the point of clinical onset, remains poorly characterized till now. This study aims to describe the clinical characteristics and treatment response of patients with late-onset vitiligo. We retrospectively reviewed the case records of all patients diagnosed with late-onset vitiligo, from January 1, 2010 to December 31, 2014. Information obtained included patient demographics, characteristics of vitiligo and treatment responses. Of the 3128 patients diagnosed with vitiligo over the 5-year period, 461 (14.7%) had late-onset disease. The study had more females (n = 260, 56.4%) than males, with an average onset age of 59.4 ± 7.4 years. Majority of patients were Chinese (n = 308, 66.8%) and 45 (9.8%) patients had an associated autoimmune disease. Focal vitiligo, defined as the localized presence of depigmented patches, was most common (n = 209, 45.3%). Treatment response was evaluated in 359 patients, of which 216 received monotherapy (topical creams: n = 210, 97.2%; phototherapy: n = 6, 2.8%) and 143 received both modalities. Fifty six (15.6%) patients received oral steroids. Patients who were treated with both topical creams and phototherapy yielded better clinical responses compared to those on monotherapy (P < 0.001) with 56.6% (n = 81) of them achieving good epidermal repigmentation, defined as >50% return of pigmentation compared to baseline (vs. n = 66, 30.6% in the monotherapy group). The choice of phototherapy (targeted, narrowband ultraviolet B or psoralen + ultraviolet A) did not significantly affect clinical response (P = 0.774). This study is limited by its retrospective nature, the nonstandardized documentation resulting in the inability to determine disease progression and associated metabolic comorbidities and also by the gradual loss to follow-up of patients. Late-onset vitiligo is not uncommon and tends to be of the focal vitiligo subtype. Nonsegmented vitiligo is more prevalent than segmental vitiligo. Combination therapy with topical medications and phototherapy is superior to monotherapy.

Clinical effects of laser immunotherapy on metastatic cancer patients

NASA Astrophysics Data System (ADS)

Naylor, Mark F.; Lam, Anh K.; Bahavar, Cody F.; Nordquist, Robert E.; Chen, Wei R.

2016-03-01

Clinical trials of late-stage breast cancer patients and late-stage melanoma patients treated by laser immunotherapy (LIT) have shown promising results. In a 2010 study of Li et al, eleven late-stage melanoma patients received LIT in one or multiple 6-week treatment cycles applied to a 200-cm2 treatment site, which usually contained multiple cutaneous metastases. Long-term, positive response was observed in six patients. All lesions in the treatment area of the patients responded to LIT, eight of which achieved complete local response (CLR). CLR was observed in the non-treatment site (regional) lesions in four patients. Five patients were still alive at the time of last follow-up. The probability of 12-month overall survival was 70%.2 In 2011, Li et al, treated ten late stage breast cancer patients with LIT.1 In 8 patients available for evaluation, the objective response rate was 62.5% and the clinical beneficial response rate was 75%.1 This review demonstrates that LIT is safe and well tolerated, so it can be easily applied on an outpatient basis and can be combined with other pharmaceutical modalities to improve the therapeutic response of metastatic cancers.

Early response to venlafaxine antidepressant correlates with lower ACTH levels prior to pharmacological treatment.

PubMed

Araya, A V; Rojas, P; Fritsch, R; Rojas, R; Herrera, L; Rojas, G; Gatica, H; Silva, H; Fiedler, J L

2006-12-01

A link between stressful life events and development or exacerbation of depression has been established via a large body of evidence. An alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression has also been associated with an increase in cortisol secretion. As arginine-vasopressin (AVP) plays an important role in the activation of HPA axis during stress, the present study investigated ACTH and cortisol secretory response induced by an AVP-related peptide desmopressin (ddAVP) in patients with major depression. Prior to antidepressant treatment, endocrinological parameters were evaluated and correlated with the clinical response to venlafaxine treatment, which offers a dual antidepressant action. Depressive patients with no other psychiatric pathology were evaluated with 17-item Hamilton Depression Scale (HAM-D) in order to follow-up the response to venlafaxine. After 1 wk of treatment, 60% of patients reduced their initial HAM-D score to at least 25%; this group was classified as early responders. The other group (40%) started to reduce significantly their HAM-D score after 3 wk of treatment and was classified as late responders. After 6 wk of treatment both groups have reduced HAM-D score to at least 25% of the baseline score. Prior to the pharmacological treatment, both early and late responders showed salivary cortisol rhythm and urinary free cortisol (UFC) in 24-h similar to healthy subjects. However, we did observe differences in basal ACTH secretion, showing that the late responder group had higher basal ACTH than both early responders and controls. The ddAVP challenge promoted a robust secretion of ACTH only in late responders, suggesting a different sensitivity of pituitary vasopressin receptor. The differences in clinical response to venlafaxine among depressive patients seem to be related to endocrinological parameters.

Intermittent Auscultation in Labor: Could It Be Missing Many Pathological (Late) Fetal Heart Rate Decelerations? Analytical Review and Rationale for Improvement Supported by Clinical Cases

PubMed Central

Sholapurkar, Shashikant L.

2015-01-01

Intermittent auscultation (IA) of fetal heart rate (FHR) is recommended/preferred in low risk labors. Its usage even in developed countries is poised to increase because of perceived benefit of reduction in operative intervention and some disillusionment with the cardiotocography (CTG). Many national guidelines have stipulated regimes (frequency/timing) of IA based on level IV evidence. These tend to get faithfully and exactingly followed. It was observed that deliveries of many unexpectedly asphyxiated infants occurred despite rigorously performed and documented IA compliant with the guidelines. This triggered a reappraisal of the robustness of IA leading to this focused review supplemented by two anonymized cases. It concludes that the current methodology of IA may be flawed in that it poses a risk of missing many or most late (pathological) FHR decelerations, one of the foremost goals of IA. This is because many late decelerations reach their nadir before the end of the contraction. Thus the currently recommended auscultation of FHR for 60 seconds after the contraction by all national guidelines seemed to encompass their “recovery” phase and appeared to be misinterpreted as normal FHR or even as a reassuring accelerative pattern in the clinical practice. A recent recommendation of recording of the FHR as a single figure (rather than a range) does not remedy this anomaly and seems even less informative. It would be better to auscultate FHR before and after the contractions (or contraction to contraction) and take the FHR just before the contraction as the baseline FHR and interpret the FHR after contraction in the context of this baseline. This relatively simple improvement would detect most late FHR decelerations thus ameliorating the risk and significantly enhancing the patient safety. PMID:26566404

Assessment of late cardiomyopathy by magnetic resonance imaging in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and idarubicin.

PubMed

Rodríguez-Veiga, Rebeca; Igual, Begoña; Montesinos, Pau; Tormo, Mar; Sayas, Mª José; Linares, Mariano; Fernández, José María; Salvador, Antonio; Maceira-González, Alicia; Estornell, Jordi; Calabuig, Marisa; Pedreño, María; Roig, Mónica; Sanz, Jaime; Sanz, Guillermo; Carretero, Carlos; Boluda, Blanca; Martínez-Cuadrón, David; Sanz, Miguel Ángel

2017-07-01

Late cardiomyopathy CMP is regarded as a potential severe long-term complication after anthracycline-based regimens for acute promyelocitic leukaemia (APL). We assess by MRI the incidence and severity of clinical and subclinical long-term CMP in a cohort of adult APL patients in first complete remission with PETHEMA trials. Adult patients diagnosed with APL in first complete remission lasting ≥2 years underwent anamnesis and physical examination and were asked to perform a cardiac MRI. Clinical CMP was defined as radiographic and physical signs of heart failure accompanied by symptoms or by left ventricle ejection fraction (LVEF) <45% by MRI with or without symptoms. Subclinical CMP was defined as the following MRI abnormalities: LVEF 45-50% or late gadolinium enhancement or two or more of LVEF ≤55%, left ventricle end-diastolic volume index ≥98 ml/m 2 , left ventricle end-systolic volume index ≥38 ml/m 2 , right ventricle end-diastolic volume index ≥106 ml/m 2 and regional wall motion abnormalities. Of the 82 patients enrolled in the study, median cumulative dose of anthracyclines (doxorubicin equivalence) was 650 mg/m 2 , and median time from APL diagnosis to the study was 87 months (range, 24-195). Seven out of 57 patients with available MRI (12%) had subclinical CMP (all of them showed late gadolinium enhancement in MRI), and none had clinical CMP. Among the 25 patients without MRI, none had CMP by chest X-ray and physical assessment. In summary, we found 12% of subclinical and no clinical late CMP assessed by MRI in APL patients treated with PETHEMA protocols. Due to the low number of patients, we must interpret our results cautiously.

Mechanism study of tumor-specific immune responses induced by laser immunotherapy

NASA Astrophysics Data System (ADS)

Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2011-03-01

Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration.

PubMed

Seo, Sang Won; Thibodeau, Marie-Pierre; Perry, David C; Hua, Alice; Sidhu, Manu; Sible, Isabel; Vargas, Jose Norberto S; Gaus, Stephanie E; Rabinovici, Gil D; Rankin, Katherine D; Boxer, Adam L; Kramer, Joel H; Rosen, Howard J; Gorno-Tempini, Maria Luisa; Grinberg, Lea T; Huang, Eric J; DeArmond, Stephen J; Trojanowski, John Q; Miller, Bruce L; Seeley, William W

2018-03-20

To examine clinicopathologic correlations in early vs late age at onset frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD). All patients were clinically evaluated and prospectively diagnosed at the UCSF Memory and Aging Center. Two consecutive series were included: (1) patients with a clinically diagnosed FTD syndrome who underwent autopsy (cohort 1) and (2) patients with a primary pathologic diagnosis of FTLD, regardless of the clinical syndrome (cohort 2). These series were divided by age at symptom onset (cutoff 65 years). In cohort 1, 48 (25.3%) were 65 years or older at symptom onset. Pathologic causes of behavioral variant FTD (bvFTD) were similar in the early age at onset (EO) and late age at onset (LO) bvFTD groups. In corticobasal syndrome (CBS), however, the most common pathologic substrate differed according to age at onset: progressive supranuclear palsy (42.9%) in LO-CBS and Alzheimer disease (AD; 40.7%) in EO-CBS. In cohort 2, 57 (28.4%) were classified as LO-FTLD. Regarding FTLD major molecular classes, FTLD with transactive response DNA-binding protein of 43 kDa was most common in EO-FTLD (44.4%), whereas FTLD-tau (58.3%) was most common in LO-FTLD. Antemortem diagnosis of a non-FTD syndrome, usually AD-type dementia, was more frequent in LO-FTLD than EO-FTLD (19.3% vs 7.7%, p = 0.017). LO-FTLD was also associated with more prevalent comorbid pathologic changes. Of these, moderate to severe AD neuropathologic change and argyrophilic grain disease were overrepresented among patients who received an antemortem diagnosis of AD-type dementia. Patients with FTD and FTLD often develop symptoms after age 65, and age at onset represents an important consideration when making antemortem neuropathologic predictions. © 2018 American Academy of Neurology.

Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism—UK Single Center Experience

PubMed Central

Rowczenio, Dorota M.; Gomes, Sónia Melo; Aróstegui, Juan I.; Mensa-Vilaro, Anna; Omoyinmi, Ebun; Trojer, Hadija; Baginska, Anna; Baroja-Mazo, Alberto; Pelegrin, Pablo; Savic, Sinisa; Lane, Thirusha; Williams, Rene; Brogan, Paul; Lachmann, Helen J.; Hawkins, Philip N.

2017-01-01

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as “mutation-negative.” We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients’ serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations. PMID:29163488

Antibodies to watch in 2018.

PubMed

Kaplon, Hélène; Reichert, Janice M

The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the 'Antibodies to watch' article series.

Antibodies to watch in 2018

PubMed Central

Kaplon, Hélène; Reichert, Janice M.

2018-01-01

ABSTRACT The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the ‘Antibodies to watch’ article series. PMID:29300693

[JUSTIFICATION OF USING EQUIVALENCE OF THE INDICES OF QUALITY, SAFETY, AND EFFICACY IN DEVELOPING BIOANALOGS].

PubMed

Niyazov, R R; Goryachev, D V; Gavrishina, E V; Romodanovskii, D P; Dranitsyna, M A

2015-01-01

We describe general principles of demonstrating biosimilarity, as well as selecting the biosimilarity margins. Any change in the structure of a biological molecule can modify its functional activity. Therefore, therapeutic equivalence between a biosimilar product and the corresponding reference product cannot be demonstrated using a single criterion. To demonstrate biosimilarity between two medicinal products, their various characteristics have to be evaluated which may, directly or indirectly, justify that clinically significant differences are absent. Insufficient understanding of 6ritical quality attributes brings a risk for the biosimilar product developer. This will either increase the number of non-clinical and clinical tests and trials needed or will result in awareness that the manufacturing process needs to be improved at the late stages of development, after investing significant resources in the development process. At the same time, the specification of the biological medicinal product cannot solely ensure safety and efficacy thereof. Properly characterized and controlled manufacturing process, which ensures consistency in its attributes not adequately controlled in specifications but influencing safety and efficacy profiles and showing their relevance in non-clinical tests and clinical trials, is an additional quality assurance factor. Justification of all development strategy details, including biosimilarity margins, has to be provided each time when the development process is initiated or when proceeding to the next steps. All problems encountered by the developer have to be resolved in close communication with the regulatory authority. In order to increase the quality of investigation and developer's adherence to good practices, clinical trial results should be published in detail.

Clinical evaluation and mutational analysis of GALK and GALE genes in patients with galactosemia in Greece: one novel mutation and two rare cases.

PubMed

Schulpis, Kleopatra H; Thodi, Georgia; Iakovou, Konstantinos; Chatzidaki, Maria; Dotsikas, Yannis; Molou, Elina; Triantafylli, Olga; Loukas, Yannis L

2017-07-26

Deficiencies of galactokinase (GALK) and UDP-epimerase (GALE) are implicated with galactose metabolic disorders. The aim of the study was the identification of mutations in GALK and GALE genes and clinical evaluation of patients. Five patients with GALK and five with GALE deficiency were picked up via the Neonatal Screening Program. Additionally, two females, 4 years old, were referred with late diagnosed galactosemia, as rare cases. Mutational analysis was conducted via Sanger sequencing, while in silico analysis tools were utilized for the novel mutation. Psychomotor and speech development tests were performed, as well. The mutation p.Pro28Thr was identified in both alleles in GALK-deficient patients of Roma (gypsy) origin, whereas the novel p.Asn39Ser was detected in two non-Roma patients. In GALE-deficient patients benign and/or likely benign mutations were found. Psychomotor and speech delay were determined in the Roma GALK patients. In each of the late diagnosed females, four mutations were identified in all galactosemia-related genes. The mutational spectrums of GALE- and GALK-deficient patients in Greece are presented for the first time along with a clinical evaluation. Mutational analysis in all galactosemia-related genes of symptomatic patients is highly recommended for future cases.

Clinical Characteristics and Outcomes of Late-Onset BK Virus Nephropathy in Kidney and Kidney-Pancreas Transplant Recipients.

PubMed

Imlay, Hannah; Whitaker, Kathryn; Fisher, Cynthia E; Limaye, Ajit P

2018-05-29

BK virus nephropathy (BKPyVAN) is a major complication in kidney transplant recipients (KTR) and typically occurs within 1 year of transplant. Guidelines vary in recommendations for BKPyV screening beyond 1 year. A systematic characterization of risk factors and outcomes of late-onset (>1 year) BKPyVAN has not previously been reported. We retrospectively compared characteristics and outcomes of early- (<1 year) and late-onset BKPyVAN (definitive [biopsy-confirmed] or presumptive [plasma BKPyV >10,000 copies/mL]) in a cohort of 671 KTR and simultaneous kidney-pancreas transplant (SPK) recipients between 2008 and 2013 at a single US transplant center. Proportions were compared using Chi square or Fisher's exact test with p < 0.05 considered significant. BKPyVAN was diagnosed in 96 (14.3%) patients (proven 16.7%, presumptive 83.3%): 79 (82.3%) early- and 17 (17.7%) late-onset. The proportion with late-onset BKPyVAN was significantly higher among SPK than KTR (4 of 7 [57.1%] vs 13 of 89 [14.6%], p=0.017). Late-onset represented "de novo" infection (no BKPyV detection within the first year) in 14 (82.4%) and progression of earlier lower-grade BKPyV reactivation in 3 (17.6%). Clinical outcomes were similar for early- and late-onset BKPyVAN (p>0.05 all comparisons). In a pooled analysis of prior studies of BKPyVAN in SPK recipients, 62.9% (17 of 27) were late-onset. A significant proportion of BKPyVAN is late-onset, especially among SPK recipients, and supports a longer duration of BKPyV monitoring for SPK recipients than recommended in some guidelines. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clinical and Microbiological Characterization of Late Breast Implant Infections after Reconstructive Breast Cancer Surgery.

PubMed

Franchelli, Simonetta; Pesce, Marianna; Savaia, Serena; Marchese, Anna; Barbieri, Ramona; Baldelli, Ilaria; De Maria, Andrea

2015-10-01

Implant infections represent a relevant problem after immediate breast cancer reconstruction. In addition to difficulties in distinguishing early infections from other post-surgical complications (such as hematoma, seroma, and liponecrosis) late breast implant infections still represent a grey area of our knowledge with regards to heir definition and management. To address this issue, we prospectively monitored breast cancer patients at their center. Between February 1, 2009, and May 31, 2013, we enrolled all patients undergoing breast implant reconstruction or expander-to-prosthesis substitution. Patients without at least 6 mo of post-operative observation were excluded. We collected data from patient records including age, days from surgery (DFS), chemotherapy/radiotherapy, infecting microorganism, type of implant, antibiotic management and eventual implant removal. Sixty days from surgery were defined as the clinical threshold between early and late infection. Infections were further classified according to a graded scale into possible, probable and microbiologically proved. Seventy-eight infections were recorded out of 766 surgical procedures (10.2%). Fifty-three (67%) cases occurred early ≤60 DFS, and 25 (33%) occurred late (i.e., beyond 60 d). By defining infection types as possible, probable or proved, the majority of late infections were classified as proved (84%) compared with 56% of early infections (p=0.0014). Microbiological isolate distribution was similar in proved early infections compared with proved late infections. Among late infections, a delayed occurrence was observed after prosthesis placement compared with expander insertion. Late infections were fraught with lower treatment success rates (12% vs. 41%, p=0.009). Late infection represents a consistent proportion of infections after immediate breast implant reconstruction or prosthesis placement and bear lower chance of salvage after treatment. An increased attention is warranted to improve prevention and treatment strategies.

The Acute and Chronic Effects of the Novel Anticonvulsant Lacosamide in an Experimental Model of Status Epilepticus

PubMed Central

Wasterlain, Claude G.; Stöhr, Thomas; Matagne, Alain

2011-01-01

The effective management of status epilepticus (SE) continues to be a therapeutic challenge. The aim of this study was to investigate the efficacy of lacosamide treatment in an experimental model of self-sustaining SE. Rats were treated with lacosamide (3, 10, 30 or 50 mg/kg) either 10 minutes (early treatment) or 40 minutes (late treatment) after the initiation of perforant path stimulation. Early lacosamide treatment significantly and dose-dependently reduced acute SE seizure activity; late treatment showed only a non-significant trend towards reduced seizure activity. Early lacosamide treatment also dose-dependently reduced the number of spontaneous recurrent seizures following a 6-week waiting period, with 70% reduction at the highest dose tested (50 mg/kg); there was also a significant reduction in the number of spikes and the cumulative time spent in seizures. Late treatment with high-dose lacosamide (30–50 mg/kg) reduced the number of animals that developed spontaneous recurrent seizures (33% vs 100% in controls, P <0.05), but did not significantly reduce seizure severity or frequency in rats that developed spontaneous recurrent seizures.. The results presented here suggest that lacosamide deserves investigation for the clinical treatment of SE. Potential for disease modification in this rat model of self-sustaining SE will require further studies. PMID:21277168

Posttraumatic syringomyelia associated with heavy weightlifting exercises: case report.

PubMed

Balmaseda, M T; Wunder, J A; Gordon, C; Cannell, C D

1988-11-01

Posttraumatic syringomyelia is a well-recognized late sequel to spinal trauma occurring in 1% to 3.2% of spinal cord injured patients. Its clinical presentation is usually marked by pain, ascending sensory loss, increased muscle weakness, and depressed deep tendon reflexes. The case of a 25-year-old man with C8 complete quadriplegia, who developed a syrinx five years after his initial injury, is presented. This patient kept a log of his daily physical workout which consisted of lifting weights of 50 to 60 pounds with his neck extensors and biceps. The diagnosis was made clinically and confirmed by magnetic resonance imaging. Repeated valsalva maneuvers from daily heavy weightlifting exercises most likely predisposed this patient to the development and extension of his syringomyelia. Dramatic improvement followed surgical placement of a subarachnoid shunt.

Why is intravenous chemotherapy cancelled and how often. Could it be prevented? A prospective analysis of all planned and given intravenous anti-tumor treatments at the Department of Oncology, Karolinska University Hospital, Stockholm during one month.

PubMed

Fuentes, Stina; Frödin, Jan-Erik

2015-07-01

Chemotherapy and targeted drugs are important tools in the treatment of malignant diseases. A number of the planned treatments are cancelled late which is a great challenge for the clinic to minimize in order to prevent the risk for misused resources. The aim of this study was to analyze the frequency and reasons for late (<48 hours) cancellations and also to get an overview of all intravenous medical anti-cancer treatment at the clinic. During four weeks in October 2010 all patients with intravenously administered chemotherapy and/or targeted drugs were registered at the Department of Oncology, Karolinska University Hospital. The survey comprehends the vast majority of all such treatment for solid tumors in adult patients in the Stockholm region with two million inhabitants. All bookings and late cancellations including their reasons were recorded. Diagnoses, treatment indication, line of treatment and survival, in particular short term survival, were analyzed. Almost 3000 bookings for 1460 patients were included and 13% were cancelled late. Patient detoriation was the dominating cause for late cancellation in patients with palliative treatment (59%), while hematological toxicity was most common in the adjuvant group (42%). The most common treatment indication was palliative (62%). Of the palliative treatments, 95% where given in the first to third treatment line. Breast cancer (31.9%) and colorectal cancer (29.9%) were the two most common diagnoses. Seventy-one patients (4.9%) died within two months after the treatment. A more careful selection and monitoring of the patients might reduce the number of late cancellations due to patient detoriation. To record performance status (PS) as a routine for all patients might be helpful in that process. If the number of late cancellations could be reduced, resources at the clinic could be used more efficiently.

Hidden flexion injury of the cervical spine.

PubMed

Webb, J K; Broughton, R B; McSweeney, T; Park, W M

1976-08-01

This paper describes seven patients who developed late vertebral deformity after flexion injuries of the cervical spine. In four the clinical and radiological features were subtle and because the patients walked into an emergency department the severity of the injury was not initially appreciated. Certain specific clinical and radiological features of flexion injury are described and emphasis is placed on the importance of correct management. A radiological tetrad is described which should alert the surgeon to the possibility of damage to the posterior interspinous complex of the cervical spine and so lead to further radiological investigations. Despite the frequency of flexion injuries the alarming complications described in this paper are rare.

Psychiatric mental health evidence-based practice.

PubMed

Rice, Michael J

2008-05-01

This article is the first in a new column focusing on evidence-based practice (EBP) in psychiatric mental health nursing. The EBP movement was strongly influenced by a British epidemiologist, Dr. Cochrane, who advocated care based on randomized clinical controlled trials in the late 1900s. Although the majority of the EBP movement is directed toward developing clinical guidelines, the critical element focuses on the therapeutic relationship and clinical judgment associated with providing care. This column will address a clinical problem, define PICO questions, report knowledge base searches, and present existing evidence. Recommendations will be offered for potential interventions and suggestions for evaluating clinical outcomes. Nurses can no longer view clinical studies as academic exercises discarded on graduation and not applied to the clinical setting. Conscientiously applying what is known about treatments and interventions of ethical, if not legal, value is consistent with the professional definition of care. J Am Psychiatr Nurses Assoc, 2008; 14(2), 107-111. DOI: 10.1177/1078390308315798.

Shared governance in a clinic system.

PubMed

Meyers, Michelle M; Costanzo, Cindy

2015-01-01

Shared governance in health care empowers nurses to share in the decision-making process, which results in decentralized management and collective accountability. Share governance practices have been present in hospitals since the late 1970s. However, shared governance in ambulatory care clinics has not been well established. The subjects of this quality project included staff and administrative nurses in a clinic system. The stakeholder committee chose what model of shared governance to implement and educated clinic staff. The Index of Professional Nursing Governance measured a shared governance score pre- and postimplementation of the Clinic Nursing Council. The Clinic Nursing Council met bimonthly for 3 months during this project to discuss issues and make decisions related to nursing staff. The Index of Professional Nursing Governance scores indicated traditional governance pre- and postimplementation of the Clinic Nursing Council, which is to be expected. The stakeholder committee was beneficial to the initial implementation process and facilitated staff nurse involvement. Shared governance is an evolutionary process that develops empowered nurses and nurse leaders.

Current State of Bioabsorbable Polymer-Coated Drug-Eluting Stents

PubMed Central

Akinapelli, Abhilash; Chen, Jack P.; Roy, Kristine; Donnelly, Joseph; Dawkins, Keith; Huibregtse, Barbara; Hou, Dongming

2017-01-01

Drug-eluting stents (DES) have been shown to significantly reduce clinical and angiograph-ic restenosis compared to bare metal stents (BMS). The polymer coatings on DES elute antiproliferative drugs to inhibit intimal proliferation and prevent restenosis after stent implantation. Permanent poly-mers which do not degrade in vivo may increase the likelihood of stent-related delayed arterial healing or polymer hypersensitivity. In turn, these limitations may contribute to an increased risk of late clinical events. Intuitively, a polymer which degrades after completion of drug release, leaving an inert metal scaffold in place, may improve arterial healing by removing a chronic source of inflammation, neoath-erosclerosis, and/or late thrombosis. In this way, a biodegradable polymer may reduce late ischemic events. Additionally, improved healing after stent implantation could reduce the requirement for long-term dual antiplatelet therapy and the associated risk of bleeding and cost. This review will focus on bioabsorbable polymer-coated DES currently being evaluated in clinical trials.

Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care.

PubMed

Apostolova, Liana G; Haider, Janelle M; Goukasian, Naira; Rabinovici, Gil D; Chételat, Gael; Ringman, John M; Kremen, Sarah; Grill, Joshua D; Restrepo, Lucas; Mendez, Mario F; Silverman, Daniel H

2016-01-01

The utility of the Appropriate Use Criteria (AUC) for amyloid imaging is not established. Fifty-three cognitively impaired patients with clinical F 18 -florbetapir imaging were classified as early and late onset, as well as AUC-consistent or AUC-inconsistent. Chi-square statistics and t test were used to compare demographic characteristics and clinical outcomes as appropriate. Early-onset patients were more likely to be amyloid positive. Change in diagnosis was more frequent in late-onset cases. Change in therapy was more common in early-onset cases. AUC-consistent and AUC-inconsistent cases had comparable rates of amyloid positivity. We saw no difference in the rate of treatment changes in the AUC-consistent group as opposed to the AUC-inconsistent group. The primary role of amyloid imaging in the early-onset group was to confirm the clinically suspected etiology, and in the late-onset group in detecting amyloid-negative cases. The rate of therapeutic changes was significantly greater in the early-onset cases.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goda, Jayant Sastri; Le, Lisa W.; Lapperriere, Normand J.

Purpose: To evaluate the clinical outcomes and late effects of radiation therapy (RT) in localized primary orbital mucosa-associated lymphoma tissue (MALT) lymphoma (POML). Methods and Materials: From 1989 to 2007, 89 patients with Stage IE POML received RT. The median age was 56 years old. Sites involved conjunctiva (59 patients [66%]), lacrimal gland (20 patients [23%]), and soft tissue (10 patients [11%]). Megavoltage beam(s) was used in 91%, electrons in 7%, and orthovoltage in 2% of cases. The dose given was 25 Gy in 97% and 30 Gy in 3% of patients. Lens shielding was possible in 57% of patients.more » Results: The median follow-up was 5.9 years. Complete response or unconfirmed complete response was seen in 88 patients (99%). Relapse occurred in 22 patients (25%). First relapse sites were local (2 patients [9%]), in the contralateral orbit (5 patients [23%]), and distant (15 patients [68%]). The 7-year overall survival (OS), cause-specific survival (CSS), relapse-free survival (RFS), and local control (LC) rates were 91%, 96%, 64%, and 97%, respectively. Radiation-related late sequelae were documented in 40 patients (45%). Cataracts were observed in 22 patients (Grade 1 in 2 patients; Grade 3 in 20 patients). The incidence of Grade 3 cataract at 7 years was 25%. Other late sequelae (n = 28) were dry eye(s) (22 patients [Grade 1 in 14 patients; Grade 2 in 2 patients; Grade 3 in 2 patients; n/s in 4 patients), keratitis (3 patients), macular degeneration/cystoid edema (2 patients), and vitreous detachment (1 patient). Five patients developed Grade 3 noncataract late effects. Lens shielding reduced the incidence of Grade 3 cataract and all Grade {>=}2 late sequelae. Seventeen patients (16 with cataracts) underwent surgery; 23 patients were treated conservatively. The outcome for managing late effects was generally successful, with 30 patients completely improved, and 9 patients with persisting late sequelae (10%). Conclusions: POML responds favorably to moderate doses of RT but results in significant late morbidity. The majority of late effects were successfully managed. Lens shielding reduced the risk of cataracts and other late sequelae.« less

Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience.

PubMed

Moreno, Lucas; Vaidya, Sucheta J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Machin, David; Pearson, Andrew D J

2013-07-01

Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial. Copyright © 2012 Wiley Periodicals, Inc.

Letter-sound processing deficits in children with developmental dyslexia: An ERP study.

PubMed

Moll, Kristina; Hasko, Sandra; Groth, Katharina; Bartling, Jürgen; Schulte-Körne, Gerd

2016-04-01

The time course during letter-sound processing was investigated in children with developmental dyslexia (DD) and typically developing (TD) children using electroencephalography. Thirty-eight children with DD and 25 TD children participated in a visual-auditory oddball paradigm. Event-related potentials (ERPs) elicited by standard and deviant stimuli in an early (100-190 ms) and late (560-750 ms) time window were analysed. In the early time window, ERPs elicited by the deviant stimulus were delayed and less left lateralized over fronto-temporal electrodes for children with DD compared to TD children. In the late time window, children with DD showed higher amplitudes extending more over right frontal electrodes. Longer latencies in the early time window and stronger right hemispheric activation in the late time window were associated with slower reading and naming speed. Additionally, stronger right hemispheric activation in the late time window correlated with poorer phonological awareness skills. Deficits in early stages of letter-sound processing influence later more explicit cognitive processes during letter-sound processing. Identifying the neurophysiological correlates of letter-sound processing and their relation to reading related skills provides insight into the degree of automaticity during letter-sound processing beyond behavioural measures of letter-sound-knowledge. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Investigational drugs for the treatment of endometriosis, an update on recent developments.

PubMed

Barra, Fabio; Scala, Carolina; Mais, Valerio; Guerriero, Stefano; Ferrero, Simone

2018-05-01

Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis. Areas covered: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents. Expert opinion: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human.

Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

PubMed

Webster, Lynn R

2007-08-01

Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

The role of fundus autofluorescence in late-onset retinitis pigmentosa (LORP) diagnosis.

PubMed

Lee, Tamara J; Hwang, John C; Chen, Royce W S; Lima, Luiz H; Wang, Nan-Kai; Tosi, Joaquin; Freund, K Bailey; Yannuzzi, Lawrence A; Tsang, Stephen H

2014-09-01

To demonstrate the utility and characteristics of fundus autofluorescence in late-onset retinitis pigmentosa. Observational case series. Patients diagnosed with late-onset retinitis pigmentosa were identified retrospectively in an institutional setting. Twelve eyes of six patients were identified and medical records were reviewed. All patients presented with slowly progressive peripheral field loss and initial clinical examination revealed only subtle retinal changes. There was a notable lack of intraretinal pigment migration in all patients. Five out of six patients underwent magnetic resonance imaging of the brain to rule out intracranial processes and all were referred from another ophthalmologist for further evaluation. Fundus autofluorescence was ultimately employed in all patients and revealed more extensive retinal pathology than initially appreciated on clinical examination. Fundus autofluorescence directed the workup toward a retinal etiology in all cases and led to the eventual diagnosis of late-onset retinitis pigmentosa through electroretinogram testing. Fundus autofluorescence may be a more sensitive marker for retinal pathology than stereo fundus biomicroscopy alone in late-onset retinitis pigmentosa. Early use of fundus autofluorescence imaging in the evaluation of patients with subtle retinal lesions and complaints of peripheral field loss may be an effective strategy for timely and cost-efficient diagnosis.

Issues in Research on Aging and Suicide

PubMed Central

Van Orden, Kimberly A.; Conwell, Yeates

2016-01-01

Late-life suicide is a complex clinical and public health problem. In this article, some of the key complexities inherent in studying late-life suicide are discussed in the service of promoting high quality late-life suicide prevention science. We discuss the following research issues: the relatively greater lethality of suicidal behavior in later life (compared to younger ages); the lack of data on whether thoughts of death in later life are indicators of suicide risk; the fact that older adults do not tend to seek specialty mental health care, necessitating moving research into primary care clinics and the community; the lack of theory-based research in late-life suicide; the unclear role of cognitive impairment; and the promise of taking a “patient centered” and “participatory research” approach to late-life suicide research efforts. We believe that these perspectives are too often not capitalized upon in research on suicide prevention with older adults and that voice of the older person could contribute much to our understanding of why older adults think about and act on suicidal thoughts, as well as the most acceptable ways to reach and intervene with those at risk. PMID:26179380

Evolution of a Multidisciplinary Clinical Pathway for the Management of Unstable Patients With Pelvic Fractures

PubMed Central

Biffl, Walter L.; Smith, Wade R.; Moore, Ernest E.; Gonzalez, Ricardo J.; Morgan, Steven J.; Hennessey, Theresa; Offner, Patrick J.; Ray, Charles E.; Franciose, Reginald J.; Burch, Jon M.

2001-01-01

Objective To determine whether the evolution of the authors’ clinical pathway for the treatment of hemodynamically compromised patients with pelvic fractures was associated with improved patient outcome. Summary Background Data Hemodynamically compromised patients with pelvic fractures present a complex challenge. The multidisciplinary trauma team must control hemorrhage, restore hemodynamics, and rapidly identify and treat associated life-threatening injuries. The authors developed a clinical pathway consisting of five primary elements: immediate trauma attending surgeon’s presence in the emergency department, early simultaneous transfusion of blood and coagulation factors, prompt diagnosis and management of associated life-threatening injuries, stabilization of the pelvic girdle, and timely insinuation of pelvic angiography and embolization. The addition of two orthopedic pelvic fracture specialists led to a revision of the pathway, emphasizing immediate emergency department presence of the orthopedic trauma attending to provide joint decision making with the trauma surgeon, closing the pelvic volume in the emergency department, and using alternatives to traditional external fixation devices. Methods Using trauma registry and blood bank records, the authors identified pelvic fracture patients receiving blood transfusions in the emergency department. They analyzed patients treated before versus after the May 1998 revision of the clinical pathway. Results A higher proportion of patients in the late period had blood pressure less than 90 mmHg (52% vs. 35%). In the late period, diagnostic peritoneal lavage was phased out in favor of torso ultrasound as a primary triage tool, and pelvic binding and C-clamp application largely replaced traditional external fixation devices. The overall death rate decreased from 31% in the early period to 15% in the later period, as did the rate of deaths from exsanguination (9% to 1%), multiple organ failure (12% to 1%), and death within 24 hours (16% to 5%). Conclusions The evolution of a multidisciplinary clinical pathway, coordinating the resources of a level 1 trauma center and directed by joint decision making between trauma surgeons and orthopedic traumatologists, has resulted in improved patient survival. The primary benefits appear to be in reducing early deaths from exsanguination and late deaths from multiple organ failure. PMID:11407336

Pediatric Hodgkin lymphoma: biomarkers, drugs, and clinical trials for translational science and medicine.

PubMed

Nagpal, Poonam; Akl, Mohamed R; Ayoub, Nehad M; Tomiyama, Tatsunari; Cousins, Tasheka; Tai, Betty; Carroll, Nicole; Nyrenda, Themba; Bhattacharyya, Pritish; Harris, Michael B; Goy, Andre; Pecora, Andrew; Suh, K Stephen

2016-10-11

Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

Vasomotor symptoms and cardiovascular events in postmenopausal women

PubMed Central

Szmuilowicz, Emily D.; Manson, JoAnn E.; Rossouw, Jacques E.; Howard, Barbara V.; Margolis, Karen L.; Greep, Nancy C.; Brzyski, Robert G.; Stefanick, Marcia L.; O'Sullivan, Mary Jo; Wu, Chunyuan; Allison, Matthew; Grobbee, Diederick E.; Johnson, Karen C.; Ockene, Judith K.; Rodriguez, Beatriz L.; Sarto, Gloria E.; Vitolins, Mara Z.; Seely, Ellen W.

2010-01-01

Objective Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS). Methods We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N=60,027): (1) No VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]); (2) VMS at menopause onset, but not at WHI-OS enrollment (early VMS); (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]); and (4) VMS at WHI-OS enrollment, but not at menopause onset (late VMS). Results For women with early VMS (N=24,753), compared to no VMS (N=18,799), hazard ratios (HRs) and 95% confidence intervals (CIs) in fully-adjusted models were: major CHD, 0.94 (0.84, 1.06); stroke, 0.83 (0.72, 0.96); total CVD, 0.89 (0.81, 0.97); and all-cause mortality, 0.92 (0.85, 0.99). For women with persistent VMS (N=15,084), there was no significant association with clinical events. For women with late VMS (N=1,391) compared to no VMS, HRs and 95% CIs were: major CHD, 1.32 (1.01, 1.71); stroke, 1.14 (0.82, 1.59); total CVD, 1.23 (1.00, 1.52); and all-cause mortality, 1.29 (1.08, 1.54). Conclusions Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from classical perimenopausal VMS. PMID:21358352

Clinical factors associated with failed trials of labor in late preterm and term twin pregnancies.

PubMed

Ko, Hyun-Joo; Jun, Jong Kwan

2014-07-01

To evaluate the perinatal outcomes and clinical factors of unsuccessful trials of labor (TOLs) in late preterm and term twin pregnancies. We enrolled 896 consecutive twin pregnancies delivered between 1999 and 2012 in a single center, which met the following inclusion criteria: a vertex first twin, live twins, and attempted TOLs after 34 weeks. Obstetric characteristics and perinatal outcomes were compared between vaginal delivery and cesarean delivery groups. Successful TOLs were carried out in 81% (726/896). Failed TOLs occurred in 15% (37/247) of late preterm twins and 20% (133/649) of term twins. Comparisons of neonatal outcomes between the groups showed no significant differences in NICU admission, ventilator use, and composite morbidity. On univariable analysis, nulliparity, preeclampsia, induced labor, excessive weight gain, and intertwin weight discordance of >30% showed significant associations with failed TOLs. Multivariable analyses revealed nulliparity (adjusted odds ratio 9.89, 95% confidence interval 4.64-21.1) and preeclampsia (adjusted odds ratio 2.17, 95% confidence interval 1.30-3.63) as significantly associated with failed TOLs. In late preterm and term twins, trials of labor can be performed successfully without a significant increase in adverse neonatal outcomes. Nulliparity and preeclampsia are clinical factors associated with failed TOLs in twin pregnancies.

Introducing universal ultrasound screening for developmental dysplasia of the hip doubled the treatment rate.

PubMed

Olsen, Stine F; Blom, Hans C; Rosendahl, Karen

2018-02-01

There is no evidence on the effect of universal ultrasound screening on developmental dysplasia of the hip. We examined the impact of adding an ultrasound examination to a one examiner clinical screening strategy on treatment, follow-up rates and the number of cases detected late in a low-prevalence population. All eligible babies born at Kongsberg Hospital, Norway, from 1998 to 2006 (n = 4245) underwent both clinical and ultrasound hip examinations within three days of life. Indications for immediate treatment were positive Barlow or Ortolani manoeuvres and, or, sonographic dysplasia. Sonographic immature hips were followed until normalisation. Treatment rates and rates from the 1989 to 1997 prestudy period (n = 3594), including late diagnoses, were collected from hospital records. Treatment was initiated in 90 (2.1%) infants (74 girls), 63 (70%) from birth, compared to 33 (0.9%) during the prestudy period. The follow-up rate did not change (11%). There were two (0.5/1000) and four (1.0/1000) cases detected late, respectively. No one underwent surgery during the first year of life and no avascular necrosis was seen. Adding universal ultrasound to clinical screening performed by the same, experienced paediatrician doubled the treatment rate, without influencing the already low numbers of late cases. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Early versus Late Parenteral Nutrition in Critically Ill Children.

PubMed

Fivez, Tom; Kerklaan, Dorian; Mesotten, Dieter; Verbruggen, Sascha; Wouters, Pieter J; Vanhorebeek, Ilse; Debaveye, Yves; Vlasselaers, Dirk; Desmet, Lars; Casaer, Michael P; Garcia Guerra, Gonzalo; Hanot, Jan; Joffe, Ari; Tibboel, Dick; Joosten, Koen; Van den Berghe, Greet

2016-03-24

Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear. We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided. Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006). In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.).

Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants.

PubMed

Ambalavanan, N; Aschner, J L

2016-06-01

While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.

Extended therapeutic window for post-exposure treatment of ricin intoxication conferred by the use of high-affinity antibodies.

PubMed

Noy-Porat, Tal; Alcalay, Ron; Epstein, Eyal; Sabo, Tamar; Kronman, Chanoch; Mazor, Ohad

2017-03-01

The plant toxin ricin is considered a potential bioterror agent against which there is no available antidote. To date, neutralizing antibodies are the most promising post-exposure treatment for ricin intoxication, yet so far they were shown to be effective only when given within several hours post exposure. As part of an ongoing effort to develop efficient ricin-countermeasures, we tested whether high-affinity antibodies that were previously isolated from immunized non-human primates, may confer effective post-exposure therapy for ricin-intoxicated mice treated at late time-points after exposure. While each antibody is capable of providing high protection rate by itself, a formulation consisting of three neutralizing antibodies that target different epitopes was tested to provide therapeutic coverage against different variants of the malicious pathogen. Indeed, the tri-antibody based cocktail was highly effective, its administration resulting in very high survival rates (>70%) when animals were treated as late as 48 h post exposure and significant protection (>30%) even at 72 h. This study establishes for the first time that anti-ricin antibodies can serve as a highly effective antidote at such late time-points after exposure. From the clinical point of view, the extended therapeutic window documented here is of high importance allowing adequate time to accurately identify the causative agent and may permit initiation of life-saving treatment with these antibodies even after the onset of clinical signs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of intellectual development of children following congenital, mildly symptomatic cytomegalovirus (CMV) infection. A prospective study.

PubMed

Milewska-Bobula, Bogumniła; Zebrowska, Joanna; Olszaniecka, Marzena; Pijanowska, Stefania; Radziszewska-Konopka, Marzanna; Lipka, Bozena

2010-01-01

Assessment of intellectual development of 6-year-old children following asymptomatic or mildly symptomatic congenital cytomegalovirus infection in infancy. A longitudinal, prospective cohort study concerning 38 (2%) children with congenital cytomegalovirus infection confirmed by specific serological and molecular tests, selected from the group of 1895 neonates preliminarily enrolled into the study. The first specialistic clinical assessment was performed during the neonatal and early infancy period, the second at the age of 12-18 months, and the final comprehensive clinical evaluation was carried out at the age of 6-6.5 years. Psychological evaluation showed normal mental development (Intelligence Quotient ranged from 88 to 114), but 12 (32%) children showed abnormalities in speech development and in 3 (8%) poor visual-motor integration was observed. Emotional and social functioning indicate a normal level of maturity, but 14 (37%) children exhibited increased emotional sensitivity. Psychological assessment indicate that 6 (16%) children may have problems with school maturity. Long-term follow-up of children with congenital cytomegalovirus infection is necessary, including those with a mild clinical course, in view of the possible late sequelae, especially concerning intellectual development and hearing impairment.

Pretreatment data is highly predictive of liver chemistry signals in clinical trials.

PubMed

Cai, Zhaohui; Bresell, Anders; Steinberg, Mark H; Silberg, Debra G; Furlong, Stephen T

2012-01-01

The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy's law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones.

Posttransplantation lymphoproliferative disorder in lung transplant recipients: a 15-year single institution experience.

PubMed

Muchtar, Eli; Kramer, Mordechai R; Vidal, Liat; Ram, Ron; Gurion, Ronit; Rosenblat, Yivgenia; Bakal, Ilana; Shpilberg, Ofer

2013-10-15

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication after solid-organ transplantation. Historically, most cases of PTLD among lung transplant recipients occurred within the first year from transplantation and were associated with Epstein-Barr virus (EBV) infection. However, there are increasing reports on a late-onset form of PTLD. We reviewed all charts of patients undergoing either lung or heart-lung transplantation in a tertiary transplantation center between the years 1997 and 2012 and compared clinical and pathologic parameters between early- and late-onset PTLD. Ten patients with PTLD were identified. Median (range) time from transplantation to PTLD diagnosis was 41 (4-128) months. Three patients developed early PTLD. All were pretransplantation EBV seronegative and asymptomatic when diagnosed during surveillance chest imaging. In contrast, the seven patients with late-onset PTLD were all EBV seropositive before transplantation and were symptomatic at diagnosis. Although early-onset PTLD uniformly involved the transplanted lung, this was relatively rare in late-onset PTLD (3 of 3 vs. 1 of 7). All patients were initially treated with reduction of immunosuppression, with at least one additional treatment modality used, mainly chemoimmunotherapy. Eight patients attained complete remission. With a median follow-up of 17 months, 8 patients died, mainly from treatment-related causes rather than disease progression. Our cohort of lung transplant recipients demonstrates a trend of late-onset PTLD with the majority of patients who died of treatment-related causes rather than disease progression. Therefore, substantial efforts should be focused on treatment-related mortality reduction.

Medical Informatics in Croatia – a Historical Survey

PubMed Central

Dezelic, Gjuro; Kern, Josipa; Petrovecki, Mladen; Ilakovac, Vesna; Hercigonja-Szekeres, Mira

2014-01-01

A historical survey of medical informatics (MI) in Croatia is presented from the beginnings in the late sixties of the 20th century to the present time. Described are MI projects, applications in clinical medicine and public health, start and development of MI research and education, beginnings of international cooperation, establishment of the Croatian Society for MI and its membership to EFMI and IMIA. The current status of computerization of the Croatian healthcare system is sketched as well as the present graduate and postgraduate study MI curricula. The information contained in the paper shows that MI in Croatia developed and still develops along with its advancement elsewhere. PMID:24648620

Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease.

PubMed

Chen, Fabian; Day, Sara L; Metcalfe, Russell A; Sethi, Gulshan; Kapembwa, Moses S; Brook, M Gary; Churchill, Duncan; de Ruiter, Annemiek; Robinson, Stephen; Lacey, Charles J; Weetman, Anthony P

2005-03-01

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies. Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.

Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: Normal tissue complication probability modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peeters, Stephanie; Hoogeman, Mischa S.; Heemsbergen, Wilma D.

2006-09-01

Purpose: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity. Methods and Materials: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifyingmore » factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used. Results: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence. Conclusions: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.« less

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.

PubMed

McNeel, Douglas G; Bander, Neil H; Beer, Tomasz M; Drake, Charles G; Fong, Lawrence; Harrelson, Stacey; Kantoff, Philip W; Madan, Ravi A; Oh, William K; Peace, David J; Petrylak, Daniel P; Porterfield, Hank; Sartor, Oliver; Shore, Neal D; Slovin, Susan F; Stein, Mark N; Vieweg, Johannes; Gulley, James L

2016-01-01

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly.

Clinical Experience in Late Antiquity: Alexander of Tralles and the Therapy of Epilepsy

PubMed Central

Bouras-vallianatos, Petros

2014-01-01

Alexander of Tralles, writing in the late sixth century, combined his wide-ranging practical knowledge with earlier medical theories. This article shows how clinical experience is used in Alexander’s works by concentrating on his therapeutic advice on epilepsy and, in particular, on pharmacology and the group of so-called natural remedies. I argue that clinical testing is used not only for the introduction of new medicines but also as an instrument for checking the therapeutic effect of popular healing practices. On another level, this article discusses Alexander’s role as the author of a medical compendium; it suggests that by marking the cases of clinical testing with a set of recurrent expressions, Alexander leads his audience to reflect on his medical authority and personal contribution. PMID:25045178

Direct percutaneous jejunostomy--an underutilized interventional technique?

PubMed

Sparrow, Patrick; David, Elizabeth; Pugash, Robyn

2008-01-01

Our aim in this study was to report our single-center experience with direct percutaneous jejunostomy over a 4-year period with regard to technical success rate, immediate and late complications, and patient tolerance of the procedure. Institutional records of 22 consecutive patients who underwent radiological insertion of a percutaneous jejunostomy for a variety of indications were reviewed. The proximal jejunum was punctured under either fluoroscopic or ultrasonic guidance, and following placement of retention sutures, a 10- to 12-Fr catheter inserted. There was a 100% technical success rate in placement involving a total of seven operators. The indications for placement were prior gastric resection, newly diagnosed resectable esophageal or gastric carcinoma, unresectable gastric carcinoma with outlet obstruction, and palliative drainage of bowel obstruction. Mean duration of follow-up was 100 days, and catheter placement 57.7 days. There were six minor early complications, consisting of loss of two retention anchors requiring repuncture, three cases of localized excessive postprocedural pain, and one failed relief of symptoms of small bowel obstruction. Four tubes developed late complications (two blocked, one catheter cracked, and one inadvertently pulled out). Three of the four were successfully replaced through the existing tracts. One patient subsequently developed a minor skin infection, while another developed late pericatheter leakage from ascites. We conclude that direct percutaneous jejunostomy is a valuable treatment modality applicable to a number of clinical scenarios, with a high technical success rate and low serious complication rate.

Benign Occipital Epilepsies of Childhood: Clinical Features and Genetics

ERIC Educational Resources Information Center

Taylor, Isabella; Berkovic, Samuel F.; Kivity, Sara; Scheffer, Ingrid E.

2008-01-01

The early and late benign occipital epilepsies of childhood (BOEC) are described as two discrete electro-clinical syndromes, eponymously known as Panayiotopoulos and Gastaut syndromes. Our aim was to explore the clinical features, classification and clinical genetics of these syndromes using twin and multiplex family studies to determine whether…

The clinical academic workforce in Australia and New Zealand: report on the second binational summit to implement a sustainable training pathway.

PubMed

Windsor, John; Garrod, Tamsin; Talley, Nicholas J; Tebbutt, Carmel; Churchill, James; Farmer, Elizabeth; Baur, Louise; Smith, Julian A

2017-04-01

There has been a decline in the proportion of clinical academics compared with full-time clinicians, since 2004. A Working Party was established to help develop and implement a model for the training of clinical academics. After a highly successful first summit in 2014 that summarised the challenges faced by clinical academics in Australia and New Zealand, a second summit was convened late in 2015 to report on progress and to identify key areas for further action. The second summit provided survey results that identified the varied training pathways currently offered to clinical academics and the institutions willing to be involved in developing improved pathways. A literature review also described the contributions that clinical academics make to the health sector and the challenges faced by this workforce sector. Current training pathways created for clinical academics by Australasian institutions were presented as examples of what can be done. The perspectives of government and research organisations presented at the summit helped define how key stakeholders can contribute. Following the summit, there was a strong commitment to continue to work towards developing a sustainable and defined training pathway for clinical academics. The need for a coordinated and integrated approach was highlighted. Some key objectives were agreed upon for the next phase, including identifying and engaging key advocates within government and leading institutions; publishing and profiling the contributions of successful clinical academics to healthcare outcomes; defining the stages of a clinical academic training pathway; and establishing a mentoring programme for training clinical academics. © 2017 Royal Australasian College of Physicians.

Risk factors for late-stage HIV disease presentation at initial HIV diagnosis in Durban, South Africa.

PubMed

Drain, Paul K; Losina, Elena; Parker, Gary; Giddy, Janet; Ross, Douglas; Katz, Jeffrey N; Coleman, Sharon M; Bogart, Laura M; Freedberg, Kenneth A; Walensky, Rochelle P; Bassett, Ingrid V

2013-01-01

After observing persistently low CD4 counts at initial HIV diagnosis in South Africa, we sought to determine risk factors for late-stage HIV disease presentation among adults. We surveyed adults prior to HIV testing at four outpatient clinics in Durban from August 2010 to November 2011. All HIV-infected adults were offered CD4 testing, and late-stage HIV disease was defined as a CD4 count <100 cells/mm(3). We used multivariate regression models to determine the effects of sex, emotional health, social support, distance from clinic, employment, perceived barriers to receiving healthcare, and foregoing healthcare to use money for food, clothing, or housing ("competing needs to healthcare") on presentation with late-stage HIV disease. Among 3,669 adults screened, 830 were enrolled, newly-diagnosed with HIV and obtained a CD4 result. Among those, 279 (33.6%) presented with late-stage HIV disease. In multivariate analyses, participants who lived ≥5 kilometers from the test site [adjusted odds ratio (AOR) 2.8, 95% CI 1.7-4.7], reported competing needs to healthcare (AOR 1.7, 95% CI 1.2-2.4), were male (AOR 1.7, 95% CI 1.2-2.3), worked outside the home (AOR 1.5, 95% CI 1.1-2.1), perceived health service delivery barriers (AOR 1.5, 95% CI 1.1-2.1), and/or had poor emotional health (AOR 1.4, 95% CI 1.0-1.9) had higher odds of late-stage HIV disease presentation. Independent risk factors for late-stage HIV disease presentation were from diverse domains, including geographic, economic, demographic, social, and psychosocial. These findings can inform various interventions, such as mobile testing or financial assistance, to reduce the risk of presentation with late-stage HIV disease.

Late-onset Rasmussen Encephalitis: A literature appraisal.

PubMed

Dupont, Sophie; Gales, Ana; Sammey, Serge; Vidailhet, Marie; Lambrecq, Virginie

2017-08-01

Rasmussen Encephalitis (RE) is classically described as a childhood encephalopathy due to a unilateral inflammation of the cerebral cortex with a presumed immune-mediated pathophysiological basis. Unusual variant forms, including adolescent and adult-onset RE have been described but there is still a doubt whether these atypical cases correspond to classical RE patients. To review evidence, a systematic PubMed search was conducted to retrieve papers addressing late onset RE to assess (i) the positivity rate of classical childhood-onset diagnostic criteria for RE in late-onset RE, (ii) the specific clinical and radiological features that could help earlier diagnosis and therapeutic interventions, (iii) the arguments for an autoimmune pathophysiology including (iiia) the association with autoimmune markers or diseases and (iiib) the effects of immunomodulatory or immunosuppressive treatments. A total of 50 papers were considered. We identified 102 late-onset RE patients with a sex ratio of 8 women for 2 men. 67% fulfilled the consensus diagnostic criteria for RE. As compared to classical RE, the late-onset RE patients exhibited: i) more frequent focal complex partial seizures, ii) less frequent epilepsia partialis continua throughout evolution, iii) a slower evolution with a delayed occurrence of cortical deficit, iv) less cognitive deterioration and v) a better outcome. A specific association with autoimmune markers or diseases was not found. Immunomodulatory therapies, even performed in a late stage, improved late-onset RE patients in 61% of cases. This review proves that late-onset RE is a reality with specific clinical and radiological features. The good response to immunomodulatory treatments brings further arguments for an immune-regulated process. Copyright © 2017 Elsevier B.V. All rights reserved.

Psychological distress, health and treatment-related factors among individuals initiating ART in Oromia, Ethiopia.

PubMed

Parcesepe, Angela M; Tymejczyk, Olga; Remien, Robert; Gadisa, Tsigereda; Kulkarni, Sarah Gorrell; Hoffman, Susie; Melaku, Zenebe; Elul, Batya; Nash, Denis

2018-03-01

HIV diagnosis may be a source of psychological distress. Late initiation of antiretroviral therapy (ART) and treatment-related beliefs may intensify psychological distress among those recently diagnosed. This analysis describes the prevalence of psychological distress among people living with HIV (PLWH) and examines the association of recent HIV diagnosis, late ART initiation and treatment-related beliefs with psychological distress. The sample includes 1175 PLWH aged 18 or older initiating ART at six HIV clinics in Ethiopia. Psychological distress was assessed with Kessler Psychological Distress Scale. Scores ≥ 29 were categorized as severe psychological distress. Individuals who received their first HIV diagnosis in the past 90 days were categorized as recently diagnosed. Multivariable logistic regression modeled the association of recent diagnosis, late ART initiation and treatment-related beliefs on severe psychological distress, controlling for age, sex, education, area of residence, relationship status, and health facility. Among respondents, 29.5% reported severe psychological distress, 46.6% were recently diagnosed and 31.0% initiated ART late. In multivariable models, relative to those who did not initiate ART late and had longer time since diagnosis, odds of severe psychological distress was significantly greater among those with recent diagnosis and late ART initiation (adjusted OR [aOR]: 1.9 [95% CI 1.4, 2.8]). Treatment-related beliefs were not associated with severe psychological distress in multivariable models. Severe psychological distress was highly prevalent, particularly among those who were recently diagnosed and initiated ART late. Greater understanding of the relationship between psychological distress, recent diagnosis, and late ART initiation can inform interventions to reduce psychological distress among this population. Mental health screening and interventions should be incorporated into routine HIV clinical care from diagnosis through treatment.

Pericoronitis: a reappraisal of its clinical and microbiologic aspects.

PubMed

Nitzan, D W; Tal, O; Sela, M N; Shteyer, A

1985-07-01

Pericoronitis is an infectious disease of the operculum overlying an erupting or semi-impacted tooth. It manifests itself mainly in late adolescence and young adulthood and nearly always occurs around the lower third molar. The distinctive location, age, clinical picture, and link with predisposing factors warranted a reappraisal of pericoronitis and its etiology. Spirochetes and fusobacteria proved prevalent at all stages of the disease. The presence of these microbacteria may provide a clue as to the late appearance, particular location, and singular clinical picture of pericoronitis. The fact that spirochetes and fusobacteria are also found in acute necrotizing ulcerative gingivitis, and have been associated with alveolar osteitis, indicates a possible relationship between these disorders and pericoronitis.

The clinical case for proton beam therapy

PubMed Central

2012-01-01

Abstract Over the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy. Summary sentence Proton beam therapy is a technically advanced and promising form of radiation therapy. PMID:23083010

Effects of cyclophosphamide on laser immunotherapy for the treatment of metastatic cancer

NASA Astrophysics Data System (ADS)

Bahavar, Cody F.; Acquaviva, Joseph T.; Rabei, Sheyla; Sikes, Allie; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2014-02-01

Laser immunotherapy (LIT) is an innovative cancer modality that uses laser irradiation and immunological stimulation to treat late-stage, metastatic cancers. The current mode of operation in LIT is through interstitial laser irradiation. Although LIT is still in development, recent clinical trials have shown that it can be used to successfully treat patients with late-stage breast cancer and melanoma. Cyclophosphamide is a chemotherapy drug that suppresses regulatory T cells when used in low doses. In this study tumor-bearing rats were treated with LIT using an 805-nm laser with a power of 2.0 W and low-dose cyclophosphamide. Glycated chitosan was used as an immunological stimulant. The goal was to observe the effects of different doses of cyclophosphamide in addition to LIT on the survival of the tumor-bearing rats.

Economics of new oncology drug development.

PubMed

DiMasi, Joseph A; Grabowski, Henry G

2007-01-10

Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.

Multiproteinopathy, neurodegeneration and old age: a case study.

PubMed

Rojas, Julio C; Stephens, Melanie L; Rabinovici, Gil D; Kramer, Joel H; Miller, Bruce L; Seeley, William W

2018-02-01

A complex spectrum of mixed brain pathologies is common in older people. This clinical pathologic conference case study illustrates the challenges of formulating clinicopathologic correlations in late-onset neurodegenerative diseases featuring cognitive-behavioral syndromes with underlying multiple proteinopathy. Studies on the co-existence and interactions of Alzheimer's disease (AD) with neurodegenerative non-AD pathologies in the aging brain are needed to understand the pathogenesis of neurodegeneration and to support the development of diagnostic biomarkers and therapies.

Multiproteinopathy, neurodegeneration and old age: a case study

PubMed Central

Rojas, Julio C.; Stephens, Melanie L.; Rabinovici, Gil D.; Kramer, Joel H.; Miller, Bruce L.; Seeley, William W.

2018-01-01

A complex spectrum of mixed brain pathologies is common in older people. This clinical pathologic conference case study illustrates the challenges of formulating clinicopathologic correlations in late-onset neurodegenerative diseases featuring cognitive-behavioral syndromes with underlying multiple proteinopathy. Studies on the co-existence and interactions of Alzheimer’s disease (AD) with neurodegenerative non-AD pathologies in the aging brain are needed to understand the pathogenesis of neurodegeneration and to support the development of diagnostic biomarkers and therapies. PMID:29307276

Operations research methods improve chemotherapy patient appointment scheduling.

PubMed

Santibáñez, Pablo; Aristizabal, Ruben; Puterman, Martin L; Chow, Vincent S; Huang, Wenhai; Kollmannsberger, Christian; Nordin, Travis; Runzer, Nancy; Tyldesley, Scott

2012-12-01

Clinical complexity, scheduling restrictions, and outdated manual booking processes resulted in frequent clerical rework, long waitlists for treatment, and late appointment notification for patients at a chemotherapy clinic in a large cancer center in British Columbia, Canada. A 17-month study was conducted to address booking, scheduling and workload issues and to develop, implement, and evaluate solutions. A review of scheduling practices included process observation and mapping, analysis of historical appointment data, creation of a new performance metric (final appointment notification lead time), and a baseline patient satisfaction survey. Process improvement involved discrete event simulation to evaluate alternative booking practice scenarios, development of an optimization-based scheduling tool to improve scheduling efficiency, and change management for implementation of process changes. Results were evaluated through analysis of appointment data, a follow-up patient survey, and staff surveys. Process review revealed a two-stage scheduling process. Long waitlists and late notification resulted from an inflexible first-stage process. The second-stage process was time consuming and tedious. After a revised, more flexible first-stage process and an automated second-stage process were implemented, the median percentage of appointments exceeding the final appointment notification lead time target of one week was reduced by 57% and median waitlist size decreased by 83%. Patient surveys confirmed increased satisfaction while staff feedback reported reduced stress levels. Significant operational improvements can be achieved through process redesign combined with operations research methods.

Factors influencing the development of early- or late-onset Parkinson's disease in a cohort of South African patients.

PubMed

van der Merwe, Celia; Haylett, William; Harvey, Justin; Lombard, Debbie; Bardien, Soraya; Carr, Jonathan

2012-10-01

Neurodegenerative disorders such as Parkinson's disease (PD) contribute significantly to global disease burden. PD can be categorised into early-onset PD (EOPD) with an age at onset (AAO) of ≤50 years and late-onset PD (LOPD) with an AAO of 50 years. To identify factors influencing EOPD and LOPD development in a group of patients in South Africa (SA). A total of 397 unrelated PD patients were recruited from the Movement Disorders Clinic at Tygerberg Hospital and via the Parkinson's Association of SA. Patient demographic and environmental data were recorded and associations with PD onset (EOPD v. LOPD) were analysed with a Pearson's Chi-squared test. The English- and Afrikaans-speaking (Afrikaner) white patients were analysed separately. Logistic regression analysis showed that ethnicity (p<0.001) and family history (p=0.004) were independently associated with AAO of PD. Average AAO was younger in black, coloured and Afrikaner patients than English-speaking white patients. A positive family history of PD, seen in 31.1% of LOPD patients, was associated with a younger AAO in the study population. These associations may be attributed to specific genetic and/or environmental risk factors that increase PD susceptibility and influence the clinical course of the disorder. More studies on PD in the unique SA populations are required to provide novel insights into mechanisms underlying this debilitating condition.

Pharmacological intervention of HIV-1 maturation.

PubMed

Wang, Dan; Lu, Wuxun; Li, Feng

2015-11-01

Despite significant advances in antiretroviral therapy, increasing drug resistance and toxicities observed among many of the current approved human immunodeficiency virus (HIV) drugs indicate a need for discovery and development of potent and safe antivirals with a novel mechanism of action. Maturation inhibitors (MIs) represent one such new class of HIV therapies. MIs inhibit a late step in the HIV-1 Gag processing cascade, causing defective core condensation and the release of non-infectious virus particles from infected cells, thus blocking the spread of the infection to new cells. Clinical proof-of-concept for the MIs was established with betulinic acid derived bevirimat, the prototype HIV-1 MI. Despite the discontinuation of its further clinical development in 2010 due to a lack of uniform patient response caused by naturally occurring drug resistance Gag polymorphisms, several second-generation MIs with improved activity against viruses exhibiting Gag polymorphism mediated resistance have been recently discovered and are under clinical evaluation in HIV/AID patients. In this review, current understanding of HIV-1 MIs is described and recent progress made toward elucidating the mechanism of action, target identification and development of second-generation MIs is reviewed.

Methylenetetrahydrofolate reductase and glutathione S-tranferase gene polymorphisms in secondary mixed phenotype acute leukemia: a case report.

PubMed

Skoric, Dejan; Ivana, Joksic; Tanja, Radic; Jovana, Jakovljevic; Petar, Ivanovski; Tatjana, Simic

2014-04-01

Therapy-induced leukemia is a well-known clinical syndrome occurring as a late complication in patients treated with cytotoxic therapy. We herein present results of analysis of common gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) genes in a 10-year-old boy who developed very rare type of cancer, mixed phenotype acute leukemia, 6 years after treatment of acute lymphoblastic leukemia. Impairment in function of GST and MTHFR enzymes found in our patient may have contributed to the development of secondary mixed phenotype acute leukemia, although precise mechanism remains elusive.

Vaginal rings for delivery of HIV microbicides

PubMed Central

Malcolm, R Karl; Fetherston, Susan M; McCoy, Clare F; Boyd, Peter; Major, Ian

2012-01-01

Following the successful development of long-acting steroid-releasing vaginal ring devices for the treatment of menopausal symptoms and contraception, there is now considerable interest in applying similar devices to the controlled release of microbicides against HIV. In this review article, the vaginal ring concept is first considered within the wider context of the early advances in controlled-release technology, before describing the various types of ring device available today. The remainder of the article highlights the key developments in HIV microbicide-releasing vaginal rings, with a particular focus on the dapivirine ring that is presently in late-stage clinical testing. PMID:23204872

Vaginal rings for delivery of HIV microbicides.

PubMed

Malcolm, R Karl; Fetherston, Susan M; McCoy, Clare F; Boyd, Peter; Major, Ian

2012-01-01

Following the successful development of long-acting steroid-releasing vaginal ring devices for the treatment of menopausal symptoms and contraception, there is now considerable interest in applying similar devices to the controlled release of microbicides against HIV. In this review article, the vaginal ring concept is first considered within the wider context of the early advances in controlled-release technology, before describing the various types of ring device available today. The remainder of the article highlights the key developments in HIV microbicide-releasing vaginal rings, with a particular focus on the dapivirine ring that is presently in late-stage clinical testing.

Early and late histamine release induced by albumin, hetastarch and polygeline: some unexpected findings.

PubMed

Celik, I; Duda, D; Stinner, B; Kimura, K; Gajek, H; Lorenz, W

2003-10-01

The perioperative use of colloidal plasma substitutes is still under discussion. We therefore conducted a prospective randomised study with three commonly used plasma substitutes to examine their histamine releasing effects in 21 volunteers. MATERIAL OR SUBJETS: 21 male volunteers were enrolled in this prospective, randomised, controlled clinical study. Endpoints were the incidence of early and late histamine release and the time course of the release kinetics. Normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6) and polygeline (n = 9). Measurement and observation period was 240 min after the start of the plasma substitute infusion. Heart rate, blood pressure, SaO(2), clinical symptoms/signs and plasma histamine were measured during the observation period. The incidence of histamine release over the whole observation period in all three groups was 100%. Histamine release occurred frequently in all three groups until 30 min (50%-78%) and up to 240 min (late release reaction: 67%-83%) after the start of infusion. Surprisingly even hydroxyethyl starch, which is regarded as a generally safe and effective plasma substitute, caused high incidences of late histamine release (67%). Histamine release is a well known side effect of polygeline and - to a lesser extent - also of albumin, but was a novel finding for hydroxyethyl starch. We demonstrated for the first time histamine releasing effects of hydroxyethyl starch over a long period of time after administration. This perioperatively and for intensive care possibly relevant finding should make clinicians aware of late side effects not yet connected with the clinical use of these colloidal plasma substitutes.

Can body temperature dysregulation explain the co-occurrence between overweight/obesity, sleep impairment, late-night eating, and a sedentary lifestyle?

PubMed

Brown, Rhonda F; Thorsteinsson, Einar B; Smithson, Michael; Birmingham, C Laird; Aljarallah, Hessah; Nolan, Christopher

2017-12-01

Overweight/obesity, sleep disturbance, night eating, and a sedentary lifestyle are common co-occurring problems. There is a tendency for them to co-occur together more often than they occur alone. In some cases, there is clarity as to the time course and evolution of the phenomena. However, specific mechanism(s) that are proposed to explain a single co-occurrence cannot fully explain the more generalized tendency to develop concurrent symptoms and/or disorders after developing one of the phenomena. Nor is there a clinical theory with any utility in explaining the development of co-occurring symptoms, disorders and behaviour and the mechanism(s) by which they occur. Thus, we propose a specific mechanism-dysregulation of core body temperature (CBT) that interferes with sleep onset-to explain the development of the concurrences. A detailed review of the literature related to CBT and the phenomena that can alter CBT or are altered by CBT is provided. Overweight/obesity, sleep disturbance and certain behaviour (e.g. late-night eating, sedentarism) were linked to elevated CBT, especially an elevated nocturnal CBT. A number of existing therapies including drugs (e.g. antidepressants), behavioural therapies (e.g. sleep restriction therapy) and bright light therapy can also reduce CBT. An elevation in nocturnal CBT that interferes with sleep onset can parsimoniously explain the development and perpetuation of common co-occurring symptoms, disorders and behaviour including overweight/obesity, sleep disturbance, late-night eating, and sedentarism. Nonetheless, a significant correlation between CBT and the above symptoms, disorders and behaviour does not necessarily imply causation. Thus, statistical and methodological issues of relevance to this enquiry are discussed including the likely presence of autocorrelation. Level V, narrative review.

Late Side Effects After Image Guided Intensity Modulated Radiation Therapy Compared to 3D-Conformal Radiation Therapy for Prostate Cancer: Results From 2 Prospective Cohorts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wortel, Ruud C.; Incrocci, Luca; Pos, Floris J.

Purpose: Technical developments in the field of external beam radiation therapy (RT) enabled the clinical introduction of image guided intensity modulated radiation therapy (IG-IMRT), which improved target conformity and allowed reduction of safety margins. Whether this had an impact on late toxicity levels compared to previously applied three-dimensional conformal radiation therapy (3D-CRT) is currently unknown. We analyzed late side effects after treatment with IG-IMRT or 3D-CRT, evaluating 2 prospective cohorts of men treated for localized prostate cancer to investigate the hypothesized reductions in toxicity. Methods and Materials: Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fractionsmore » were recruited from 2 Dutch randomized trials with identical toxicity scoring protocols. Late toxicity (>90 days after treatment) was derived from self-assessment questionnaires and case report forms, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG-EORTC) scoring criteria. Grade ≥2 endpoints included gastrointestinal (GI) rectal bleeding, increased stool frequency, discomfort, rectal incontinence, proctitis, and genitourinary (GU) obstruction, increased urinary frequency, nocturia, urinary incontinence, and dysuria. The Cox proportional hazards regression model was used to compare grade ≥2 toxicities between both techniques, adjusting for other modifying factors. Results: The 5-year cumulative incidence of grade ≥2 GI toxicity was 24.9% for IG-IMRT and 37.6% following 3D-CRT (adjusted hazard ratio [HR]: 0.59, P=.005), with significant reductions in proctitis (HR: 0.37, P=.047) and increased stool frequency (HR: 0.23, P<.001). GU grade ≥2 toxicity levels at 5 years were comparable with 46.2% and 36.4% following IG-IMRT and 3D-CRT, respectively (adjusted HR: 1.19, P=.33). Other strong predictors (P<.01) of grade ≥2 late toxicity were baseline complaints, acute toxicity, and age. Conclusions: Treatment with IG-IMRT reduced the risk of late grade ≥2 complications, whereas GU toxicities remained comparable. This clinically relevant observation demonstrates that IMRT and image-guidance should therefore be the preferred treatment option, provided that margin reduction is implemented with caution.« less

Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants.

PubMed

Morrow, Lindsey A; Wagner, Brandie D; Ingram, David A; Poindexter, Brenda B; Schibler, Kurt; Cotten, C Michael; Dagle, John; Sontag, Marci K; Mourani, Peter M; Abman, Steven H

2017-08-01

Mechanisms contributing to chronic lung disease after preterm birth are incompletely understood. To identify antenatal risk factors associated with increased risk for bronchopulmonary dysplasia (BPD) and respiratory disease during early childhood after preterm birth, we performed a prospective, longitudinal study of 587 preterm infants with gestational age less than 34 weeks and birth weights between 500 and 1,250 g. Data collected included perinatal information and assessments during the neonatal intensive care unit admission and longitudinal follow-up by questionnaire until 2 years of age. After adjusting for covariates, we found that maternal smoking prior to preterm birth increased the odds of having an infant with BPD by twofold (P = 0.02). Maternal smoking was associated with prolonged mechanical ventilation and respiratory support during the neonatal intensive care unit admission. Preexisting hypertension was associated with a twofold (P = 0.04) increase in odds for BPD. Lower gestational age and birth weight z-scores were associated with BPD. Preterm infants who were exposed to maternal smoking had higher rates of late respiratory disease during childhood. Twenty-two percent of infants diagnosed with BPD and 34% of preterm infants without BPD had no clinical signs of late respiratory disease during early childhood. We conclude that maternal smoking and hypertension increase the odds for developing BPD after preterm birth, and that maternal smoking is strongly associated with increased odds for late respiratory morbidities during early childhood. These findings suggest that in addition to the BPD diagnosis at 36 weeks, other factors modulate late respiratory outcomes during childhood. We speculate that measures to reduce maternal smoking not only will lower the risk for preterm birth but also will improve late respiratory morbidities after preterm birth.

Social support and depression across the perinatal period: A longitudinal study.

PubMed

Li, Yang; Long, Zhouting; Cao, Danfeng; Cao, Fenglin

2017-09-01

To report changes in the prevalence of depression and the level of social support at three different time points in the perinatal period (late pregnancy, 1 week postpartum and 4 weeks postpartum) and to examine the relationship between depression and social support at these points in time. Social support is a modifiable factor for depression. Existing research is limited to examining social support at a single time point in relation to antepartum or postpartum depression. A longitudinal study. In total, 240 pregnant women were recruited from the prenatal clinic at a general hospital in China between June-September 2013. The Edinburgh Postnatal Depression Scale and Perceived Social Support Scale were used to measure the risk of depression and perceived social support at late pregnancy, within the first week postpartum, and at 4 weeks postpartum. The Perceived Social Support Scale scores within the first week after birth were higher than scores at the late pregnancy and postpartum week 4, while the Edinburgh Postnatal Depression Scale scores at late pregnancy were higher than scores at the two postpartum times. Women who had higher Perceived Social Support Scale scores at late pregnancy had less likelihood of developing antepartum depression, and women with higher Perceived Social Support Scale scores at postpartum week 4 were less likely to have postpartum depression. However, the Perceived Social Support Scale scores at late pregnancy did not predict the risk of postpartum depression. The study revealed that social support perceived by women changed over the perinatal period. Social support at each stage of the perinatal period was an important buffer against depression at this stage. An increased focus on the relationship between social support and depression at each stage of the perinatal period is necessary for future research and practice. © 2017 John Wiley & Sons Ltd.

The AREST CF experience in biobanking - More than just tissues, tubes and time.

PubMed

Garratt, Luke W; Kicic, Anthony; Robertson, Colin; Ranganathan, Sarath; Sly, Peter D; Stick, Stephen M

2017-09-01

Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Late-onset ADHD in adults: milder, but still dysfunctional.

PubMed

Karam, Rafael G; Bau, Claiton H D; Salgado, Carlos A I; Kalil, Katiane L S; Victor, Marcelo M; Sousa, Nyvia O; Vitola, Eduardo S; Picon, Felipe A; Zeni, Gregory D; Rohde, Luis A; Belmonte-de-Abreu, Paulo; Grevet, Eugenio H

2009-04-01

The requirement in classificatory systems that some impairment from attention-deficit/hyperactivity disorder (ADHD) symptoms starts before 7 years of age (age of onset of impairment criteria - AOC) has been harshly criticized. Although there is evidence that late-onset ADHD is a valid diagnosis, little is known about the role of age of onset of impairment on the clinical profile of adult patients. The diagnoses of 349 adults with ADHD followed DSM-IV criteria. ADHD and oppositional defiant disorder (ODD) were evaluated with the K-SADS-E, and other comorbidities with the SCID-IV and the MINI. Subjects were divided in early and late-onset groups (age of onset of impairment between 7 and 12 years old). The effect of age of onset over clinical and demographic characteristics was tested by regression models. Late-onset subjects were diagnosed later (P=0.04), had a lower frequency of problems with authority and discipline (P=0.004), and lower scores in SNAP-IV (P<0.001) and in Barkley's scale for problems in areas of life activities (P=0.03). On the other hand, late-onset patients presented a higher prevalence of comorbid general anxiety disorder (GAD) (P=0.01). Both groups had a similar profile in the remaining comorbidities and sociodemographic characteristics. This study provides initial evidence that adults with late-onset ADHD have less severity, lower frequency of externalizing symptoms and increased comorbidity with GAD, but similar profile in other comorbidities. In addition, the data suggest that late-onset patients have a higher probability of delayed diagnosis despite the significant impairment of their condition.

Myocardial Tissue Characterization by Magnetic Resonance Imaging

PubMed Central

Ferreira, Vanessa M.; Piechnik, Stefan K.; Robson, Matthew D.; Neubauer, Stefan

2014-01-01

Cardiac magnetic resonance (CMR) imaging is a well-established noninvasive imaging modality in clinical cardiology. Its unsurpassed accuracy in defining cardiac morphology and function and its ability to provide tissue characterization make it well suited for the study of patients with cardiac diseases. Late gadolinium enhancement was a major advancement in the development of tissue characterization techniques, allowing the unique ability of CMR to differentiate ischemic heart disease from nonischemic cardiomyopathies. Using T2-weighted techniques, areas of edema and inflammation can be identified in the myocardium. A new generation of myocardial mapping techniques are emerging, enabling direct quantitative assessment of myocardial tissue properties in absolute terms. This review will summarize recent developments involving T1-mapping and T2-mapping techniques and focus on the clinical applications and future potential of these evolving CMR methodologies. PMID:24576837

Demographic and clinical variables influencing gestational age at booking among South African pregnant women.

PubMed

Basu, J K; Basu, D; Jeketera, C M

2011-11-01

A retrospective record review was made of 758 women who delivered over a 2-month period at the Charlottee Maxeke Johannesburg Academic Hospital. Women booking early (up to 14 weeks) were compared with women booking late (from 15 weeks onwards). A total of 45 (6%) and 713 (94%) women booked in the early and late groups, respectively. Women of white ethnicity and women who experienced previous fetal loss booked significantly early. Primigravidae booked significantly late.

Depressive symptoms in relation to overall survival in people with head and neck cancer: a longitudinal cohort study.

PubMed

Jansen, Femke; Verdonck-de Leeuw, Irma M; Cuijpers, Pim; Leemans, C René; Waterboer, Tim; Pawlita, Michael; Penfold, Chris; Thomas, Steven J; Waylen, Andrea; Ness, Andrew R

2018-06-21

To investigated the relation between pre-treatment depressive symptoms (DS) and the course of DS during the first year after cancer diagnosis, and overall survival among people with head and neck cancer (HNC). Data from the Head and Neck 5000 prospective clinical cohort study were used. DS were measured using the Hospital Anxiety and Depression Scale (HADS) pre-treatment, at 4 and 12 months follow-up. Also socio-demographic, clinical, lifestyle and mortality data were collected. The association between pre-treatment DS (HADS-depression>7) and course (never DS, recovered from DS, or persistent/recurrent/late DS at 12 months follow-up), and survival was investigated using Cox regression. Unadjusted and adjusted analyses were performed. In total, 384 of the 2,144 persons (18%) reported pre-treatment DS. Regarding DS course, 63% never had DS, 16% recovered, and 20% had persistent/recurrent/late DS. People with pre-treatment DS had a higher risk of earlier death than people without DS (Hazard Ratio (HR) =1.65; 95% confidence interval (CI) 1.33-2.05), but this decreased after correcting for socio-demographic, clinical, and lifestyle-related factors (HR=1.21; 95%CI 0.97-1.52). Regarding the course of DS, people with persistent/recurrent/late DS had a higher risk of earlier death (HR=2.04; 95%CI 1.36-3.05), while people who recovered had a comparable risk (HR=1.12; 95%CI 0.66-1.90) as the reference group who never experienced DS. After correcting for socio-demographic and clinical factors, people with persistent/recurrent/late DS still had a higher risk of earlier death (HR=1.66; 95%CI 1.09-2.53). Pre-treatment DS and persistent/recurrent/late DS were associated with worse survival among people with HNC. This article is protected by copyright. All rights reserved.

Late adverse events after implantation of sirolimus-eluting stent and bare-metal stent: long-term (5-7 years) follow-up of the Coronary Revascularization Demonstrating Outcome study-Kyoto registry Cohort-2.

PubMed

Natsuaki, Masahiro; Morimoto, Takeshi; Furukawa, Yutaka; Nakagawa, Yoshihisa; Kadota, Kazushige; Yamaji, Kyohei; Ando, Kenji; Shizuta, Satoshi; Shiomi, Hiroki; Tada, Tomohisa; Tazaki, Junichi; Kato, Yoshihiro; Hayano, Mamoru; Abe, Mitsuru; Tamura, Takashi; Shirotani, Manabu; Miki, Shinji; Matsuda, Mitsuo; Takahashi, Mamoru; Ishii, Katsuhisa; Tanaka, Masaru; Aoyama, Takeshi; Doi, Osamu; Hattori, Ryuichi; Kato, Masayuki; Suwa, Satoru; Takizawa, Akinori; Takatsu, Yoshiki; Shinoda, Eiji; Eizawa, Hiroshi; Takeda, Teruki; Lee, Jong-Dae; Inoko, Moriaki; Ogawa, Hisao; Hamasaki, Shuichi; Horie, Minoru; Nohara, Ryuji; Kambara, Hirofumi; Fujiwara, Hisayoshi; Mitsudo, Kazuaki; Nobuyoshi, Masakiyo; Kita, Toru; Kimura, Takeshi

2014-04-01

Late adverse events such as very late stent thrombosis (VLST) or late target-lesion revascularization (TLR) after first-generation sirolimus-eluting stents (SES) implantation have not been yet fully characterized at long term in comparison with those after bare-metal stent (BMS) implantation. Among 13 058 consecutive patients undergoing first percutaneous coronary intervention in the Coronary REvascularization Demonstrating Outcome study-Kyoto registry Cohort-2, 5078 patients were treated with SES only, and 5392 patients were treated with BMS only. During 7-year follow-up, VLST and late TLR beyond 1 year after SES implantation occurred constantly and without attenuation at 0.24% per year and at 2.0% per year, respectively. Cumulative 7-year incidence of VLST was significantly higher in the SES group than that in the BMS group (1.43% versus 0.68%, P<0.0001). However, there was no excess of all-cause death beyond 1 year in the SES group as compared with that in the BMS group (20.8% versus 19.6%, P=0.91). Cumulative incidences of late TLR (both overall and clinically driven) were also significantly higher in the SES group than in the BMS group (12.0% versus 4.1%, P<0.0001 and 8.5% versus 2.6%, P<0.0001, respectively), leading to late catch-up of the SES group to the BMS group regarding TLR through the entire 7-year follow-up (18.8% versus 25.2%, and 10.6% versus 10.2%, respectively). Clinical presentation as acute coronary syndrome was more common at the time of late SES TLR compared with early SES TLR (21.2% and 10.0%). Late catch-up phenomenon regarding stent thrombosis and TLR was significantly more pronounced with SES than that with BMS. This limitation should remain the target for improvements of DES technology.

Signet-ring Cells in the Skin: A Case of Late-onset Cutaneous Metastasis of Gastric Carcinoma and a Brief Review of Histological Approach

PubMed Central

Gündüz, Özgür; Emeksiz, Mehmet Can; Atasoy, Pinar; Kidir, Mehtap; Yalçin, Selim; Demirkan, Serkan

2017-01-01

Up to 10% of patients with visceral malignancies develop skin metastases during their clinical course and these metastases constitute about 2% of all skin cancers. Skin metastasis may be the first sign of a clinically silent visceral cancer or represent recurrence of an internal malignancy. In both situations, they are associated with poor prognosis, which can partly be attributed to underdiagnosis. In this paper, a case of relapsing gastric adenocarcinoma, which manifested itself as asymptomatic cutaneous papules and nodules on a patient’s head and neck, is reported and histopathological approach to the cutaneous lesions containing signet-ring cell is briefly reviewed. PMID:28326183

From blood to breath: New horizons for esophageal cancer biomarkers.

PubMed

Yazbeck, Roger; Jaenisch, Simone E; Watson, David I

2016-12-14

Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non-invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers.

The Role of Fundus Autofluorescence in Late-Onset Retinitis Pigmentosa (LORP) Diagnosis

PubMed Central

Lee, Tamara J.; Hwang, John C.; Chen, Royce W. S.; Lima, Luiz H.; Wang, Nan-Kai; Tosi, Joaquin; Freund, K. Bailey; Yannuzzi, Lawrence A.; Tsang, Stephen H.

2015-01-01

Purpose To demonstrate the utility and characteristics of fundus autofluorescence in late-onset retinitis pigmentosa. Methods Observational case series. Patients diagnosed with late-onset retinitis pigmentosa were identified retrospectively in an institutional setting. Twelve eyes of six patients were identified and medical records were reviewed. Results All patients presented with slowly progressive peripheral field loss and initial clinical examination revealed only subtle retinal changes. There was a notable lack of intraretinal pigment migration in all patients. Five out of six patients underwent magnetic resonance imaging of the brain to rule out intracranial processes and all were referred from another ophthalmologist for further evaluation. Fundus autofluorescence was ultimately employed in all patients and revealed more extensive retinal pathology than initially appreciated on clinical examination. Fundus autofluorescence directed the workup toward a retinal etiology in all cases and led to the eventual diagnosis of late-onset retinitis pigmentosa through electroretinogram testing. Conclusion Fundus autofluorescence may be a more sensitive marker for retinal pathology than stereo fundus biomicroscopy alone in late-onset retinitis pigmentosa. Early use of fundus autofluorescence imaging in the evaluation of patients with subtle retinal lesions and complaints of peripheral field loss may be an effective strategy for timely and cost-efficient diagnosis. PMID:23899229

Late onset globoid cell leukodystrophy.

PubMed

Grewal, R P; Petronas, N; Barton, N W

1991-11-01

A 29 year old male with onset of globoid cell leukodystrophy at age 14 is described. This is the first case of enzymatically confirmed globoid cell leukodystrophy with onset of symptoms after the age of ten. This patient is unique because of the late onset and slow progression and extends the clinical spectrum of globoid cell leukodystrophy.

Senecavirus A infection in sows, neonates, and market weight gilts with subsequent protective immunity

USDA-ARS?s Scientific Manuscript database

Objective: The objectives of this study were to 1) characterize SVA infection late-gestation sows, neonates, and market weight gilts and 2) examine protective immunity in late-gestation gilts Methods: For Part 1, 15 market weight gilts were inoculated with SVA, bled regularly, and clinical observat...

ON THE SO-CALLED LATE OR THERAPEUTICAL RADIONECROSIS (in Italian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piemonte, M.

1960-01-01

Anatomical and clinical characteristics of the alteration known as late or therapeutical necrosis are reviewed and the most characteristical aspects of this alteration in various anatomical sites are discussed. Radionecroses of the tongue, of the palate, of the skin, of the uterus cervix, of the vulva, and of the penis are illustrated. (auth)

Before it is too late: professional responsibilities in late-onset Alzheimer's research and pre-symptomatic prediction.

PubMed

Schicktanz, Silke; Schweda, Mark; Ballenger, Jesse F; Fox, Patrick J; Halpern, Jodi; Kramer, Joel H; Micco, Guy; Post, Stephen G; Thompson, Charis; Knight, Robert T; Jagust, William J

2014-01-01

The development of a wide array of molecular and neuroscientific biomarkers can provide the possibility to visualize the course of Alzheimer's disease (AD) at early stages. Many of these biomarkers are aimed at detecting not only a preclinical, but also a pre-symptomatic state. They are supposed to facilitate clinical trials aiming at treatments that attack the disease at its earliest stage or even prevent it. The increasing number of such biomarkers currently tested and now partly proposed for clinical implementation calls for critical reflection on their aims, social benefits, and risks. This position paper summarizes major challenges and responsibilities. Its focus is on the ethical and social problems involved in the organization and application of dementia research, as well as in healthcare provision from a cross-national point of view. The paper is based on a discussion of leading dementia experts from neuroscience, neurology, social sciences, and bioethics in the United States and Europe. It thus reflects a notable consensus across various disciplines and national backgrounds. We intend to initiate a debate on the need for actions within the researchers' national and international communities.

Prospective evaluation of [11C]Choline PET/CT in therapy response assessment of standardized docetaxel first-line chemotherapy in patients with advanced castration refractory prostate cancer.

PubMed

Schwarzenböck, Sarah M; Eiber, Matthias; Kundt, Günther; Retz, Margitta; Sakretz, Monique; Kurth, Jens; Treiber, Uwe; Nawroth, Roman; Rummeny, Ernst J; Gschwend, Jürgen E; Schwaiger, Markus; Thalgott, Mark; Krause, Bernd J

2016-11-01

The aim of this study was to prospectively evaluate the value of [ 11 C] Choline PET/CT in monitoring early and late response to a standardized first-line docetaxel chemotherapy in castration refractory prostate cancer (mCRPC) patients. Thirty-two patients were referred for [ 11 C] Choline PET/CT before the start of docetaxel chemotherapy, after one and ten chemotherapy cycles (or - in case of discontinuation - after the last administered cycle) for therapy response assessment. [ 11 C] Choline uptake (SUV max , SUV mean ), CT derived Houndsfield units (HU max , HU mean ), and volume of bone, lung, and nodal metastases and local recurrence were measured semi-automatically at these timepoints. Change in SUV max , SUV mean , HU max , HU mean, and volume was assessed between PET 2 and 1 (early response assessment, ERA) and PET 3 and 1 (late response assessment, LRA) on a patient and lesion basis. Results of PET/CT were compared to clinically used RECIST 1.1 and clinical criteria based therapy response assessment including PSA for defining progressive disease (PD) and non-progressive disease (nPD), respectively. Relationships between changes of SUV max and SUV mean (early and late) and changes of PSA early and PSA late were evaluated. Prognostic value of initial SUV max and SUV mean was assessed. Statistical analyses were performed using SPSS. In the patient-based ERA and LRA there were no statistically significant differences in change of choline uptake, HU, and volume between PD and nPD applying RECIST or clinical response criteria. In the lesion-based ERA, decrease in choline uptake of bone metastases was even higher in PD (applying RECIST criteria), whereas in LRA the decrease was higher in nPD (applying clinical criteria). There were only significant correlations between change in choline uptake and PSA in ERA in PD, in LRA no significant correlations were discovered. Initial SUV max and SUV mean were statistically significantly higher in nPD (applying clinical criteria). There is no significant correlation between change in choline uptake in [ 11 C] Choline PET/CT and clinically routinely used objective response assessment during the early and late course of docetaxel chemotherapy. Therefore, [ 11 C] Choline PET/CT seems to be of limited use in therapy response assessment in standardized first-line chemotherapy in mCRPC patients.

Dysphagia After Chemoradiotherapy for Head-and-Neck Squamous Cell Carcinoma: Dose-Effect Relationships for the Swallowing Structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dirix, Piet; Abbeel, Sarah; Vanstraelen, Bianca

2009-10-01

Purpose: To evaluate late dysphagia after chemoradiotherapy for locally advanced head-and-neck squamous cell carcinoma, and to examine its correlation with clinical and dosimetric parameters. Methods and Materials: Consecutive patients, treated with radiotherapy (70-72 Gy) and concomitant chemotherapy (cisplatinum 100 mg/m{sup 2} every 3 weeks) between 2004 and 2007, were examined. Swallowing was evaluated by four quality-of-life questionnaires: EORTC C30 and H and N35, the Performance Status Scale of List, and the MD Anderson Dysphagia Inventory. Clinical and dosimetric parameters were correlated with late dysphagia. Results: A total of 53 disease-free patients were evaluated; mean follow-up was 20.4 months (range, 6-45more » months). The volume of the middle pharyngeal constrictor muscle receiving {>=}50 Gy (p = 0.04), the mean dose to this structure (p = 0.02) and to the supraglottic larynx (p = 0.04) were significantly associated with late swallowing problems at univariate analysis, along with tumor localization (p = 0.008), T-classification (p = 0.02), and pretreatment swallowing problems (p = 0.01). Only this last factor significantly correlated with late dysphagia at multivariate analysis. Conclusion: These findings motivate further efforts to reduce the dose to the swallowing structures, especially to the pharyngeal constrictor muscles and the larynx. However, clinical parameters are also important and should be included in future prospective trials.« less

Morbidity, mortality and economic burden of renal impairment in cardiac intensive care.

PubMed

Chew, D P; Astley, C; Molloy, D; Vaile, J; De Pasquale, C G; Aylward, P

2006-03-01

Moderate to severe impairment of renal function has emerged as a potent risk factor for adverse short- and long-term outcomes among patients presenting with cardiac disease. We sought to define the clinical, late mortality and economic burden of this risk factor among patients presenting to cardiac intensive care. A clinical audit of patients presenting to cardiac intensive care was undertaken between July 2002 and June 2003. All patients presenting with cardiac diagnoses were included in the study. Baseline creatinine levels were assessed in all patients. Late mortality was assessed by the interrogation of the National Death Register. Renal impairment was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m2, as calculated by the Modified Diet in Renal Disease formula. In-hospital and late outcomes were compared by Cox proportional hazards modelling, adjusting for known confounders. A matched analysis and attributable risk calculation were undertaken to assess the proportion of late mortality accounted for by impairment of renal function and other known negative prognostic factors. The in-hospital total cost associated with renal impairment was assessed by linear regression. Glomerular filtration rate <60 mL/min per 1.73 m2 was evident in 33.0% of this population. Among these patients, in-hospital and late mortality were substantially increased: risk ratio 13.2; 95% CI 3.0-58.1; P < 0.001 and hazard ratio 6.2; 95% CI 3.6-10.7; P < 0.001, respectively. In matched analysis, renal impairment to this level was associated with 42.1% of all the late deaths observed. Paradoxically, patients with renal impairment were more conservatively managed, but their hospitalizations were associated with an excess adjusted in-hospital cost of $A1676. Impaired renal function is associated with a striking clinical and economic burden among patients presenting to cardiac intensive care. As a marker for future risk, renal function accounts for a substantial proportion of the burden of late mortality. The burden of risk suggests a greater potential opportunity for improvement of outcomes through optimisation of therapeutic strategies.

Perceived Barriers to Clinic Appointments for Adolescents with Sickle Cell Disease

PubMed Central

Crosby, Lori E.; Modi, Avani C.; Lemanek, Kathleen L.; Guilfoyle, Shanna M.; Kalinyak, Karen A.; Mitchell, Monica J.

2009-01-01

Purpose The purpose of the study was to examine perceived barriers to clinic attendance and strategies to overcome these barriers for adolescents with sickle cell disease (SCD). Materials and Methods This was a two-phased study which utilized focus groups (n = 13) and individual semi-structured interviews (n = 32) with adolescent patients (aged 13–21 years) from three pediatric sickle cell clinics in the Mid-west. Results Adolescents identified competing activities, health status, patient-provider relationships, adverse clinic experiences, and forgetting as barriers to clinic attendance. Calendars/reminders and parent reminders were the most commonly reported strategies to facilitate clinic attendance. Adolescents also reported the need for flexible scheduling and improved patient-provider communication. Discussion Adolescents with SCD and their families may benefit from on-going education about the importance of attending routine clinic visits. Adherence to clinic appointments for adolescents may be enhanced by developing interventions to decrease forgetting (e.g., phone call reminders, text-messaging) and increase patient satisfaction with clinic visits. Scheduling appointments to accommodate busy schedules/scheduling conflicts (e.g., late clinic hours), providing teen-friendly clinic environments and utilizing technology may also facilitate attendance. PMID:19636266

DOE Office of Scientific and Technical Information (OSTI.GOV)

Machtay, Mitchell, E-mail: mitchell.machtay@uhhospitals.org; Moughan, Jennifer; Farach, Andrew

Purpose: Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. Methods and Materials: This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis asmore » chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube {>=}2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors. Results: A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P=.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P=.016). The subgroup of patients receiving {<=}60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome. Conclusions: Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.« less

A Rare Case of Infectious Mononucleosis Complicated by Guillain-Barre Syndrome

PubMed Central

Kennedy, Margaret; Apostolova, Mariya

2013-01-01

Infectious mononucleosis is a clinical syndrome characterized by fever, lymphadenopathy and pharyngitis. Neurologic complications of infectious mononucleosis, such as the development of Guillain-Barre syndrome, have been rarely reported and usually present late in the course of the disease. We describe a case of a 29 year old male with no significant past medical history who was diagnosed with Guillain-Barre syndrome following an infection with Epstein-Barr virus associated infectious mononucleosis. Supportive treatment resulted in full recovery. PMID:23888210

A novel ETFB mutation in a patient with glutaric aciduria type II.

PubMed

Sudo, Yosuke; Sasaki, Ayako; Wakabayashi, Takashi; Numakura, Chikahiko; Hayasaka, Kiyoshi

2015-01-01

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth.

A novel ETFB mutation in a patient with glutaric aciduria type II

PubMed Central

Sudo, Yosuke; Sasaki, Ayako; Wakabayashi, Takashi; Numakura, Chikahiko; Hayasaka, Kiyoshi

2015-01-01

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth. PMID:27081516

Diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A clinical and genetic study.

PubMed Central

Nagi, N. A.

1979-01-01

Two Iraqi sisters and a female cousin developed diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and deafness (D), (the 'DIDMOAD' syndrome) before the age of 12 years. One girl exhibited all the features of this disease complex only 3 months after an unusually late onset of recognizable symptoms at 11 years 9 months. Another girl died suddenly and unexpectedly. This family study illustrates the recessive inheritance pattern of the syndrome. Images Fig. 2 Fig. 3 PMID:482181

Global medicinal chemistry and GCPR conference.

PubMed

Schio, Laurent

2018-06-01

Laurent Schio speaks to Benjamin Walden, Commissioning Editor. Laurent Schio is leading the group of Integrated Drug Discovery of Sanofi, France. He joined Sanofi more than 25 years ago and is an organic chemist by training. He has made most of his career in medicinal chemistry supporting and leading projects, especially in the anti-infective and then in the oncology fields. He has developed a strong expertise in kinases and lately has contributed to the discovery of several clinical candidates for cancer treatment.

A rare case of infectious mononucleosis complicated by guillain-barre syndrome.

PubMed

Kennedy, Margaret; Apostolova, Mariya

2013-06-25

Infectious mononucleosis is a clinical syndrome characterized by fever, lymphadenopathy and pharyngitis. Neurologic complications of infectious mononucleosis, such as the development of Guillain-Barre syndrome, have been rarely reported and usually present late in the course of the disease. We describe a case of a 29 year old male with no significant past medical history who was diagnosed with Guillain-Barre syndrome following an infection with Epstein-Barr virus associated infectious mononucleosis. Supportive treatment resulted in full recovery.

Late-onset agoraphobia: general population incidence and evidence for a clinical subtype.

PubMed

Ritchie, Karen; Norton, Joanna; Mann, Anthony; Carrière, Isabelle; Ancelin, Marie-Laure

2013-07-01

The purpose of this study was to estimate the general population incidence of late-life agoraphobia and to define its clinical characteristics and risk factors. A total of 1,968 persons ≥65 years old were randomly recruited from the electoral rolls of the district of Montpellier, France. Prevalent and incident agoraphobia diagnosed with a standardized psychiatric examination and validated by a clinical panel were assessed at baseline and over a 4-year follow-up. The 1-month baseline prevalence of agoraphobia was estimated to be 10.4%. Among persons with agoraphobia, 10.9% reported having their first episode at age 65 or above. During the 4-year follow-up, 11.2% of participants without agoraphobia at baseline had a first episode, resulting in an incidence rate of 32 per 1,000 person-years. These 132 incident late-onset cases were associated with higher incidence rates of anxiety disorders and suicidal ideation. Of the incident cases, only two were characterized by past or concurrent panic attacks, a rate that was not significantly different from that of the noncase group. The principal baseline risk factors for incident cases, derived from a multivariate model incorporating all significant risk factors, were younger age at onset (odds ratio=0.94, 95% CI=0.90-0.99), poorer visuospatial memory performance (odds ratio=1.60, 95% CI=1.02-2.49), severe depression (odds ratio=2.62, 95% CI=1.34-5.10), and trait anxiety (odds ratio=1.73, 95% CI=1.03-2.90). No significant association was found with cardiac pathologies. Agoraphobia has a high prevalence in the elderly, and unlike cases in younger populations, late-onset cases are not more common in women and are not associated with panic attacks, suggesting a late-life subtype. Severe depression, trait anxiety, and poor visuospatial memory are the principal risk factors for late-onset agoraphobia.

Late presentation to HIV testing is overestimated when based on the consensus definition.

PubMed

Sasse, A; Florence, E; Pharris, A; De Wit, S; Lacor, P; Van Beckhoven, D; Deblonde, J; Delforge, M-L; Fransen, K; Goffard, J-C; Legrand, J-C; Moutschen, M; Piérard, D; Ruelle, J; Vaira, D; Vandercam, B; Van Ranst, M; Van Wijngaerden, E; Vandekerckhove, L; Verhofstede, C

2016-03-01

In 2011, a consensus was reached defining "late presenters" (LPs) as individuals presenting for care with a CD4 count < 350 cells/μL or with an AIDS-defining event, regardless of CD4 count. However, a transient low CD4 count is not uncommon in recent infections. The objective of this study was to investigate how measurements of late presentation change if the clinical stage at the time of diagnosis is taken into account. Case surveillance data for newly diagnosed patients in Belgium in 1998-2012 were analysed, including CD4 count at diagnosis, the presence of AIDS-defining events, and recent infections (< 6 months) as reported by clinicians in the case of acute illness or a recent negative test. First, proportions of LPs were calculated according to the consensus definition. Secondly, LPs were reclassified as "nonlate" if infections were reported as recent. A total of 7949 HIV diagnoses were included in the study. Recent infections were increasingly reported over time, accounting for 8.2% of new infections in 1998 and 37.5% in 2012. The consideration of clinical stage significantly modified the proportion of LPs: 18.2% of men who have sex with men (MSM) diagnosed in 2012 would be classified as LPs instead of 30.9% using the consensus definition (P < 0.001). The proportion of patients misclassified as LPs increased significantly over time: 5% in MSM in 1998 vs. 41% in 2012. This study suggests that low CD4 counts in recent infections may lead to overestimation of late presentation when applying the consensus definition. The impact of transient CD4 count on late presentation estimates should be assessed and, if relevant, the introduction of clinical stage in the definition of late presentation should be considered. © 2015 British HIV Association.

Paradox of Prescribing Late Chemotherapy: Oncologists Explain.

PubMed

Bluhm, Minnie; Connell, Cathleen M; De Vries, Raymond G; Janz, Nancy K; Bickel, Kathleen E; Silveira, Maria J

2016-12-01

The value of chemotherapy for patients with cancer in the last weeks of life warrants examination. Late chemotherapy may not improve survival or quality of life but typically precludes hospice enrollment and may result in additional symptoms, increased use of other aggressive treatments, and worsening quality of life. Few studies have explored oncologists' rationales for administering chemotherapy near death. This study examines the self-reported factors that influence oncologists' decisions about late chemotherapy. In-depth individual interviews were conducted with 17 oncologists through a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. Transcripts were coded and analyzed using conventional content analysis, a qualitative method that allows the detection and analysis of patterns in the data. Clinical factors take priority in determining late chemotherapy decisions when clear treatment choices exist. When clinical factors are ambiguous, emotion becomes a highly salient influence. Oncologists view late chemotherapy to be patient driven and use it to palliate emotional distress and maintain patient hope even when physical benefit is unexpected. Oncologists experience unique and difficult challenges when caring for dying patients, including emotionally draining communication, overwhelming responsibility for life/death, limitations of oncology to heal, and prognostic uncertainty. These challenges are also eased by offering late chemotherapy. The findings reveal a nuanced understanding of why oncologists find it difficult to refuse chemotherapy treatment for patients near death. Optimal end-of-life treatment decisions require supportive interventions and system change, both of which must take into account the challenges oncologists face.

Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder.

PubMed

Takahashi, Sho; Mizukami, Katsuyoshi; Arai, Tetsuaki; Ogawa, Ryoko; Kikuchi, Norihiro; Hattori, Satoshi; Darby, David; Asada, Takashi

2016-01-01

Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB. Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD. Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy. Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters. In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.

Depressive symptoms and symptoms of post-traumatic stress disorder in women after childbirth.

PubMed

Zaers, Stefanie; Waschke, Melanie; Ehlert, Ulrike

2008-03-01

This study examined the course of psychological problems in women from late pregnancy to six months postpartum, the rates of psychiatric, especially depressive and post-traumatic stress symptoms and possible related antecedent variables. During late pregnancy, one to three days postpartum, six weeks and six months postpartum, 47 of the 60 participating women completed a battery of questionnaires including the General Health Questionnaire, the State-Trait Anxiety Inventory, the Edinburgh Postnatal Depression Scale, and the PTSD Symptom Scale. In general, most women recovered from psychiatric and somatic problems over the period of investigation. However, depressive and post-traumatic stress symptoms in particular were not found to decline significantly. Six weeks postpartum, 22% of the women had depressive symptoms, with this figure remaining at 21.3% six months postpartum. In addition, 6% of the women studied reported clinically significant PTSD symptoms at six weeks postpartum with 14.9% reporting such symptoms at six months postpartum. The most important predictor for depressive and post-traumatic stress symptoms was the block variable "anxiety in late pregnancy". Other predictors were the variables "psychiatric symptoms in late pregnancy", "critical life events" and the "experience of delivery". The results of our study show a high prevalence rate of psychiatric symptoms in women after childbirth and suggest, besides the experience of the delivery itself, a vulnerability or predisposing history that makes the development of psychiatric symptoms after childbirth more probable.

[INTERACT: a model of evaluation and intervention for children who are "late talkers"].

PubMed

Bonifacio, Serena; Stefani, Loredana Hvastja; Zocconi, Elisabetta

2005-01-01

According to criteria applied in literature toddlers were identified as late talkers if they had less than 50-word expressive vocabulary and no word combinations at 24 months of age. The intervention programmes that use the parents as the primary agents of intervention and use child-centred techniques maximise the quality of parental communication during the emerging language period of the child. INTERACT is an early highly individualised parent and child-centered clinical intervention based on the social-pragmatic theorical approach. It is developed for 24-30 months old children with emerging language. The aims of this study are: to evaluate the gains of the child's expressive language skills and the use of multiword utterances and the changes of the maternal/parental communicative style. Six male children described as late talkers and their mothers participated for six months to INTERACT program. At initial intervention children's average age was 27 months and the average of number words producted was 26. All the mothers show high levels of directiveness. At the end of intervention the expressive vocabulary of late talkers increase in number of different words reaching an average of 407 words and an average linguistic age of 31 months, the gain is fourteen months in six months. The mothers show significant changes in their communicative style, the directiveness and the asynchronous/devaluing behaviours decrease.

Nanoparticle-Delivered Chemotherapy: Old Drugs in New Packages.

PubMed

Lee, Michael S; Dees, E Claire; Wang, Andrew Z

2017-03-15

Cytotoxic chemotherapies have a narrow therapeutic window, with high peaks and troughs of plasma concentration. Novel nanoparticle formulations of cytotoxic chemotherapy drugs can enhance pharmacokinetic characteristics and facilitate passive targeting of drugs to tumors via the enhanced permeability and retention effect, thus mitigating toxicity. Nanoparticle vehicles currently in clinical use or undergoing clinical investigation for anticancer therapies include liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers. Multiple nanoparticle formulations of existing cytotoxic chemotherapies are approved for use in several indications, with clinical data indeed showing optimization of pharmacokinetics and different toxicity profiles compared with their parent drugs. There are also many new nanoparticle drug formulations in development and undergoing early- and late-phase clinical trials, including several that utilize active targeting or triggered release based on environmental stimuli. Here, we review the rationale for nanoparticle formulations of existing or previously investigated cytotoxic drugs, describe currently approved nanoparticle formulations of drugs, and discuss some of the most promising clinical trials currently underway.

High-Dose-Rate Interstitial Brachytherapy as Monotherapy for Clinically Localized Prostate Cancer: Treatment Evolution and Mature Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zamboglou, Nikolaos; Tselis, Nikolaos, E-mail: ntselis@hotmail.com; Baltas, Dimos

2013-03-01

Purpose: To report the clinical outcome of high-dose-rate (HDR) interstitial (IRT) brachytherapy (BRT) as sole treatment (monotherapy) for clinically localized prostate cancer. Methods and Materials: Between January 2002 and December 2009, 718 consecutive patients with clinically localized prostate cancer were treated with transrectal ultrasound (TRUS)-guided HDR monotherapy. Three treatment protocols were applied; 141 patients received 38.0 Gy using one implant in 4 fractions of 9.5 Gy with computed tomography-based treatment planning; 351 patients received 38.0 Gy in 4 fractions of 9.5 Gy, using 2 implants (2 weeks apart) and intraoperative TRUS real-time treatment planning; and 226 patients received 34.5 Gy,more » using 3 single-fraction implants of 11.5 Gy (3 weeks apart) and intraoperative TRUS real-time treatment planning. Biochemical failure was defined according to the Phoenix consensus, and toxicity was evaluated using Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 52.8 months. The 36-, 60-, and 96-month biochemical control and metastasis-free survival rates for the entire cohort were 97%, 94%, and 90% and 99%, 98%, and 97%, respectively. Toxicity was scored per event, with 5.4% acute grade 3 genitourinary and 0.2% acute grade 3 gastrointestinal toxicity. Late grade 3 genitourinary and gastrointestinal toxicities were 3.5% and 1.6%, respectively. Two patients developed grade 4 incontinence. No other instance of grade 4 or greater acute or late toxicity was reported. Conclusion: Our results confirm IRT-HDR-BRT is safe and effective as monotherapy for clinically localized prostate cancer.« less

Effects of prenatal dexamethasone treatment on physical growth, pituitary-adrenal hormones, and performance of motor, motivational, and cognitive tasks in juvenile and adolescent common marmoset monkeys.

PubMed

Hauser, Jonas; Knapman, Alana; Zürcher, Nicole R; Pilloud, Sonia; Maier, Claudia; Diaz-Heijtz, Rochellys; Forssberg, Hans; Dettling, Andrea; Feldon, Joram; Pryce, Christopher R

2008-12-01

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.

Clinical features and long-term progression of reticular pseudodrusen in age-related macular degeneration: findings from a multicenter cohort.

PubMed

Gil, J Q; Marques, J P; Hogg, R; Rosina, C; Cachulo, M L; Santos, A; Staurenghi, G; Chakravarthy, U; Silva, R

2017-03-01

PurposeTo determine whether reticular pseudodrusen (RPD) confer a long-term increased risk of progression to late age-related macular degeneration (AMD) in the fellow eye of patients with unilateral wet-AMD.Patients and methodsThis was a multicenter, combined prospective and retrospective, longitudinal, observational, study. Patients with wet-AMD in one eye were recruited from two centers and evaluated on the risk of progression to late-AMD in the second eye (study eye). A minimum follow-up of 5 years was required, unless progression occurred first. Baseline retinal profile of patients was evaluated using multimodal imaging. Baseline images were graded by two separate centers.ResultsWe recruited 88 patients (48 female) with a mean age of 75.6±7.1 years and mean follow-up of 65.7±20.9 months. Baseline prevalence of RPD was 58% (n=51). There was no statistically significant association of RPD with increased age (P=0.29) or sex distribution (P=0.39). The most sensitive image modality for RPD was IR (93%), followed by FAF (92%), OCT (74%, RF (33%) and CFP (29%). After 5 years, 54.50% (n=48) of the study eyes progressed to late-AMD. Of those, 81.25% (n=39) developed CNV and 18.75% (n=9) geographic atrophy. After correcting for age and sex, the presence of RPD was significantly associated with development of late-stage AMD (OR=2.55, P=0.03).ConclusionA multimodal approach is mandatory for RPD detection. RPD are highly prevalent in the fellow eyes of patients with unilateral neovascular AMD. Presence of RPD is associated with increased long-term risk of progression, highlighting the importance of comprehensive multimodal retinal imaging and careful monitoring of at-risk patients.

Experimental modelling of the consequences of brief late gestation asphyxia on newborn lamb behaviour and brain structure.

PubMed

Castillo-Melendez, Margie; Baburamani, Ana A; Cabalag, Carlos; Yawno, Tamara; Witjaksono, Anissa; Miller, Suzie L; Walker, David W

2013-01-01

Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle--compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.

Late onset of progressive neurological deficits in severe angular kyphosis related to tuberculosis spondylitis.

PubMed

Ha, Kee-Yong; Kim, Young-Hoon

2016-04-01

To investigate the causes of late-onset, progressive neurological deficits in patients with severe angular kyphosis caused by spondylitis secondary to tuberculosis (TB spondylitis). From 2000 to 2011, 36 patients with severe angular kyphosis secondary to TB spondylitis (TB kyphosis) were enrolled in the study. All patients had late-onset, progressive neurological deficits. The causes of these deficits were classified with respect to the level of the causative lesion. Group A (n = 25, 69.4%) comprised patients whose neurological deficits resulted from the kyphosis itself. Patients in group B (n = 11, 30.6%) had developed neurological symptoms related to a lesion cephalad or caudal from the kyphosis. Surgical intervention was performed in 23 patients; 13 patients were treated conservatively. Clinical outcomes were evaluated using the American Spinal Injury Association (ASIA) impairment scale. The late onset of neurological deficits was attributed to cord compression, pure cord distraction, stenosis, and instability above or below the level of the angular kyphosis. An improvement of the neurological symptoms at the cord level after surgical intervention, as indicated by a change from a non-ambulatory (ASIA impairment scale A/C) to an ambulatory (ASIA D/E) status, occurred in four of nine (44.4%) surgically treated patients. However, only 2 of 10 (20.0%) patients treated conservatively showed cord level improvement, as assessed using the ASIA impairment scale. In their evaluation of paraplegic patients, spine surgeons should consider the many potential causes of late-onset neurological deficits in TB spondylitis to avoid performing unnecessary surgery. A simpler procedure may yield equivalent results.

Location and cellular stages of NK cell development

PubMed Central

Yu, Jianhua; Freud, Aharon G.; Caligiuri, Michael A

2013-01-01

The identification of distinct tissue-specific natural killer (NK) cell populations that apparently mature from local precursor populations has brought new insight into the diversity and developmental regulation of this important lymphoid subset. NK cells provide a necessary link between the early (innate) and late (adaptive) immune responses to infection. Gaining a better understanding of the processes that govern NK cell development should allow us to better harness NK cell functions in multiple clinical settings as well as to gain further insight into how these cells undergo malignant transformation. In this review, we summarize recent advances in understanding sites and cellular stages of NK cell development in humans and mice. PMID:24055329

[Pubertal growth of 1,453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study].

PubMed

Carrascosa, Antonio; Yeste, Diego; Moreno-Galdó, Antonio; Gussinyé, Miquel; Ferrández, Ángel; Clemente, María; Fernández-Cancio, Mónica

2018-02-20

Pubertal growth pattern differs according to age at pubertal growth spurt onset which occurs over a five years period (girls: 8-13 years, boys: 10-15 years). The need for more than one pubertal reference pattern has been proposed. We aimed to obtain five 1-year-age-interval pubertal patterns. Longitudinal (6 years of age-adult height) growth study of 1,453 healthy children to evaluate height-for-age, growth velocity-for-age and weight-for-age values. According to age at pubertal growth spurt onset girls were considered: very-early matures (8-9 years, n=119), early matures (9-10 years, n=157), intermediate matures (10-11 years, n=238), late matures (11-12 years, n=127) and very-late matures (12-13 years, n=102), and boys: very-early matures (10-11 years, n=110), early matures (11-12 years, n=139), intermediate matures (12-13 years, n=225), late matures (13-14 years, n=133) and very-late matures (14-15 years, n=103). Age at menarche and growth up to adult height were recorded. In both sexes, statistically-significant (P<.0001) and clinically-pertinent differences in pubertal growth pattern (mean height-for-age, mean growth velocity-for-age and mean pubertal height gain, values) were found among the five pubertal maturity groups and between each group and the whole population, despite similar adult height values. The same occurred for age at menarche and growth from menarche to adult height (P<.05). In both sexes, pubertal growth spurt onset is a critical milestone determining pubertal growth and sexual development. The contribution of our data to better clinical evaluation of growth according to the pubertal maturity tempo of each child will obviate the mistakes made when only one pubertal growth reference is used. Copyright © 2018. Publicado por Elsevier España, S.L.U.

Hemolytic disease of the fetus and newborn with late-onset anemia due to anti-M: a case report and review of the Japanese literature.

PubMed

Yasuda, Hiroyasu; Ohto, Hitoshi; Nollet, Kenneth E; Kawabata, Kinuyo; Saito, Shunnichi; Yagi, Yoshihito; Negishi, Yutaka; Ishida, Atsushi

2014-01-01

Hemolytic disease of the fetus and newborn (HDFN) attributed to M/N-incompatibility varies from asymptomatic to lethally hydropic. Case reports are rare, and the clinical significance of anti-M is not completely understood. A challenging case of HDFN due to anti-M prompted an investigation of the Japanese literature, in order to characterize the clinical spectrum of M/N-incompatibility pregnancies in Japan and report results to English-language readers. Japanese reports of HDFN attributed to M/N incompatibility were compiled. Abstracted data include maternal antibody titers at delivery, fetal direct antiglobulin test, hemoglobin, total bilirubin, reticulocyte count at birth, and therapeutic interventions. We investigated characteristics of HDFN due to M/N-incompatible pregnancies in Japan after encountering a case of severe HDFN along with late-onset anemia in an infant born to a woman carrying IgG anti-M with a titer of 1. In total, thirty-three babies with HDFN due to anti-M and one due to anti-N have been reported in Japan since 1975. The median maternal antibody titer was 64 at delivery and was 16 or less in 10 of 34 women (29%). Five of 34 babies (15%) were stillborn or died as neonates. Twenty-one of 29 survivors (72%) had severe hemolytic anemia and/or hydrops fetalis. The reticulocyte count of neonates with anemia stayed below the reference interval. Sixteen (55%) developed late-onset anemia and 14 (48%) were transfused with M-negative RBCs. Significant positive correlation (P < .05) between the hemoglobin value and the reticulocyte count within 4 days of birth was obtained in 16 babies with anti-M HDFN. In the Japanese population, 21 of 34 cases of M/N-incompatible HDFN (72%) have manifested as severe hemolytic anemia and/or hydrops fetalis. Low reticulocyte count in neonates with late-onset anemia is consistent with suppressed erythropoiesis due to anti-M. © 2013.

Joseph's Story: A Case Study of Late-Onset Necrotizing Enterocolitis From Early Birth to Recovery.

PubMed

Gephart, Sheila M; Martin, Laura B; Kijewski, Amy; Johnson, Scott R

2015-01-01

Although necrotizing enterocolitis (NEC) is often catastrophic among premature infants, most cases occur in the first month after birth. This case study presents Joseph's story about a 24-week surviving twin who developed severe NEC at 5 months of age just days before he was to go home. The purpose of this case study report is to place Joseph and his parents' experience in the context of what is known about NEC risk factors, clinical presentation, and treatment, and then to offer recommendations to healthcare professionals to support families from NEC diagnosis to recovery. Now 5 years old, Joseph continues to manage consequences of NEC including deafness, developmental delay, multiple food allergies, and recurrent gastrointestinal challenges from short gut syndrome. Although NEC struck late and kept Joseph in the neonatal intensive care unit for 228 days, its consequences remain with this resilient child and his family.

Cerebral blood flow changes in very-late-onset schizophrenia-like psychosis with catatonia before and after successful treatment.

PubMed

Tsujino, Naohisa; Nemoto, Takahiro; Yamaguchi, Taiju; Katagiri, Naoyuki; Tohgi, Nao; Ikeda, Ryu; Shiraga, Nobuyuki; Mizumura, Sunao; Mizuno, Masafumi

2011-10-01

The purpose of the present study was to investigate regional cerebral blood flow (rCBF) changes in a patient with very-late-onset schizophrenia-like psychosis (VLOS) with catatonia. A 64-year-old woman developed catatonia after experiencing persecutory delusions. The patient's rCBF was examined using single photon emission computed tomography (SPECT) with easy Z-score imaging system. Before treatment, hypoperfusion was observed in the striatum and the thalamus, whereas hyperperfusion was observed in the left lateral frontal cortex and the left temporal cortex. After treatment, the disproportions in rCBF disappeared, and hyperperfusion was observed in the motor cortex. Sequential SPECT findings suggest that rCBF abnormalities may be correlated with the symptomatology of catatonia in patients with VLOS. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

Trends in baseline CD4 cell counts and risk factors for late antiretroviral therapy initiation among HIV-positive patients in Shanghai, a retrospective cross-sectional study.

PubMed

Sun, Jianjun; Liu, Li; Shen, Jiayin; Chen, Panpan; Lu, Hongzhou

2017-04-19

There are few studies focus on the factors underlying the late initiation of ART in China. We analyzed the trends in the median CD4 cell counts among different patient groups over time and the risk factors for the late initiation of ART in Shanghai, China. A retrospective cross-sectional survey was made in the Department of Infectious Disease of Shanghai Public Health Clinical Center which is a designated diagnosis and treatment center for HIV-positive patients in Shanghai during the period of January 1st, 2008--June 30th, 2014. Late ART initiation was defined as a CD4 cell count <200 cells/mm 3 or having a clinical AIDS diagnosis prior to ART initiation. Trends in the median CD4 cell count at ART initiation and the proportion of late ART initiation by year were evaluated using Spearman's correlations and Chi-squared methods, respectively. We used a logistic regression model to analyze the risk factors for late ART initiation. The related factors collected in the multivariate model were the patient's age, gender, infection routes and marital status. A total of 3796 patients were analyzed in this study, with a median baseline CD4 cell count of 205 cells/mm 3 [interquartile range: 75-287]. The median CD4 cell counts of patients initiating ART late increased from 76 cells/mm 3 in 2008 to 103 cells/mm 3 in 2014 (p < 0.001), and the proportion of late ART initiation decreased from 80% to 45% (p < 0.001). The risk factors for late ART initiation were male gender, heterosexual transmission and older age (>30 years) (p < 0.001). Notable improvements were made in the median CD4 cell count at ART initiation and the proportion of late ART initiation from 2008 to 2014. However, persons with high risk of HIV exposure who are male, older even heterosexual orientation should be given more opportunities to receive frequently screening, earlier diagnoses and timely treatment.

Hypothyroidism in late-onset Pompe disease.

PubMed

Schneider, Joseph; Burmeister, Lynn A; Rudser, Kyle; Whitley, Chester B; Jarnes Utz, Jeanine

2016-09-01

In Pompe disease, a deficiency of acid α-glucosidase enzyme activity leads to pathologic accumulation of glycogen in tissues. Phenotype heterogeneity in Pompe includes an infantile form and late-onset forms (juvenile- and adult-onset forms). Symptoms common to all phenotypes include progressive muscle weakness and worsening respiratory function. Patients with late-onset forms of Pompe disease commonly complain of chronic fatigue and generalized muscle weakness prior to being diagnosed with Pompe disease, and this may lead to consideration of hypothyroidism in the differential diagnosis. This study aimed to evaluate the prevalence of hypothyroidism in the adult-onset form of Pompe disease. Electronic chart review was performed at the Advanced Therapies Clinic at the University of Minnesota Medical Center (UMMC) to identify patients with late-onset Pompe disease. The identified charts were reviewed for a co-diagnosis of hypothyroidism. A query was made to the clinical data repository at UMMC searching diagnosis ICD9 code 244.9 (hypothyroidism not otherwise specified) and/or presence of levothyroxine from 2011 to 2014 in patients 18 years of age and older. The clinical data repository found a prevalence of hypothyroidism of 3.15% (56,072 of 1,782,720 patients) in the adult patient population at UMMC. Ten adult patients with Pompe disease were identified, five with the diagnosis of hypothyroidism (50%, 95% CI: 23.7, 76.3, p < 0.001 compared with the general UMMC adult population). Hypothyroidism was found at a higher prevalence in patients with late-onset Pompe disease compared to the general adult population at UMMC. Studies in larger populations of patients with Pompe disease would be needed to confirm an association of Pompe disease and hypothyroidism. Challenges include finding an adequate sample size, due the rarity of Pompe disease.

Fresh Osteochondral Allograft Transplantation: Is Graft Storage Time Associated With Clinical Outcomes and Graft Survivorship?

PubMed

Schmidt, Kenneth J; Tírico, Luís E; McCauley, Julie C; Bugbee, William D

2017-08-01

Regulatory concerns and the popularity of fresh osteochondral allograft (OCA) transplantation have led to a need for prolonged viable storage of osteochondral grafts. Tissue culture media allow a longer storage time but lead to chondrocyte death within the tissue. The long-term clinical consequence of prolonged storage is unknown. Patients transplanted with OCAs with a shorter storage time would have lower failure rates and better clinical outcomes than those transplanted with OCAs with prolonged storage. Cohort study; Level of evidence, 3. A matched-pair study was performed of 75 patients who received early release grafts (mean storage, 6.3 days [range, 1-14 days]) between 1997 and 2002, matched 1:1 by age, diagnosis, and graft size, with 75 patients who received late release grafts (mean storage time, 20.0 days [range, 16-28 days]) from 2002 to 2008. The mean age was 33.5 years, and the median graft size was 6.3 cm 2 . All patients had a minimum 2-year follow-up. Evaluations included pain, satisfaction, function, failures, and reoperations. Outcome measures included the modified Merle d'Aubigné-Postel (18-point) scale, International Knee Documentation Committee (IKDC) form, and Knee Society function (KS-F) scale. Clinical failure was defined as revision OCA transplantation or conversion to arthroplasty. Among patients with grafts remaining in situ, the mean follow-up was 11.9 years (range, 2.0-16.8 years) and 7.8 years (range, 2.3-11.1 years) for the early and late release groups, respectively. OCA failure occurred in 25.3% (19/75) of patients in the early release group and 12.0% (9/75) of patients in the late release group ( P = .036). The median time to failure was 3.5 years (range, 1.7-13.8 years) and 2.7 years (range, 0.3-11.1 years) for the early and late release groups, respectively. The 5-year survivorship of OCAs was 85% for the early release group and 90% for the late release group ( P = .321). No differences in postoperative pain and function were noted between the groups. Ninety-one percent of the early release group and 93% of the late release group reported satisfaction with OCA results. The transplantation of OCA tissue with prolonged storage is safe and effective for large osteochondral lesions of the knee and has similar clinical outcomes and satisfaction to the transplantation of early release grafts.

Predicting Time to Hospital Discharge for Extremely Preterm Infants

PubMed Central

Hintz, Susan R.; Bann, Carla M.; Ambalavanan, Namasivayam; Cotten, C. Michael; Das, Abhik; Higgins, Rosemary D.

2010-01-01

As extremely preterm infant mortality rates have decreased, concerns regarding resource utilization have intensified. Accurate models to predict time to hospital discharge could aid in resource planning, family counseling, and perhaps stimulate quality improvement initiatives. Objectives For infants <27 weeks estimated gestational age (EGA), to develop, validate and compare several models to predict time to hospital discharge based on time-dependent covariates, and based on the presence of 5 key risk factors as predictors. Patients and Methods This was a retrospective analysis of infants <27 weeks EGA, born 7/2002-12/2005 and surviving to discharge from a NICHD Neonatal Research Network site. Time to discharge was modeled as continuous (postmenstrual age at discharge, PMAD), and categorical variables (“Early” and “Late” discharge). Three linear and logistic regression models with time-dependent covariate inclusion were developed (perinatal factors only, perinatal+early neonatal factors, perinatal+early+later factors). Models for Early and Late discharge using the cumulative presence of 5 key risk factors as predictors were also evaluated. Predictive capabilities were compared using coefficient of determination (R2) for linear models, and AUC of ROC curve for logistic models. Results Data from 2254 infants were included. Prediction of PMAD was poor, with only 38% of variation explained by linear models. However, models incorporating later clinical characteristics were more accurate in predicting “Early” or “Late” discharge (full models: AUC 0.76-0.83 vs. perinatal factor models: AUC 0.56-0.69). In simplified key risk factors models, predicted probabilities for Early and Late discharge compared favorably with observed rates. Furthermore, the AUC (0.75-0.77) were similar to those of models including the full factor set. Conclusions Prediction of Early or Late discharge is poor if only perinatal factors are considered, but improves substantially with knowledge of later-occurring morbidities. Prediction using a few key risk factors is comparable to full models, and may offer a clinically applicable strategy. PMID:20008430

A late neurological complication following posterior correction surgery of severe cervical kyphosis.

PubMed

Hojo, Yoshihiro; Ito, Manabu; Abumi, Kuniyoshi; Kotani, Yoshihisa; Sudo, Hideki; Takahata, Masahiko; Minami, Akio

2011-06-01

Though a possible cause of late neurological deficits after posterior cervical reconstruction surgery was reported to be an iatrogenic foraminal stenosis caused not by implant malposition but probably by posterior shift of the lateral mass induced by tightening screws and plates, its clinical features and pathomechanisms remain unclear. The aim of this retrospective clinical review was to investigate the clinical features of these neurological complications and to analyze the pathomechanisms by reviewing pre- and post-operative imaging studies. Among 227 patients who underwent cervical stabilization using cervical pedicle screws (CPSs), six patients who underwent correction of cervical kyphosis showed postoperative late neurological complications without any malposition of CPS (ND group). The clinical courses of the patients with deficits were reviewed from the medical records. Radiographic assessment of the sagittal alignment was conducted using lateral radiographs. The diameter of the neural foramen was measured on preoperative CT images. These results were compared with the other 14 patients who underwent correction of cervical kyphosis without late postoperative neurological complications (non-ND group). The six patients in the ND group showed no deficits in the immediate postoperative periods, but unilateral muscle weakness of the deltoid and biceps brachii occurred at 2.8 days postoperatively on average. Preoperative sagittal alignment of fusion area showed significant kyphosis in the ND group. The average of kyphosis correction in the ND was 17.6° per fused segment (range 9.7°-35.0°), and 4.5° (range 1.3°-10.0°) in the non-ND group. A statistically significant difference was observed in the degree of preoperative kyphosis and the correction angles at C4-5 between the two groups. The diameter of the C4-5 foramen on the side of deficits was significantly smaller than that of the opposite side in the ND group. Late postoperative neurological complications after correction of cervical kyphosis were highly associated with a large amount of kyphosis correction, which may lead foraminal stenosis and enhance posterior drift of the spinal cord. These factors may lead to both compression and traction of the nerves, which eventually cause late neurological deficits. To avoid such complications, excessive kyphosis correction should not be performed during posterior surgery to avoid significant posterior shift of the spinal cord and prophylactic foraminotomies are recommended if narrow neuroforamina were evident on preoperative CT images. Regardless of revision decompression or observation, the majority of this late neurological complication showed complete recovery over time.

Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases

PubMed Central

Owen, Dawn; Laack, Nadia N.; Mayo, Charles S.; Garces, Yolanda I.; Park, Sean S.; Bauer, Heather J.; Nelson, Kathryn; Miller, Robert W.; Brown, Paul D.; Olivier, Kenneth R.

2015-01-01

Purpose Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases. Methods and Materials Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity <90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria. Results The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1–2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities. Conclusions Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects. PMID:24890360

Causes and outcome of late referral of children who develop end-stage kidney disease.

PubMed

Kennedy, Sean E; Bailey, Rohan; Kainer, Gad

2012-03-01

This study aims to characterise the timing of referral to a paediatric nephrology unit of children who develop end-stage kidney disease (ESKD). This study also aims to determine whether late referral (LR) influences outcomes and to explore factors that may lead to LR. A retrospective case review of all incident patients with ESKD who received renal replacement therapy (RRT) at a single paediatric centre. Time between referral to a paediatric nephrologist and commencement of RRT, demographic and clinical data were collated. Estimated glomerular filtration rate (eGFR) at referral was calculated using height and creatinine. LR was defined as having an eGFR ≤ 30 mL/min/1.73 m(2) when first seen by a paediatric nephrologist. RRT was initiated for 74 patients < 18 years of age between 1988 and 2010. The median age at referral was 2.0 years (birth-15.9 years) and age at RRT was 10.0 years (6 days-17.4 years). Children referred before age 1 year (41%) had a more prolonged course before ESKD. Median (interquartile range) eGFR at referral of children > 1 year was 27.2 (9.0-52.0) mL/min/1.73 m(2) . Twenty-two (55%) of these children were referred late (LR) with an eGFR ≤ 30 mL/min/1.73 m(2) . LR patients were more likely to have glomerulonephritis or haemolytic uraemic syndrome and to live in a remote or outer regional area. LR patients had higher urea, lower haemoglobin and were more likely to receive haemodialysis via a vascular catheter. A significant proportion of children who develop ESKD are referred late to nephrology units with potentially preventable complications. Aetiology of renal disease and geographic isolation contribute to LR. © 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases.

PubMed

Owen, Dawn; Laack, Nadia N; Mayo, Charles S; Garces, Yolanda I; Park, Sean S; Bauer, Heather J; Nelson, Kathryn; Miller, Robert W; Brown, Paul D; Olivier, Kenneth R

2014-01-01

Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases. Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity <90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria. The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1-2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities. Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease.

PubMed

Schöll, Michael; Ossenkoppele, Rik; Strandberg, Olof; Palmqvist, Sebastian; Jögi, Jonas; Ohlsson, Tomas; Smith, Ruben; Hansson, Oskar

2017-09-01

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Determinants and prevalence of late HIV testing in Tijuana, Mexico.

PubMed

Carrizosa, Claudia M; Blumberg, Elaine J; Hovell, Melbourne F; Martinez-Donate, Ana P; Garcia-Gonzalez, Gregorio; Lozada, Remedios; Kelley, Norma J; Hofstetter, C Richard; Sipan, Carol L

2010-05-01

Timely diagnosis of HIV is essential to improve survival rates and reduce transmission of the virus. Insufficient progress has been made in effecting earlier HIV diagnoses. The Mexican border city of Tijuana has one of the highest AIDS incidence and mortality rates in all of Mexico. This study examined the prevalence and potential correlates of late HIV testing in Tijuana, Mexico. Late testers were defined as participants who had at least one of: (1) an AIDS-defining illness within 1 year of first positive HIV test; (2) a date of AIDS diagnosis within 1 year of first positive HIV test; or (3) an initial CD4 cell count below 200 cells per microliter within 1 year of first positive HIV test. Medical charts of 670 HIV-positive patients from two HIV/AIDS public clinics in Tijuana were reviewed and abstracted; 362 of these patients were interviewed using a cross-sectional survey. Using multivariate logistic regression, we explored potential correlates of late HIV testing based on the Behavioral Ecological Model. From 342 participants for whom late testing could be determined, the prevalence of late testing was 43.2%. Multivariate logistic regression results (n = 275) revealed five significant correlates of late testing: "I preferred not to know I had HIV" (adjusted odds ratio [AOR] = 2.78, 1.46-5.31); clinic (AOR = 1.90, 1.06-3.41); exposure to peers engaging in high-risk sexual behavior (AOR = 1.14, 1.02-1.27); stigma regarding HIV-infected individuals (AOR = 0.65, 0.47-0.92); and stigma regarding HIV testing (AOR = 0.66, 0.45-0.97). These findings may inform the design of interventions to increase timely HIV testing and help reduce HIV transmission in the community at large.

Preventability of early vs. late readmissions in an academic medical center

PubMed Central

Graham, Kelly L.; Dike, Ogechi; Doctoroff, Lauren; Jupiter, Marisa; Vanka, Anita

2017-01-01

Background It is unclear if the 30-day unplanned hospital readmission rate is a plausible accountability metric. Objective Compare preventability of hospital readmissions, between an early period [0–7 days post-discharge] and a late period [8–30 days post-discharge]. Compare causes of readmission, and frequency of markers of clinical instability 24h prior to discharge between early and late readmissions. Design, setting, patients 120 patient readmissions in an academic medical center between 1/1/2009-12/31/2010 Measures Sum-score based on a standard algorithm that assesses preventability of each readmission based on blinded hospitalist review; average causation score for seven types of adverse events; rates of markers of clinical instability within 24h prior to discharge. Results Readmissions were significantly more preventable in the early compared to the late period [median preventability sum score 8.5 vs. 8.0, p = 0.03]. There were significantly more management errors as causative events for the readmission in the early compared to the late period [mean causation score [scale 1–6, 6 most causal] 2.0 vs. 1.5, p = 0.04], and these errors were significantly more preventable in the early compared to the late period [mean preventability score 1.9 vs 1.5, p = 0.03]. Patients readmitted in the early period were significantly more likely to have mental status changes documented 24h prior to hospital discharge than patients readmitted in the late period [12% vs. 0%, p = 0.01]. Conclusions Readmissions occurring in the early period were significantly more preventable. Early readmissions were associated with more management errors, and mental status changes 24h prior to discharge. Seven-day readmissions may be a better accountability measure. PMID:28622384

Late onset globoid cell leukodystrophy.

PubMed Central

Grewal, R P; Petronas, N; Barton, N W

1991-01-01

A 29 year old male with onset of globoid cell leukodystrophy at age 14 is described. This is the first case of enzymatically confirmed globoid cell leukodystrophy with onset of symptoms after the age of ten. This patient is unique because of the late onset and slow progression and extends the clinical spectrum of globoid cell leukodystrophy. Images PMID:1800646

Brief Report: Direct and Indirect Relations of Risk Factors with Eating Behavior Problems in Late Adolescent Females

ERIC Educational Resources Information Center

Mayer, Birgit; Muris, Peter; Meesters, Cor; Zimmermann-van Beuningen, Ritine

2009-01-01

This study explored correlations between risk factors and eating behavior problems in late adolescent, non-clinical females (N = 301). Participants completed questionnaires for assessing eating problems, the closely associated factors of Body Mass Index (BMI) and body dissatisfaction, and a number of other risk variables that are thought to be…

Pretreatment data is highly predictive of liver chemistry signals in clinical trials

PubMed Central

Cai, Zhaohui; Bresell, Anders; Steinberg, Mark H; Silberg, Debra G; Furlong, Stephen T

2012-01-01

Purpose The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. Patients and methods Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. Results Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy’s law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. Conclusion It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones. PMID:23226004

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach.

PubMed

Bukowski, Ronald M

2010-10-01

Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual. The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and--most recently--pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed. This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients. As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.

Development of the small-molecule antiviral ST-246® as a smallpox therapeutic

PubMed Central

Grosenbach, Douglas W; Jordan, Robert; Hruby, Dennis E

2011-01-01

Naturally occurring smallpox has been eradicated, yet it remains as one of the highest priority pathogens due to its potential as a biological weapon. The majority of the US population would be vulnerable in a smallpox outbreak. SIGA Technologies, Inc. has responded to the call of the US government to develop and supply to the Strategic National Stockpile a smallpox antiviral to be deployed in the event of a smallpox outbreak. ST-246® (tecovirimat) was initially identified via a high-throughput screen in 2002, and in the ensuing years, our drug-development activities have spanned in vitro analysis, preclinical safety, pharmacokinetics and efficacy testing (all according to the ‘animal rule’). Additionally, SIGA has conducted Phase I and II clinical trials to evaluate the safety, tolerability and pharmacokinetics of ST-246, bringing us to our current late stage of clinical development. This article reviews the need for a smallpox therapeutic and our experience in developing ST-246, and provides perspective on the role of a smallpox antiviral during a smallpox public health emergency. PMID:21837250

A Pathological Late Pleistocene canid from San Sidero (Italy): implications for social- and feeding-behaviour

NASA Astrophysics Data System (ADS)

Iurino, Dawid Adam; Fico, Rosario; Petrucci, Mauro; Sardella, Raffaele

2013-03-01

Evidence of diseases on vertebrate fossil bones can provide detailed information on many aspects of extinct animals. This study focused on pathological craniodental remains (left maxilla and dentary) referred to the canid Cuon alpinus unearthed from a Late Pleistocene karst filling deposit at San Sidero (Apulia, southern Italy). These fossils show clear evidence of a chronic periodontitis that caused the animal's death. Clinical diagnosis of the disease and the timing of its development have been defined on the basis of a veterinary odontostomatology approach, in addition to radiographic and tomographic techniques. From the initiation of the infection until death, a time span of at least 6 months occurred, and three main steps have been defined: (1) the bacterial infections of the buccal cavity turning into severe periodontitis, (2) the fracture of the lower carnassial and (3) the loss of teeth due to the worsening infection that deformed and/or eroded maxillary and mandibular bones and enlarged alveoli. The analysis of the palaeopathology also provides information about the biomechanics of the bite, on the feeding behaviour and on the relationships of injured members in a pack of Late Pleistocene canids.

Risk factors of infant anemia in the perinatal period.

PubMed

Hirata, Michio; Kusakawa, Isao; Ohde, Sachiko; Yamanaka, Michiko; Yoda, Hitoshi

2017-04-01

Infants are at particular risk of iron-deficiency anemia. We investigated changes in the blood count of the mother and infant as well as the relationship between them and the relationship between infant nutrition method and infant anemia. This retrospective cohort study included healthy neonates born between August 2011 and July 2014 at St Luke's International Hospital, Tokyo, Japan. Data from maternal blood samples obtained during late pregnancy and those of infants obtained at birth and at the age of 3, 6, and 9 months were analyzed. Using multivariate logistic regression, we investigated nutrition methods, maternal anemia, and other clinically relevant parameters that were potential risk factors for infant anemia. In total, data for 3472 infants and their mothers were analyzed. Nutrition method was the most significant risk factor for infant anemia, with risk of future anemia decreasing in the following order: exclusive breast-feeding, partial breast-feeding, and formula feeding. Furthermore, low umbilical cord blood hemoglobin led to a tendency toward anemia in the child. Infant nutrition method was the most significant factor related to anemia in late infancy. Infants with low umbilical cord blood hemoglobin are more likely to develop anemia in late infancy. © 2016 Japan Pediatric Society.

IQ at age 12 following a history of institutional care: Findings from the Bucharest Early Intervention Project

PubMed Central

Almas, Alisa N.; Degnan, Kathryn A.; Nelson, Charles A.; Zeanah, Charles H.; Fox, Nathan A.

2016-01-01

Young children removed from institutions and placed into foster care or adoptive homes have been shown to experience significant gains in IQ relative to children who remain in institutions. Less is known about the long-term impact of severe early deprivation on development in late childhood. Data are presented from a follow-up of children at 12 years of age in the Bucharest Early Intervention Project, a randomized clinical trial of foster care for institutionally reared children. One hundred and seven of the original 136 children in the study were tested with the WISC IV. Results revealed continued benefit from the intervention through age 12, with 12-year-old children placed in foster care scoring significantly higher on full scale IQ compared to their peers who received prolonged institutional care. Longitudinal IQ data revealed two IQ profiles from early to late childhood. Attachment security emerged as a significant predictor of a profile of stable, typical IQ scores over time. We demonstrate the continued importance of foster care intervention and the negative effects of severe, early psychosocial deprivation on IQ into late childhood. PMID:27709994

IQ at age 12 following a history of institutional care: Findings from the Bucharest Early Intervention Project.

PubMed

Almas, Alisa N; Degnan, Kathryn A; Nelson, Charles A; Zeanah, Charles H; Fox, Nathan A

2016-11-01

Young children removed from institutions and placed into foster care or adoptive homes have been shown to experience significant gains in IQ relative to children who remain in institutions. Less is known about the long-term impact of severe early deprivation on development in late childhood. Data are presented from a follow-up of children at 12 years of age in the Bucharest Early Intervention Project, a randomized clinical trial of foster care for institutionally reared children. Of the original 136 children in the study, 107 were tested with the Wechsler Intelligence Scale for Children-IV. Results revealed continued benefit from the intervention through age 12, with 12-year-old children placed in foster care scoring significantly higher on full-scale IQ compared to their peers who received prolonged institutional care. Longitudinal IQ data revealed 2 IQ profiles from early to late childhood. Attachment security emerged as a significant predictor of a profile of stable, typical IQ scores over time. We demonstrate the continued importance of foster care intervention and the negative effects of severe, early psychosocial deprivation on IQ into late childhood. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Late-onset schizophrenia: do recent studies support categorizing LOS as a subtype of schizophrenia?

PubMed

Maglione, Jeanne E; Thomas, Scot E; Jeste, Dilip V

2014-05-01

To review recent literature about late-onset schizophrenia (LOS): schizophrenia with onset between ages 40 and 60 years. New findings are presented in the context of the previous literature. Newer studies continue to suggest that early-onset schizophrenia (EOS) and LOS share fundamental clinical features (i.e., positive symptoms, negative symptoms, functional deficits). One larger recent study confirmed earlier findings that LOS differs from EOS in several important ways, including predominance of women, lower severity of positive symptoms, and lower average antipsychotic dose requirement. However, this study did not find LOS patients were more likely to have the paranoid subtype or to have less severe negative symptoms compared with EOS patients. New neuroimaging and molecular studies are identifying possible differences in the underlying pathophysiology of EOS and schizophrenia developing in mid-life to late-life; however, more research is needed to confirm these findings and determine their significance. No studies evaluated treatment strategies specifically in LOS. LOS continues to be an understudied area. Recent studies add support to the idea that LOS may be a distinct subtype of schizophrenia. Studies designed to elucidate the pathophysiology of LOS in comparison with EOS and to assess treatment strategies in this population are needed.

Surgery without papilla incision: tunneling flap procedures in plastic periodontal and implant surgery.

PubMed

Zuhr, Otto; Rebele, Stephan F; Cheung, Stefani L; Hürzeler, Markus B

2018-06-01

Diverse clinical advancements, together with some relevant technical innovations, have led to an increase in popularity of tunneling flap procedures in plastic periodontal and implant surgery in the recent past. This trend is further promoted by the fact that these techniques have lately been introduced to a considerably expanded range of indications. While originally described for the treatment of gingival recession-type defects, tunneling flap procedures may now be applied successfully in a variety of clinical situations in which augmentation of the soft tissues is indicated in the esthetic zone. Potential clinical scenarios include surgical thickening of thin buccal gingiva or peri-implant mucosa, alveolar ridge/socket preservation and implant second-stage surgery, as well as soft-tissue ridge augmentation or pontic site development. In this way, tunneling flap procedures developed from a technique, originally merely intended for surgical root coverage, into a capacious surgical conception in plastic periodontal and implant surgery. The purpose of this article is to provide a comprehensive overview on tunneling flap procedures, to introduce the successive development of the approach along with underlying ideas on surgical wound healing and to present contemporary clinical scenarios in step-by-step photograph-illustrated sequences, which aim to provide clinicians with guidance to help them integrate tunneling flap procedures into their daily clinical routine. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Metabolic syndrome pathophysiology and clinical presentation.

PubMed

Handelsman, Yehuda

2009-01-01

Metabolic syndrome is a relatively new definition, designed to help the health care practitioner to easily identify people at risk for the development of cardiovascular disease and diabetes. With the obesity epidemic, we are witnessing an epidemic of multiple-risk patients. Insulin resistance is the perceived pathophysiology of metabolic syndrome and defines its clinical presentation. Hypertension, dyslipedemia, polycystic ovarian syndrome, fatty liver disease, pre-diabetes, sleep and breathing disorder, certain cancers, and cognitive impairment are many of the presentations of the syndrome; patients with any of these conditions are at a high risk of developing cardiovascular disease and diabetes. The metabolic syndrome helps identify people at risk to allow early intervention for prevention. Lifestyle modification is the most important part of the management of people with the syndrome. Lately medications--though none approved by the U.S. Food and Drug Administration (FDA)--have been recommended by major medical societies when lifestyle modification is not enough or when it fails.

A Brief History of Vaccines Against Polio.

PubMed

Vashishtha, Vipin M; Kamath, Sachidanand

2016-08-07

Poliomyelitis, a dreaded disease of the last century that had already crippled millions of people across the globe, is now on the verge of eradication thanks mainly to two polio vaccines, inactivated polio vaccine (IPV) and oral polio vaccine (OPV). Ever since their development in late 1950s and early 1960s, the journey of their early development process, clinical trials, licensure and ultimately widespread clinical use in different countries provide a fascinating tale of events. Oral polio vaccine has been the mainstay of global polio eradication initiative (GPEI) in most of the countries. With the advent of 'polio endgame', the focus has now shifted back to IPV. However, there are certain issues associated with global cessation of OPV use and universal implementation of IPV in routine immunization schedules across the globe that need to be dealt with some urgency, before proclaiming the global victory over polio.

Proton radiography and tomography with application to proton therapy

PubMed Central

Allinson, N M; Evans, P M

2015-01-01

Proton radiography and tomography have long promised benefit for proton therapy. Their first suggestion was in the early 1960s and the first published proton radiographs and CT images appeared in the late 1960s and 1970s, respectively. More than just providing anatomical images, proton transmission imaging provides the potential for the more accurate estimation of stopping-power ratio inside a patient and hence improved treatment planning and verification. With the recent explosion in growth of clinical proton therapy facilities, the time is perhaps ripe for the imaging modality to come to the fore. Yet many technical challenges remain to be solved before proton CT scanners become commonplace in the clinic. Research and development in this field is currently more active than at any time with several prototype designs emerging. This review introduces the principles of proton radiography and tomography, their historical developments, the raft of modern prototype systems and the primary design issues. PMID:26043157

Factors determining late antenatal care booking and the content of care among pregnant mother attending antenatal care services in East Wollega administrative zone, West Ethiopia.

PubMed

Ejeta, Eyasu; Dabsu, Regea; Zewdie, Olifan; Merdassa, Elias

2017-01-01

Antenatal care (ANC) is important for both maternal and fetal health. However, the existing evidence from developing countries indicates that most pregnant women attending ANC in their late pregnancy. Little is known about the factors determining ANC booking and the content of care among pregnant women in West part of Ethiopia. Therefore, the present study was conducted to identify factors determining late ANC booking and the content of care among pregnant mother attending antenatal care services in East Wollega administrative zone, West Ethiopia. Institutional based cross-sectional study was conducted from July to September, 2014 among 421 pregnant women's attending ANC services in purposively selected health facilities, East Wollega zone, Ethiopia. The pretested-structured questionnaires were used to collect socio-demographic data and predictor factors of late initiation of ANC services. Five trained nurse working at ANC clinic at each health institution administered the questionnaire. The collected data was analysed using SPSS version 20. The prevalence of late ANC booking was 81.5% (343/421) in the study area. Being from Oromo ethnic group (AOR 4.27, (95% CI, 1.48-12.33)), maternal age equal or more than 25 year old (AOR 3.09 (95% CI, 1.53-6.27)), second trimester (AOR 6.05(95% CI, 3.08-11.88)) and third trimester (AOR 7.97 (95% CI, 3.92-16.23)) were main factors identified as contributing (favoring factors) for the likely occurrence of late booking for ANC whereas; monthly income more than and/or equal to 15000 Ethiopian birrs (AOR 0.38 (95% CI, 0.18-084)) were factors compromising (decreasing) the chances for late attendance for the services among the pregnant women. Late ANC initiation is high in the study area despite the services is provided free of charge. Hence, it is important to provide health education on the timing of ANC among women with reproductive age. Community's awareness on importance of receiving early ANC also needs to be promoted.

Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury.

PubMed

Su, Hong-Lin; Chiang, Chien-Yi; Lu, Zong-Han; Cheng, Fu-Chou; Chen, Chun-Jung; Sheu, Meei-Ling; Sheehan, Jason; Pan, Hung-Chuan

2018-06-25

High-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery. Animals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-α and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-α, synaptophysin, and NGF in accordance with the in vivo results. Immediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application.

Clinical and epidemiological features of HIV/AIDS infection among migrants at first access to healthcare services as compared to Italian patients in Italy: a retrospective multicentre study, 2000-2010.

PubMed

Sulis, G; El Hamad, I; Fabiani, M; Rusconi, S; Maggiolo, F; Guaraldi, G; Bozzi, G; Bernardini, C; Lichtner, M; Stentarelli, C; Carenzi, L; Francisci, D; Saracino, A; Castelli, F

2014-10-01

Migrants account for approximately 8.7% of the resident population in Italy. The immigration status deeply influences access to prevention and care, thus contributing to increase the burden of HIV/AIDS among such a fragile category. The aim of this study was to investigate socio-demographic and baseline clinical and immunological features of HIV-infected migrants, as compared to Italians. We retrospectively analysed data for all the 1,611 HIV-infected migrant patients and a random sample of 4,230 HIV-infected Italian patients aged 18 or older who first accessed nine Italian clinical centres in 2000-2010 and were followed up at least 1 year. Differences in baseline characteristics between migrants and Italians were evaluated in univariate analysis, while factors associated with late presentation were evaluated in multivariate analysis using logistic regression models. The baseline profile differs between the HIV-infected migrant and Italian patients, substantially reflecting what reported by current statistics in terms of gender, age, risk category as well as clinical features. Late presenters were more frequent among migrants as compared to Italians (53.0 vs 45.8%; adjusted odds ratio [(AOR) = 1.55, 95% confidence interval (CI) 1.34-1.78]. Other factors associated with late presentation included increasing age, as well as undocumented legal status among foreign-born subjects (AOR = 1.41, 95% CI 0.97-2.04), though of borderline significance. Late presentation still represents a relevant problem despite the advances in the management of HIV infection. More efforts are needed to allow early diagnosis and access to care among the most vulnerable, such as undocumented foreign-born subjects in a country where migration flows are on the rise.

Skin denervation and its clinical significance in late-stage chronic kidney disease.

PubMed

Chao, Chi-Chao; Wu, Vin-Cent; Tan, Chun-Hsiang; Wang, Yi-Mei; Tseng, Ming-Tsung; Wu, Pei-Chen; Lin, Yea-Huey; Lin, Whei-Min; Wu, Kwan-Dun; Hsieh, Sung-Tsang

2011-02-01

To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD). Case series. National Taiwan University Hospital, Taipei, Taiwan. Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease. Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg. Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response. Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P < .001). Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03). Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease.

PCMO L01-Setting Specifications for Biological Investigational Medicinal Products.

PubMed

Krause, Stephan O

2015-01-01

This paper provides overall guidance and best practices for the setting of specifications for clinical biological drug substances and drug products within the framework of ICH guidelines on pharmaceutical development [Q8(R2) and Q11], quality risk management (Q9), and quality systems (Q10). A review is provided of the current regulatory expectations for the specification setting process as part of a control strategy during product development, pointing to existing challenges for the investigational new drug/investigational medicinal product dossier (IND/IMPD) sponsor. A case study illustrates how the investigational medicinal product specification revision process can be managed within a flexible quality system, and how specifications can be set and justified for early and late development stages. This paper provides an overview for the setting of product specifications for investigational medicinal products used in clinical trials. A case study illustrates how product specifications of investigational medicinal products can be justified and managed within a modern product quality system. © PDA, Inc. 2015.

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer.

PubMed

Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Tomiguchi, Mai; Sueta, Aiko; Murakami, Keiichi; Iwase, Hirotaka

2018-02-26

The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.

Morfeo Study II: Clinical Course and Complications in Patients With Long-Term Disorders of Consciousness.

PubMed

Romaniello, Caterina; Bertoletti, Erik; Matera, Nunzio; Farinelli, Marina; Pedone, Vincenzo

2016-06-01

The life expectancy of patients with disorders of consciousness (DOCs) is ever-increasing, but little is known about their clinical course over late stages. Several issues (premorbid conditions, complications and pressure sores) are to be considered for their effect on clinical outcome, risk of death and recovery of functional performance. Unfortunately, in late stages of long-term rehabilitation, these aspects are still more neglected than in acute and postacute stages. The aim of this study was to investigate the clinical course and the complications of patients in the late stages of DOCs and to explore the relationship between mortality and specific biomarkers. A total of 112 patients, admitted over 10 years in a dedicated ward, were retrospectively studied. Sociodemographic data, preadmission and inpatient clinical features were collected. Disability Rating Scale scores, complications including pressure sores and blood markers were assessed monthly. Data were analyzed through descriptive statistics and correlations using SPSS. Most patients were men older than 50 years with a nontraumatic etiology and a history of hypertension (42.86%). The most common complication was pneumonia (76.79%). No association was found between sex and mortality or between etiology and mortality (P > 0.05). Mortality correlated significantly with sepsis (ρ = 0.253), albumin (ρ = -0.558), hemoglobin (ρ = -0.354) and white blood cells (ρ = 0.243). Only 42% of patients remained unchanged at Disability Rating Scale evaluation. These data confirmed that DOCs are not static conditions and they require ongoing monitoring and assessment of clinical status, level of consciousness and laboratory biomarkers. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Clinical outcome and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation: Case report and literature review.

PubMed

Li, Suyun; Li, Zhi; Hua, Wenbin; Wang, Kun; Li, Shuai; Zhang, Yunkun; Ye, Zhewei; Shao, Zengwu; Wu, Xinghuo; Yang, Cao

2017-12-01

Thoracic-lumbar vertebral fracture is very common in clinic, and late post-traumatic kyphosis is the main cause closely related to the patients' life quality, which has evocated extensive concern for the surgical treatment of the disease. This study aimed to analyze the clinical outcomes and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation. All patients presented back pain with kyphotic apex vertebrae between T12 and L3. According to Frankel classification grading system, among them, 3 patients were classified as grade D, with the ability to live independently. A systematic review of 12 case series of post-traumatic kyphosis after failed thoracolumbar fracture operation was involved. Wedge osteotomy was performed as indicated-posterior closing osteotomy correction in 5 patients and anterior open-posterior close correction in 7 patients.Postoperatively, thoracolumbar x-rays were obtained to evaluate the correction of kyphotic deformity, visual analog scales (VAS) and Frankel grading system were used for access the clinical outcomes. All the patients were followed up, with the average period of 38.5 months (range 24-56 months). The Kyphotic Cobb angle was improved from preoperative (28.65 ± 11.41) to postoperative (1.14 ± 2.79), with the correction rate of 96.02%. There was 1 case of intraoperative dural tear, without complications such as death, neurological injury, and wound infection. According to Frankel grading system, no patient suffered deteriorated neurological symptoms after surgery, and 2 patients (2/3) experienced significant relief after surgery. The main VAS score of back pain was improved from preoperative (4.41 ± 1.08) to postoperative (1.5 ± 0.91) at final follow-up, with an improvement rate of 65.89%. Surgical treatment of late post-traumatic kyphosis after failed thoracolumbar fracture operation can obtain good radiologic and clinical outcomes by kyphosis correction, decompression, and posterior stability.

Clinical outcome and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation

PubMed Central

Li, Suyun; Li, Zhi; Hua, Wenbin; Wang, Kun; Li, Shuai; Zhang, Yunkun; Ye, Zhewei; Shao, Zengwu; Wu, Xinghuo; Yang, Cao

2017-01-01

Abstract Rationale: Thoracic-lumbar vertebral fracture is very common in clinic, and late post-traumatic kyphosis is the main cause closely related to the patients’ life quality, which has evocated extensive concern for the surgical treatment of the disease. This study aimed to analyze the clinical outcomes and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation. Patient concerns: All patients presented back pain with kyphotic apex vertebrae between T12 and L3. According to Frankel classification grading system, among them, 3 patients were classified as grade D, with the ability to live independently. Diagnoses: A systematic review of 12 case series of post-traumatic kyphosis after failed thoracolumbar fracture operation was involved. Interventions: Wedge osteotomy was performed as indicated—posterior closing osteotomy correction in 5 patients and anterior open-posterior close correction in 7 patients.Postoperatively, thoracolumbar x-rays were obtained to evaluate the correction of kyphotic deformity, visual analog scales (VAS) and Frankel grading system were used for access the clinical outcomes. Outcomes: All the patients were followed up, with the average period of 38.5 months (range 24–56 months). The Kyphotic Cobb angle was improved from preoperative (28.65 ± 11.41) to postoperative (1.14 ± 2.79), with the correction rate of 96.02%. There was 1 case of intraoperative dural tear, without complications such as death, neurological injury, and wound infection. According to Frankel grading system, no patient suffered deteriorated neurological symptoms after surgery, and 2 patients (2/3) experienced significant relief after surgery. The main VAS score of back pain was improved from preoperative (4.41 ± 1.08) to postoperative (1.5 ± 0.91) at final follow-up, with an improvement rate of 65.89%. Lessons: Surgical treatment of late post-traumatic kyphosis after failed thoracolumbar fracture operation can obtain good radiologic and clinical outcomes by kyphosis correction, decompression, and posterior stability. PMID:29245233

Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

PubMed

Maruyama, Hiroki; Miyata, Kaori; Mikame, Mariko; Taguchi, Atsumi; Guili, Chu; Shimura, Masaru; Murayama, Kei; Inoue, Takeshi; Yamamoto, Saori; Sugimura, Koichiro; Tamita, Koichi; Kawasaki, Toshihiro; Kajihara, Jun; Onishi, Akifumi; Sugiyama, Hitoshi; Sakai, Teiko; Murata, Ichijiro; Oda, Takamasa; Toyoda, Shigeru; Hanawa, Kenichiro; Fujimura, Takeo; Ura, Shigehisa; Matsumura, Mimiko; Takano, Hideki; Yamashita, Satoshi; Matsukura, Gaku; Tazawa, Ryushi; Shiga, Tsuyoshi; Ebato, Mio; Satoh, Hiroshi; Ishii, Satoshi

2018-03-15

PurposePlasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females.MethodsBetween 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively.ResultsOf 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml -1 ) and low α-Gal A activity (≤4.0 nmol h -1  ml -1 ), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance).ConclusionPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.Genet Med advance online publication, 15 March 2018; doi:10.1038/gim.2018.31.

Future directions in bladder cancer immunotherapy: towards adaptive immunity

PubMed Central

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

Future directions in bladder cancer immunotherapy: towards adaptive immunity.

PubMed

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

From blood to breath: New horizons for esophageal cancer biomarkers

PubMed Central

Yazbeck, Roger; Jaenisch, Simone E; Watson, David I

2016-01-01

Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non-invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers. PMID:28028355

Reliability and validity of the PHQ-9 for screening late-life depression in Chinese primary care.

PubMed

Chen, Shulin; Chiu, Helen; Xu, Baihua; Ma, Yan; Jin, Tao; Wu, Manhua; Conwell, Yeates

2010-11-01

The aim of this study was to examine the reliability and validation of the 9-item Patient Health Questionnaire (PHQ-9) for late-life depression in Chinese primary care. In the primary care clinics (PCCs) of Hangzhou city, we recruited 364 older patients (aged ≥ 60) for the PHQ-9 screening. Then 77 of them were further interviewed with Structured Clinical Interview for DSM Disorders (SCID) for the diagnosis of major depression in late life. Statistic strategies for the feasibility, reliability, validity, and receiver operating characteristic curve were performed. The mean administration time was 7.5 min, and the Cronbach's α was 0.91. The optimal cut-off score of PHQ-9 ≥ 9 revealed a sensitivity of 0.86, specificity of 0.77, and positive likelihood ratio of 5.73. The area under the curve (AUC) in this study was 0.92 (SD = 0.02, 95% CI 0.88-0.96). The PHQ-2 also revealed good sensitivity (0.84) and specificity (0.90) at the cut-off point ≥ 3. The PHQ-9 performs well and has acceptable psychometric properties for screening of patients with late-life depression in Chinese primary care settings.

A prospective cohort study on the clinical utility of second trimester mean arterial blood pressure in the prediction of late-onset preeclampsia among Nigerian women.

PubMed

Udenze, I C; Arikawe, A P; Makwe, C C; Olowoselu, O F

2017-06-01

Early detection of preeclampsia will help reduce the morbidities and mortalities associated with the disorder. Late-onset preeclampsia was the predominant presentation in this cohort. The search for biomarkers for predicting preeclampsia is still ongoing. Mean arterial blood pressure (MABP), which has the advantage of presenting a single cutoff value compared with the use of systolic and diastolic blood pressure measurements, merits evaluation. The study aims to evaluate the clinical utility of second trimester MABP in the prediction of preeclampsia. This was a prospective cohort study of 155 normotensive, nonproteinuric pregnant women without prior history of gestational hypertension. The women were booked patients attending the antenatal clinic at the Lagos University Teaching Hospital and were all in their second trimesters of pregnancy. The outcome measures were systolic blood pressure, diastolic blood pressure, and MABP. The end point of the study was the development of preeclampsia. The diagnosis of preeclampsia was made by the attending obstetrician. The data were analyzed using the IBM SPSS statistical software. Statistical significance was set at P < 0.05. One hundred and fifty-five pregnant women participated in the study. Eleven (7.1%) of the women developed preeclampsia after 34 weeks gestation and 144 (92.9%) had normal pregnancy. The mean gestational age at the time of assessment was 18.88 ± 3.15 weeks with a range of 14 weeks to 27 completed weeks. There was a statistically significant increase in the systolic blood pressure, diastolic blood pressure, and MABP values in the group of women who later developed preeclampsia, P = 0.005, 0.001, and <0.001, respectively. At a false-positive rate of 10%, MABP value of 88.33 mmHg predicted preeclampsia with a specificity of 90% and a sensitivity of 45.5%, P <0.05. The area under the receiver-operative characteristics curve (AUC) was 0.732 (95% confidence interval, 0.544-0.919, P = 0.011). The negative predictive value (NPV) was 88.88% and the positive predictive value (PPV) was 45.45%, P < 0.05. At an MABP cutoff of 88.33 mmHg, preeclampsia was predicted with a relative risk of 4.44 and a positive likelihood ratio of 6.46, P < 0.05. With an AUC of 0.732, MABP performed moderately (considering that excellent performance has an AUC of 1.0) in the prediction of late-onset preeclampsia in Nigerian women. Its high NPV suggests a strong ability to rule out preeclampsia and help to appropriate management.

Early- versus late-onset obsessive-compulsive disorder: investigating genetic and clinical correlates.

PubMed

Hemmings, Sîan M J; Kinnear, Craig J; Lochner, Christine; Niehaus, Dana J H; Knowles, James A; Moolman-Smook, Johanna C; Corfield, Valerie A; Stein, Dan J

2004-09-30

There is increasing evidence that obsessive-compulsive disorder (OCD) is mediated by genetic factors. Although the precise mechanism of inheritance is unclear, recent evidence has pointed towards the involvement of the serotonergic and dopaminergic systems in the disorder's development. Furthermore, early-onset OCD appears to be a subtype that exhibits distinct clinical features and that is associated with greater familial loading. In the present investigation, South African OCD patients (n=252) were stratified according to age of onset and were clinically assessed. Additionally, selected variants in genes encoding serotonergic and dopaminergic components were investigated in a Caucasian OCD subset (n=180). This subgroup was further stratified to evaluate the role that these candidate genes may play in the genetically homogeneous Afrikaner subset (n=80). Analysis of the clinical data revealed an association between early age of onset and an increased frequency of tics, Tourette's disorder, and trichotillomania (TTM). The genetic studies yielded statistically significant results when the allelic distributions of genetic variants in the dopamine receptor type 4 gene (DRD4) were analysed in the Caucasian OCD cohort. These data support a role for the dopaminergic system, which may be relevant to the development of early-onset OCD.

Neurodevelopmental outcome of the late preterm infant.

PubMed

Adams-Chapman, Ira

2006-12-01

There is very limited information about the developmental outcome of the late preterm infant. The developing brain is vulnerable to injury during this very active and important stage of fetal brain development; therefore, it is important to carefully monitor the neurologic outcome of these infants. This article discusses gestational brain development and complications of late preterm birth that contribute to the overall risk of brain injury.

Development and use of biochemical markers in osteoarthritis: current update.

PubMed

Bay-Jensen, Anne C; Thudium, Christian S; Mobasheri, Ali

2018-01-01

There is an increasing demand for noninvasive and descriptive biochemical markers (biomarkers) in osteoarthritis; for enabling early drug development (including translational research), evaluating clinical trial at an early stage and for subtyping. Purpose of the review is to review and comment on current availability of such biomarkers. Many different biomarkers have been tested in the last 18 months. The main focus has been on testing whether the biomarkers, whether is reflect joint tissue turnover or inflammatory status, can differentiate osteoarthritis patients from healthy controls or whether the biomarkers are associated with progression. Less than a handful of studies, investigate the role of the biomarkers as response markers. Thus, there is still a great need for developing biomarkers that reflect disease activity and thereby can be used for treatment response or patient phenotyping. Osteoarthritis is the most common form of joint disease. This presents the osteoarthritis research community and pharmaceutical companies developing disease-modifying osteoarthritis drugs (DMOADs) with great opportunities. There are different osteoarthritis subtypes, which complicates the traditional approaches for developing new treatments. If we can identify new markers that can distinguish different subtypes, this can greatly facilitate drug development from early discovery to late clinical development.

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space.

PubMed

Dockendorf, Marissa F; Vargo, Ryan C; Gheyas, Ferdous; Chain, Anne S Y; Chatterjee, Manash S; Wenning, Larissa A

2018-06-01

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

A clinician's personal view of assisted reproductive technology over 35 years.

PubMed

Yovich, John L

2011-12-01

This invited presentation is intended to cover clinical developments in the evolution of assisted reproductive technology (ART), a process which was attempted during the 1940's and 50's and culminated in the first fruition in 1978. The first in vitro fertilisation (IVF) child ensued following the partnership by a scientist with a focussed ambition (Nobel laureate Robert Edwards) joining with the gynaecologist who introduced laparoscopy to Britain in the late 60's (Patrick Steptoe). My journey commenced in 1976 as a clinician who became immersed in the embryological and endocrinological science, whence most progress in ART emanates, and continued into a medical directorship position from which this personal view is documented. Several clinical advances have been important developments in the understanding and management of sub-fertile patients. However evolution of the various laboratory sciences has been the major key essential to meeting both the immediate as well as the long-term needs for human reproduction. The future requires a much better understanding and control over gametogenesis and a laboratory process which much more closely duplicates intrinsic reproductive physiology, avoiding gamete and embryo exposure to the atmosphere.This invited presentation is intended to cover clinical developments in the evolution of assisted reproductive technology (ART), a process which was attempted during the 1940's and 50's and culminated in the first fruition in 1978. The first in vitro fertilisation (IVF) child ensued following the partnership by a scientist with a focussed ambition (Nobel laureate Robert Edwards) joining with the gynaecologist who introduced laparoscopy to Britain in the late 60's (Patrick Steptoe). My journey commenced in 1976 as a clinician who became immersed in the embryological and endocrinological science, whence most progress in ART emanates, and continued into a medical directorship position from which this personal view is documented. Several clinical advances have been important developments in the understanding and management of sub-fertile patients. However evolution of the various laboratory sciences has been the major key essential to meeting both the immediate as well as the long-term needs for human reproduction. The future requires a much better understanding and control over gametogenesis and a laboratory process which much more closely duplicates intrinsic reproductive physiology, avoiding gamete and embryo exposure to the atmosphere.

Late-life dementia. Review of the APA guidelines for patient management.

PubMed

Schindler, R J; Cucio, C P

2000-10-01

Management of dementia in older patients requires an individualized and multimodal approach that involves use of psychiatric, psychotherapeutic, psychosocial, and somatic tools and treatments, in addition to patient and family education. The progressive nature of dementia and the invariable presence of comorbidity complicates the management task, although symptoms characteristic of dementia's phases can provide helpful clinical clues to guide evolving care. In 1997, the American Psychiatric Association published the "Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life." To date, this is the most comprehensive clinical guideline available to physicians caring for patients with Alzheimer's disease and other related dementias.

Two cases of traumatic head injury mimicking acute encephalopathy with biphasic seizures and late reduced diffusion.

PubMed

Nishiyama, Masahiro; Fujita, Kyoko; Maruyama, Azusa; Nagase, Hiroaki

2014-11-01

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) presents a distinct clinical course of biphasic seizures and impaired consciousness. These symptoms are followed by reduced diffusion in the subcortical white matter on magnetic resonance imaging that is typically observed between 3 and 9 days after illness onset. Here, we report two cases of traumatic head injury with clinical and radiological features similar to those for AESD. The similarities between our cases and AESD may be useful in understanding the pathogenesis of AESD. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Anti-Rh(c), "little c," isoimmunization: the role of rHuEpo in preventing late anemia.

PubMed

Zuppa, Antonio A; Cardiello, Valentina; Alighieri, Giovanni; Cota, Francesco; D'Antuono, Annamaria; Riccardi, Riccardo; Catenazzi, Piero; Romagnoli, Costantino

2013-08-01

The overall prevalence of non-Rh-D isoimmunization seems to lie between 0.15% and 1.1%. Anti-Rh(c) alloimmunization, "little c," occurs in 0.07% of pregnancies and shows a quite broad clinical presentation. Late anemia is a frequent problem occurring in the setting of isoimmunization. It occurs more frequently after intrauterine blood transfusions or exsanguinotransfusion, and it can be thought as a hyporegenerative anemia. The authors describe the use of human recombinant erythropoietin in preventing late anemia in a case of anti-Rh(c) isoimmunization. The use of human recombinant erythropoietin is a valid tool for preventing late-onset anemia due to either anti-Rh-D or non-anti-Rh-D isoimmunization.

The late open infarct-related artery hypothesis: evidence-based medicine or not?

PubMed

Brueck, Martin; Bandorski, Dirk; Kramer, Wilfried; Vogt, Paul R; Heidt, Martin C

2007-11-01

Randomized clinical trials have clearly shown that early reperfusion of coronary arteries is the established treatment of myocardial infarction preserving left ventricular function and reducing mortality. However, late patency of the infarct-related artery is an independent predictor of survival leading to the late open-artery hypothesis. This concept implies restoration of antegrade blood flow of the infarct-related artery in patients with myocardial infarction to improve survival by mechanisms less time-dependent or even time-independent. Possible explanations for this benefit include improved left ventricular function and electrical stability by perfusion of hibernating myocardium, accelerated infarct healing and limitation of ventricular remodeling. This review focuses on the evidence of late recanalization of occluded infarct-related arteries in patients with coronary artery disease.

On the discovery of the genetic association of Apolipoprotein E genotypes and common late-onset Alzheimer disease.

PubMed

Roses, Allen D

2006-01-01

The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer's disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer's Disease Research Center) group. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13. The 1991 multilocus analysis of linkage had been considered very controversial. The second stream came from a series of amyloid-beta binding studies in which a consistent protein "impurity" was present on gel separation analyses. After sequencing this "impurity" band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer's disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980's. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype. The earliest submitted paper reported the familial association and amyloid-beta binding. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain. Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. Rosiglitazone, a PPARgamma agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis.

Introducing Systems Approaches

NASA Astrophysics Data System (ADS)

Reynolds, Martin; Holwell, Sue

Systems Approaches to Managing Change brings together five systems approaches to managing complex issues, each having a proven track record of over 25 years. The five approaches are: System Dynamics (SD) developed originally in the late 1950s by Jay Forrester Viable Systems Model (VSM) developed originally in the late 1960s by Stafford Beer Strategic Options Development and Analysis (SODA: with cognitive mapping) developed originally in the 1970s by Colin Eden Soft Systems Methodology (SSM) developed originally in the 1970s by Peter Checkland Critical Systems Heuristics (CSH) developed originally in the late 1970s by Werner Ulrich

Postthrombotic syndrome.

PubMed

Pesavento, Raffaele; Bernardi, Enrico; Concolato, Alessia; Dalla Valle, Fabio; Pagnan, Antonio; Prandoni, Paolo

2006-10-01

Despite considerable progress in the diagnosis and treatment of deep vein thrombosis (DVT) of the lower extremities, one of every three patients will develop postthrombotic sequelae within 2 years; these sequelae are severe in approximately 20% of cases and produce considerable socioeconomic consequences. Among factors potentially related to the development of the postthrombotic syndrome (PTS) are older age, obesity, insufficient oral anticoagulant therapy, and recurrent ipsilateral thrombosis. Whether the extent and location of the initial thrombosis are associated with the development of PTS is controversial. Based on recent findings, the lack of vein recanalization within the first 6 months appears to be an important predictor of PTS, whereas the development of transpopliteal venous reflux is not. The diagnosis of PTS can be made on clinical grounds for patients with a history of DVT. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasound helps diagnose or exclude a previous proximal vein thrombosis. According to the results of recent clinical studies, the prompt administration of adequate compression elastic stockings in patients with symptomatic DVT has the potential to reduce the frequency of late PTS development by half. The management of this condition is demanding and often frustrating. However, when carefully supervised and instructed to wear proper elastic stockings, more than 50% of patients will either remain stable or improve during long-term follow-up. Clinical presentation helps predict the prognosis; the outcome of patients who refer with initially severe manifestations is more favorable than that of patients whose symptoms deteriorate progressively over time.

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffman, Karen E., E-mail: khoffman1@mdanderson.org; Voong, K. Ranh; Pugh, Thomas J.

Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men receivedmore » CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.« less

HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine.

PubMed

Graziani, Gina M; Angel, Jonathan B

2016-07-01

Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.

The genetics of age-related macular degeneration (AMD)--Novel targets for designing treatment options?

PubMed

Grassmann, Felix; Fauser, Sascha; Weber, Bernhard H F

2015-09-01

Age-related macular degeneration (AMD) is a progressive disease of the central retina and the main cause of legal blindness in industrialized countries. Risk to develop the disease is conferred by both individual as well as genetic factors with the latter being increasingly deciphered over the last decade. Therapeutically, striking advances have been made for the treatment of the neovascular form of late stage AMD while for the late stage atrophic form of the disease, which accounts for almost half of the visually impaired, there is currently no effective therapy on the market. This review highlights our current knowledge on the genetic architecture of early and late stage AMD and explores its potential for the discovery of novel, target-guided treatment options. We reflect on current clinical and experimental therapies for all forms of AMD and specifically note a persisting lack of efficacy for treatment in atrophic AMD. We further explore the current insight in AMD-associated genes and pathways and critically question whether this knowledge is suited to design novel treatment options. Specifically, we point out that known genetic factors associated with AMD govern the risk to develop disease and thus may not play a role in its severity or progression. Treatments based on such knowledge appear appropriate rather for prevention than treatment of manifest disease. As a consequence, future research in AMD needs to be greatly focused on approaches relevant to the patients and their medical needs. Copyright © 2015 Elsevier B.V. All rights reserved.

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.

PubMed

Cagdas, Deniz; Gur Cetinkaya, Pınar; Karaatmaca, Betül; Esenboga, Saliha; Tan, Cagman; Yılmaz, Togay; Gümüş, Ersin; Barış, Safa; Kuşkonmaz, Barış; Ozgur, Tuba Turul; Bali, Pawan; Santisteban, Ines; Orhan, Diclehan; Yüce, Aysel; Cetinkaya, Duygu; Boztug, Kaan; Hershfield, Michael; Sanal, Ozden; Tezcan, İlhan

2018-05-09

Adenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT). Measurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening. Ten out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6-71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1-8.9). All but one patient with SCID had T-B-NK- phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients. The genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.

Validation of Sensititre Dry-Form Broth Microdilution Panels for Susceptibility Testing of Ceftazidime-Avibactam, a Broad-Spectrum-β-Lactamase Inhibitor Combination.

PubMed

Jones, Ronald N; Holliday, Nicole M; Krause, Kevin M

2015-08-01

Ceftazidime-avibactam is a broad-spectrum-β-lactamase inhibitor combination in late-stage clinical development for the treatment of serious infections. In preparation for clinical microbiology laboratory use, a validation experiment was initiated to evaluate a commercial broth microdilution product (Sensititre dried MIC susceptibility system) compared to reference panels using 525 recent clinical isolates. Among 11 pathogen groups, all had Sensititre MIC/reference MIC ratios predominantly at 1 (47.5% to 97.5%), and automated and manual endpoint results did not differ. Enterobacteriaceae MIC comparisons showed a modest skewing of Sensititre MIC results toward an elevated MIC (33.9%), but the essential agreement was 98.9% with 100.0% reproducibility. In conclusion, Sensititre panels produced accurate ceftazidime-avibactam MIC results, allowing quality MIC guidance for therapy following regulatory approvals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Validation of Sensititre Dry-Form Broth Microdilution Panels for Susceptibility Testing of Ceftazidime-Avibactam, a Broad-Spectrum-β-Lactamase Inhibitor Combination

PubMed Central

Holliday, Nicole M.; Krause, Kevin M.

2015-01-01

Ceftazidime-avibactam is a broad-spectrum-β-lactamase inhibitor combination in late-stage clinical development for the treatment of serious infections. In preparation for clinical microbiology laboratory use, a validation experiment was initiated to evaluate a commercial broth microdilution product (Sensititre dried MIC susceptibility system) compared to reference panels using 525 recent clinical isolates. Among 11 pathogen groups, all had Sensititre MIC/reference MIC ratios predominantly at 1 (47.5% to 97.5%), and automated and manual endpoint results did not differ. Enterobacteriaceae MIC comparisons showed a modest skewing of Sensititre MIC results toward an elevated MIC (33.9%), but the essential agreement was 98.9% with 100.0% reproducibility. In conclusion, Sensititre panels produced accurate ceftazidime-avibactam MIC results, allowing quality MIC guidance for therapy following regulatory approvals. PMID:26014937

A Collaborative Step-Wise Process to Implementing an Innovative Clinic for Adult Survivors of Childhood Cancer.

PubMed

McClellan, Wendy; Fulbright, Joy M; Doolittle, Gary C; Alsman, Kyla; Klemp, Jennifer R; Ryan, Robin; Nelson, Eve-Lynn; Stegenga, Kristin; Krebill, Hope; Al-hihi, Eyad M; Schuetz, Nik; Heiman, Ashley; Lowry, Becky

2015-01-01

With a 5 year survival rate of approximately 80%, there is an increasing number of childhood cancer survivors in the United States. Childhood cancer survivors are at an increased risk for physical and psychosocial health problems many years after treatment. Long-term follow-up care should include education, development of individualized follow up plans and screening for health problems in accordance with the Children's Oncology Group survivor guidelines. Due to survivor, provider and healthcare system related barriers, adult survivors of childhood cancer (ASCC) infrequently are receiving care in accordance to these guidelines. In this paper we describe the stepwise process and collaboration between a children's hospital and an adult academic medical center that was implemented to develop the Survivorship Transition Clinic and address the needs of ASCC in our region. In the clinic model that we designed ASCC follow-up with a primary care physician in the adult setting who is knowledgeable about late effects of childhood cancer treatment and are provided transition support and education by a transition nurse navigator. Copyright © 2015 Elsevier Inc. All rights reserved.

Technologies for Controlled, Local Delivery of siRNA

PubMed Central

Sarett, Samantha M.; Nelson, Christopher E.; Duvall, Craig L.

2015-01-01

The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While topical siRNA delivery has progressed into numerous clinical trials, an enormous opportunity also exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation. PMID:26476177

Brachytherapy for cervix cancer: low-dose rate or high-dose rate brachytherapy – a meta-analysis of clinical trials

PubMed Central

Viani, Gustavo A; Manta, Gustavo B; Stefano, Eduardo J; de Fendi, Ligia I

2009-01-01

Background The literature supporting high-dose rate brachytherapy (HDR) in the treatment of cervical carcinoma derives primarily from retrospective series. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy, in particular, due to inadequate tumor coverage for stage III patients. Whether LDR or HDR brachytherapy produces better results for these patients in terms of survival rate, local control rate and the treatment complications remain controversial. Methods A meta-analysis of RCT was performed comparing LDR to HDR brachytherapy for cervix cancer treated for radiotherapy alone. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. We used "recommend" for strong recommendations, and "suggest" for weak recommendations. Results Pooled results from five randomized trials (2,065 patients) of HDR brachytherapy in cervix cancer showed no significant increase of mortality (p = 0.52), local recurrence (p = 0.68), or late complications (rectal; p = 0.7, bladder; p = 0.95 or small intestine; p = 0.06) rates as compared to LDR brachytherapy. In the subgroup analysis no difference was observed for overall mortality and local recurrence in patients with clinical stages I, II and III. The quality of evidence was low for mortality and local recurrence in patients with clinical stage I, and moderate for other clinical stages. Conclusion Our meta-analysis shows that there are no differences between HDR and LDR for overall survival, local recurrence and late complications for clinical stages I, II and III. By means of the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer. PMID:19344527

Antibiotic resistance: the challenge from an industry perspective.

PubMed

Tillotson, Glenn S

2009-03-01

Trained in medical microbiology and infectious diseases in the UK, Glenn Tillotson has over 20 years pharmaceutical experience in various areas, including clinical research, marketing, scientific communications, strategic development and global launch programs. Mainly in the field of anti-infectives, Tillotson has been instrumental in the development of ciprofloxacin and moxifloxacin, as well as other drugs in the Bayer portfolio. After leaving Bayer, he worked as a consultant microbiologist and, in 2003, consulted with Genesoft to help with the commercialization and launch of gemifloxacin, leading to the development of Oscient following the merger of Genesoft and Genome Therapeutics. From late 2003 to early 2006, he focused his efforts on the launch of gemifloxacin into US clinical practice, as well as comarketing and business development deals globally. In April 2006, Tillotson joined Replidyne Inc. as Executive Director of Scientific Affairs working on faropenem, REP 8839 and REP 3123. Presently, Tillotson is Head of Medical Affairs at ViroPharma Inc., where he oversees educational, publication and other related activities for Vancocin(®), maribavir and Cinryze™. Most recently, Tillotson was a member of the Scientific Steering Committee for the International Society of Chemotherapy's Symposium on Clostridium difficile in Leipzig, Germany. Here, he talks with Expert Review of Clinical Pharmacology about the challenge of antibiotic resistance from an industry perspective.

Differential effects of subtype-specific nicotinic acetylcholine receptor agonists on early and late hippocampal LTP.

PubMed

Kroker, Katja S; Rast, Georg; Rosenbrock, Holger

2011-12-05

Brain nicotinic acetylcholine receptors are involved in several neuropsychiatric disorders, e.g. Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, autism, attention deficit hyperactivity disorder, and anxiety. Currently, approaches selectively targeting the activation of specific nicotinic acetylcholine receptors are in clinical development for treatment of memory impairment of Alzheimer's disease patients. These are α4β2 and α7 nicotinic acetylcholine receptor agonists which are believed to enhance cholinergic and glutamatergic neurotransmission, respectively. In order to gain a better insight into the mechanistic role of these two nicotinic acetylcholine receptors in learning and memory, we investigated the effects of the α4β2 nicotinic acetylcholine receptor agonist TC-1827 and the α7 nicotinic acetylcholine receptor partial agonist SSR180711 on hippocampal long-term potentiation (LTP), a widely accepted cellular experimental model of memory formation. Generally, LTP is distinguished in an early and a late form, the former being protein-synthesis independent and the latter being protein-synthesis dependent. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the α7 nicotinic acetylcholine receptor partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but also transformed it into late LTP, which was not observed with the α4β2 nicotinic acetylcholine receptor agonist. Therefore, based on these findings α7 nicotinic acetylcholine receptor (partial) agonists appear to exhibit stronger efficacy on memory improvement than α4β2 nicotinic acetylcholine receptor agonists. Copyright © 2011 Elsevier B.V. All rights reserved.

Cryoplasty for femoropopliteal arterial disease: late angiographic results of initial human experience.

PubMed

Fava, Mario; Loyola, Soledad; Polydorou, Antonios; Papapavlou, Prodromos; Polydorou, Adamandia; Mendiz, Oscar; Joye, James D

2004-11-01

A new form of angioplasty, called cryoplasty, was developed to improve the late results typically associated with percutaneous transluminal angioplasty. Cryoplasty combines the dilation force of percutaneous transluminal angioplasty with the delivery of cold thermal energy to the vessel wall. This study reports the authors' early clinical experience with cryoplasty in patients with femoropopliteal disease. Fifteen patients with femoropopliteal arterial lesions were treated with cryoplasty (CryoVascular Systems, Los Gatos, CA). Cryoplasty was performed at 6 atm of pressure and delivered at -10 degrees C for 60 seconds. The ankle-brachial index (ABI) was measured at baseline, 24 hours after cryoplasty, and at 1 and 3 months during follow-up. Repeated angiography was performed at 6 and 18 months to determine short-term and late primary patency. Cryoplasty was technically successful in 93% of patients (< 30% residual stenosis and less then grade C dissection). ABIs at baseline were 0.64 +/- 0.08 and improved the day after cryoplasty to 0.95 +/- 0.09 (P < .05). ABIs were well maintained at 1 and 3 months with measurements of 0.94 +/- 0.09 and 0.92 +/- 0.10, respectively (P < .05 vs baseline). Baseline angiographic diameter stenosis improved significantly immediately following cryoplasty (86% +/- 12% to 16% +/- 3%; P < .05). Angiography at 6 months revealed 0% binary restenosis and insignificant change in residual stenosis from the acute cryoplasty results (16 +/- 3% vs 21 +/- 5%; P = NS). Late angiographic follow-up at 14 months +/- 4 demonstrated primary patency of 83.3%. Cryoplasty was able to achieve substantial dilation of femoropopliteal lesions with well-preserved late angiographic patency. Cryoplasty represents a potential advance in the field of endovascular medicine.

Early detection of congenital syphilis.

PubMed

Chowdhary, Nagalakshmi; Rani, Bs Kavya; Mukunda, K S; Kiran, N K

2014-01-01

Late congenital syphilis is a very rare clinical entity, and its early diagnosis and treatment is essential. Dental findings often provide valuable evidence for the diagnosis of late congenital syphilis. It occurs due to the transmission of the disease from an infected mother to her fetus through placenta. This long forgotten disease continues to effect pregnant women resulting in perinatal morbidity and mortality. Congenital syphilis is a preventable disease, and its presence reflects a failure of prenatal care delivery system, as well as syphilis control programs. We are reporting a case of late congenital syphilis with only Hutchinson's teeth.

What are the causes of late-life depression?

PubMed

Aziz, Rehan; Steffens, David C

2013-12-01

Although depression in old age is less common than depression in younger populations, it still affects more than 1 million community-living older adults. Depression in late life has been associated with reduced quality of life and increased mortality from both suicide and illness. Its causes are multifactorial but are prominently related to both biologic and social factors. Psychological factors, although less studied in elders, are also important in understanding its cause. In this article, multiple facets of late-life depression are reviewed, including its clinical presentation, epidemiology, and biopsychosocial causes. Copyright © 2013 Elsevier Inc. All rights reserved.

Head Trauma as a Precipitating Factor for Late-onset Leigh Syndrome: a Case Report.

PubMed

Ashrafi, Farzad; Pakdaman, Hossein; Arabahmadi, Mehran; Behnam, Behdad

2017-01-01

Leigh syndrome is a severe progressive neurodegenerative disorder with different clinical presentationsthat usually becomes apparent in the first year of life and rarely in late childhood and elderly years. It is causedby failure of mitochondrial respiratory chain and often results in regression of both mental and motor skills and might even lead to death. In some of the inherited neurodegenerative diseases like Alexander disease, head trauma is reported as a trigger for onset of the disease. We present a late onset Leigh syndrome in a 14-year-old girl whose symptoms were initiating following head trauma.

Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit

PubMed Central

Molinuevo, José L.; Cami, Jordi; Carné, Xavier; Carrillo, Maria C.; Georges, Jean; Isaac, Maria B.; Khachaturian, Zaven; Kim, Scott Y. H.; Morris, John C.; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

2016-01-01

Alzheimer’s disease (AD) is among the most significant healthcare burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals’ biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants and disclose or not biomarker status with attention to study type (observational studies versus clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

Toward a comprehensive model of antisocial development: a dynamic systems approach.

PubMed

Granic, Isabela; Patterson, Gerald R

2006-01-01

The purpose of this article is to develop a preliminary comprehensive model of antisocial development based on dynamic systems principles. The model is built on the foundations of behavioral research on coercion theory. First, the authors focus on the principles of multistability, feedback, and nonlinear causality to reconceptualize real-time parent-child and peer processes. Second, they model the mechanisms by which these real-time processes give rise to negative developmental outcomes, which in turn feed back to determine real-time interactions. Third, they examine mechanisms of change and stability in early- and late-onset antisocial trajectories. Finally, novel clinical designs and predictions are introduced. The authors highlight new predictions and present studies that have tested aspects of the model

Otitis Media and Speech/Language Development in Late-Talkers.

ERIC Educational Resources Information Center

Paul, Rhea; And Others

This study examines otitis media as a possible factor associated with increased risk for communicative handicap in a group of children with a possible vulnerability for language delay: "late-talkers." Speech and language outcomes at ages 3 and 4 were examined in 28 late talkers and 24 children with normal language development. Late…

Gender Differences in Internalizing Symptoms and Suicide Risk Among Men and Women Seeking Treatment for Cannabis Use Disorder from Late Adolescence to Middle Adulthood.

PubMed

Foster, Katherine T; Li, Ningfei; McClure, Erin A; Sonne, Susan C; Gray, Kevin M

2016-07-01

Cannabis continues to rise in popularity as the perception of its harmfulness decreases and evidence of its deleterious developmental effect increases. While internalizing distress and suicide risk have been linked with cannabis use problems [DSM-5 cannabis use disorder (CUD); DSM-IV cannabis abuse and dependence] it remains unclear how this association varies over the course of development in treatment-seeking men and women. The current study utilized the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) to conduct a cross-sectional comparison of internalizing distress and suicide risk among men (n=437) and women (n=163) spanning ages 18-50 who met DSM-5 criteria for CUD. Interactions between gender and developmental stage (i.e., late adolescence, early adulthood, and middle adulthood) were observed for suicide risk and anxiety but not depression problems. Specifically, women seeking CUD treatment in late adolescence and middle adulthood exhibited significantly higher rates of anxiety and suicide risk compared to men seeking treatment during the same developmental stages. Internalizing distress and suicide risk did not differ between treatment-seeking men and women in the early adult stage. Overall, results suggest that the structure of risk for CUD may differ in men and women across the lifespan and that women presenting for CUD treatment during late adolescence and middle adulthood may uniquely benefit from intervention designed to address these elevations in anxiety and suicide risk. Published by Elsevier Inc.

Gender differences in internalizing symptoms and suicide risk among men and women seeking treatment for cannabis use disorder from late adolescence to middle adulthood

PubMed Central

Foster, Katherine T.; Li, Ningfei; McClure, Erin A.; Sonne, Susan C.; Gray, Kevin M.

2016-01-01

Cannabis continues to rise in popularity as the perception of its harmfulness decreases and evidence of its deleterious developmental effect increases. While internalizing distress and suicide risk have been linked with cannabis use problems (DSM-5 cannabis use disorder (CUD); DSM-IV cannabis abuse and dependence) it remains unclear how this association varies over the course of development in treatment-seeking men and women. The current study utilized the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) to conduct a cross-sectional comparison of internalizing distress and suicide risk among men (n=437) and women (n=163) spanning ages 18–50 who met DSM-5 criteria for CUD. Interactions between gender and developmental stage (i.e., late adolescence, early adulthood, and middle adulthood) were observed for suicide risk and anxiety but not depression problems. Specifically, women seeking CUD treatment in late adolescence and middle adulthood exhibited significantly higher rates of anxiety and suicide risk compared to men seeking treatment during the same developmental stages. Internalizing distress and suicide risk did not differ between treatment-seeking men and women in the early adult stage. Overall, results suggest that the structure of risk for CUD may differ in men and women across the lifespan and that women presenting for CUD treatment during late adolescence and middle adulthood may uniquely benefit from intervention designed to address these elevations in anxiety and suicide risk. PMID:27211992

Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review.

PubMed

Jardim, Denis L; Groves, Eric S; Breitfeld, Philip P; Kurzrock, Razelle

2017-01-01

We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development. We searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period. Forty-two drugs fit our criteria for development failures. These failed drugs (49% targeted, 23% cytotoxics, and 28% other) were tested in 43 cancer indications (drug programs). Only 16% (7/43) of failed drug programs adopted a biomarker-driven rationale for patient selection versus 57% (21/37) of successful drug programs (P<0.001). Phase II trial information was available in 32 of 43 failed drug programs and in 32 of 37 successful programs. Nine of the 32 trials (28%) of failed drugs versus 28 of 32 trials (87%) of successful drugs (P<0.001) achieved proof of concept (single agent response rate (RR) ⩾20% or combination therapy showing a ⩾20% RR increase above the median historical RR without the experimental agent (with a minimal absolute increase of 5%) or a randomized phase II trial showing significance (P⩽0.05) for its primary outcome). No pattern of study sites, trial design or funding characteristics emerged from the failed drug analysis. For drugs that reached Phase III, lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation, especially for targeted agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Late follow-up in women with nephrosclerosis diagnosed at pregnancy.

PubMed

Peyser, M R; Toaff, R; Leiserowitz, D M; Aviram, A; Griffel, B

1978-11-01

Thirteen nephrosclerotic women were followed for 2 to 7 years from the time a diagnosis was made following a pregnancy complicated by hypertension. Ten patients developed sustained hypertension. Twelve women who were examined responded with a hypertensive pattern to acute salt load. Of the 10 patients who were examined, seven had a reduced renal plasma flow (RPF) demonstrated by the phenolsulfonphthalein (PSP) excretion test. The present observations support the view that the vascular lesion in the kidneys precedes and persists independently of pregnancy. The pregnant state brings the hypertensive disease to clinical expression.

Pregnancy toxemia of ewes, does, and beef cows.

PubMed

Rook, J S

2000-07-01

Pregnancy toxemia commonly affects pregnant ewes and does during late gestation. This metabolic disease is thought to result from disruption of the dam's glucose homeostatic mechanism in response to increased nutritional demands of the rapidly developing fetal placental unit. Commercial production systems are comprised of a variety of nutritional, metabolic, genetic, physiologic, environmental, economic, health, and management factors that singularly or as a group influence the clinical expression of pregnancy toxemia. Recognizing the role management plays in controlling these inputs is crucial to pregnancy toxemia prevention and treatment programs.

Noninvasive prenatal testing using cell-free fetal DNA in maternal plasma.

PubMed

Dharajiya, Nilesh; Zwiefelhofer, Tricia; Guan, Xiaojun; Angkachatchai, Vach; Saldivar, Juan-Sebastian

2015-01-20

Noninvasive prenatal testing (NIPT) represents an outstanding example of how novel scientific discoveries can be quickly and successfully developed into hugely impactful clinical diagnostic tests. Since the introduction of NIPT to detect trisomy 21 in late 2011, the technology has rapidly advanced to analyze other autosomal and sex chromosome aneuploidies, and now includes the detection of subchromosomal deletion and duplication events. Here we provide a brief overview of how noninvasive prenatal testing using next-generation sequencing is performed. Copyright © 2015 John Wiley & Sons, Inc.

Early-onset dementias: diagnostic and etiological considerations

PubMed Central

2013-01-01

This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect. PMID:24565469

Characteristics of children with unilateral hearing loss.

PubMed

Fitzpatrick, Elizabeth M; Al-Essa, Rakan S; Whittingham, JoAnne; Fitzpatrick, Jessica

2017-11-01

The purpose of this study was to describe the clinical characteristics of children with unilateral hearing loss (UHL), examine deterioration in hearing, and explore amplification decisions. Population-based data were collected prospectively from time of diagnosis. Serial audiograms and amplification details were retrospectively extracted from clinical charts to document the trajectory and management of hearing loss. The study included all children identified with UHL in one region of Canada over a 13-year period (2003-2015) after implementation of universal newborn hearing screening. Of 537 children with permanent hearing loss, 20.1% (108) presented with UHL at diagnosis. They were identified at a median age of 13.9 months (IQR: 2.8, 49.0). Children with congenital loss were identified at 2.8 months (IQR: 2.0, 3.6) and made up 47.2% (n = 51), reflecting that a substantial portion had late-onset, acquired or late-identified loss. A total of 42.4% (n = 39) showed deterioration in hearing, including 16 (17.4%) who developed bilateral loss. By study end, 73.1% (79/108) of children had received amplification recommendations. Up to 20% of children with permanent HL are first diagnosed with UHL. About 40% are at risk for deterioration in hearing either in the impaired ear and/or in the normal hearing ear.

Simple method to distinguish between primary and secondary C3 deficiencies.

PubMed

Pereira de Carvalho Florido, Marlene; Ferreira de Paula, Patrícia; Isaac, Lourdes

2003-03-01

Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

Construction of a novel multi-gene assay (42-gene classifier) for prediction of late recurrence in ER-positive breast cancer patients.

PubMed

Tsunashima, Ryo; Naoi, Yasuto; Shimazu, Kenzo; Kagara, Naofumi; Shimoda, Masashi; Tanei, Tomonori; Miyake, Tomohiro; Kim, Seung Jin; Noguchi, Shinzaburo

2018-05-04

Prediction models for late (> 5 years) recurrence in ER-positive breast cancer need to be developed for the accurate selection of patients for extended hormonal therapy. We attempted to develop such a prediction model focusing on the differences in gene expression between breast cancers with early and late recurrence. For the training set, 779 ER-positive breast cancers treated with tamoxifen alone for 5 years were selected from the databases (GSE6532, GSE12093, GSE17705, and GSE26971). For the validation set, 221 ER-positive breast cancers treated with adjuvant hormonal therapy for 5 years with or without chemotherapy at our hospital were included. Gene expression was assayed by DNA microarray analysis (Affymetrix U133 plus 2.0). With the 42 genes differentially expressed in early and late recurrence breast cancers in the training set, a prediction model (42GC) for late recurrence was constructed. The patients classified by 42GC into the late recurrence-like group showed a significantly (P = 0.006) higher late recurrence rate as expected but a significantly (P = 1.62 × E-13) lower rate for early recurrence than non-late recurrence-like group. These observations were confirmed for the validation set, i.e., P = 0.020 for late recurrence and P = 5.70 × E-5 for early recurrence. We developed a unique prediction model (42GC) for late recurrence by focusing on the biological differences between breast cancers with early and late recurrence. Interestingly, patients in the late recurrence-like group by 42GC were at low risk for early recurrence.

Comparison of Parent-Implemented and Clinician-Directed Intervention for Toddlers Identified as Late Talkers: A Literature Review. EBP Briefs. Volume 10, Issue 6

ERIC Educational Resources Information Center

DeVeney, Shari L.; Hagman, Jessica L.

2016-01-01

Clinical Questions: Would a child who is a late talker (P) show greater improvement with parent-implemented intervention models (I) or with clinician-directed intervention models (C) as shown by improvements in expressive language skills (O)? If so, under what circumstances? Method: Literature Review. Study Sources: Education Source, ERIC,…

Clinical Use of Aromatase Inhibitors in Adult Males.

PubMed

Tan, Ronny B W; Guay, Andre T; Hellstrom, Wayne J G

2014-04-01

There is a growing interest in the treatment of late-onset hypogonadism, another name for the study of testosterone deficiency in an older age group. Initial attempts at testosterone replacement have also brought attention to the possible adverse effects on the patients' cardiovascular risk factors and their prostate health. The "female" hormone estradiol is no longer considered as the feminizing hormone, as it has been identified to have an effect on the sexual and general well-being of adult males. Urologists and endocrinologists alike have started to pay attention to the serum T/E 2 (testosterone : estradiol) ratio that appears to be more important than the respective individual hormonal levels. Therein lies the possible role of aromatase inhibitors (AIs) in restoring the normal balance of serum testosterone and estradiol levels for the adequate treatment of late-onset hypogonadism, while limiting the potential adverse effects. Currently, other established clinical indications of AIs include the treatment of breast cancer in female patients and developmental growth problems in pediatric patients. This review evaluates the role of AIs as a treatment option for late-onset hypogonadism and the evidence for its other clinical uses in men, including its possible adverse effects. A literature review was performed with regards to the use of aromatase inhibitors in adult males, the role of estrogens in adult males, as well as adverse effect of AIs on bone health in adult males. To evaluate the evidence for the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, and male subfertility. To evaluate the evidence for the possible adverse effects on the bone health of adult males with the use of AIs. Currently there is no literature to recommend the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, or male subfertility, although some positive effects have been reported. The adverse effects on bone health seen in females treated with AIs are not seen in males. With the better understanding of the T/E 2 ratio in adult males, the lack of scientific data to show that bone health is adversely affected by AI usage in adult males, the positive effects of AIs on the treatment of conditions like late-onset hypogonadism and male subfertility encourages conducting large-scale, multicenter, randomized controlled trials for the clinical use of AIs in adult males. Tan RBW, Guay AT, and Hellstrom WJG. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90. Copyright © 2014 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Postoperative Complications in the Ahmed Baerveldt Comparison Study during Five Years of Follow-up

PubMed Central

Budenz, Donald L.; Feuer, William J.; Barton, Keith; Schiffman, Joyce; Costa, Vital P.; Godfrey, David G.; Buys, Yvonne M.

2016-01-01

PURPOSE To compare the late complications in the Ahmed Baerveldt Comparison Study during 5 years of follow-up. DESIGN Multicenter, prospective, randomized clinical trial. METHODS SETTINGS Sixteen international clinical centers. STUDY POPULATION Two hundred seventy six subjects aged 18 to 85 years with previous intraocular surgery or refractory glaucoma with intraocular pressure of > 18 mmHg. INTERVENTIONS Ahmed Glaucoma Valve FP7 or Baerveldt Glaucoma Implant BG 101-350. MAIN OUTCOME MEASURES Late postoperative complications (beyond 3 months), reoperations for complications, and decreased vision from complications. RESULTS Late complications developed in 56 subjects (46.8 ± 4.8 5 year cumulative % ± SE) in the Ahmed Glaucoma Valve group and 67 (56.3 ± 4.7 5 year cumulative % ± SE) in the Baerveldt Glaucoma Implant group (P = 0.082). The cumulative rates of serious complications were 15.9% and 24.7% in the Ahmed Glaucoma Valve and Baerveldt Glaucoma Implant groups respectively (P = 0.034) although this was largely driven by subjects who had tube occlusions in the two groups (0.8% in the Ahmed Glaucoma Valve group and 5.7% in the Baerveldt Glaucoma Implant group, P = 0.037). Both groups had a relatively high incidence of persistent diplopia (12%) and corneal edema (20%), although half of the corneal edema cases were likely due to pre-existing causes other than the aqueous shunt. The incidence of tube erosion was 1% and 3% in the Ahmed Glaucoma Valve and Baerveldt Glaucoma Implant groups, respectively (P = 0.04). CONCLUSIONS Long term rates of vision threatening complications and complications resulting in reoperation were higher in the Baerveldt Glaucoma Implant than the Ahmed Glaucoma Valve group over 5 years of follow-up. PMID:26596400

Staging of cortical and deep grey matter functional connectivity changes in multiple sclerosis.

PubMed

Meijer, Kim A; Eijlers, Anand J C; Geurts, Jeroen J G; Schoonheim, Menno M

2018-02-01

Functional connectivity is known to increase as well as decrease throughout the brain in multiple sclerosis (MS), which could represent different stages of the disease. In addition, functional connectivity changes could follow the atrophy pattern observed with disease progression, that is, moving from the deep grey matter towards the cortex. This study investigated when and where connectivity changes develop and explored their clinical and cognitive relevance across different MS stages. A cohort of 121 patients with early relapsing-remitting MS (RRMS), 122 with late RRMS and 53 with secondary progressive MS (SPMS) as well as 96 healthy controls underwent MRI and neuropsychological testing. Functional connectivity changes were investigated for (1) within deep grey matter connectivity, (2) connectivity between the deep grey matter and cortex and (3) within-cortex connectivity. A post hoc regional analysis was performed to identify which regions were driving the connectivity changes. Patients with late RRMS and SPMS showed increased connectivity of the deep grey matter, especially of the putamen and palladium, with other deep grey matter structures and with the cortex. Within-cortex connectivity was decreased, especially for temporal, occipital and frontal regions, but only in SPMS relative to early RRMS. Deep grey matter connectivity alterations were related to cognition and disability, whereas within-cortex connectivity was only related to disability. Increased connectivity of the deep grey matter became apparent in late RRMS and further increased in SPMS. The additive effect of cortical network degeneration, which was only seen in SPMS, may explain the sudden clinical deterioration characteristic to this phase of the disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Auditory neuropathy spectrum disorder in late preterm and term infants with severe jaundice.

PubMed

Saluja, Satish; Agarwal, Asha; Kler, Neelam; Amin, Sanjiv

2010-11-01

To evaluate if severe jaundice is associated with acute auditory neuropathy spectrum disorder in otherwise healthy late preterm and term neonates. In a prospective observational study, all neonates who were admitted with severe jaundice at which exchange transfusion may be indicated as per American Academy of Pediatrics guidelines had comprehensive auditory evaluation performed before discharge to home. Neonates with infection, perinatal asphyxia, chromosomal disorders, cranio-facial malformations, or family history of childhood hearing loss were excluded. Comprehensive auditory evaluations (tympanometry, oto-acoustic emission tests, and auditory brainstem evoked responses) were performed by an audiologist unaware of the severity of jaundice. Total serum bilirubin and serum albumin were measured at the institutional chemistry laboratory using the Diazo and Bromocresol purple method, respectively. A total of 13 neonates with total serum bilirubin concentration at which exchange transfusion is indicated as per American Academy of Pediatrics were admitted to the Neonatal Intensive Care Unit over 3 month period. Six out of 13 neonates (46%) had audiological findings of acute auditory neuropathy spectrum disorder. There was no significant difference in gestational age, birth weight, hemolysis, serum albumin concentration, peak total serum bilirubin concentrations, and peak bilirubin:albumin molar ratio between six neonates who developed acute auditory neuropathy and seven neonates who had normal audiological findings. Only two out of six infants with auditory neuropathy spectrum disorder had clinical signs and symptoms of acute bilirubin encephalopathy. Our findings strongly suggest that auditory neuropathy spectrum disorder is a common manifestation of acute bilirubin-induced neurotoxicity in late preterm and term infants with severe jaundice. Our findings also suggest that comprehensive auditory evaluations should be routinely performed in neonates with severe jaundice irrespective of the presence of clinical findings of acute bilirubin encephalopathy. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Premature brain aging in humans exposed to maternal nutrient restriction during early gestation.

PubMed

Franke, Katja; Gaser, Christian; Roseboom, Tessa J; Schwab, Matthias; de Rooij, Susanne R

2018-06-01

Prenatal exposure to undernutrition is widespread in both developing and industrialized countries, causing irreversible damage to the developing brain, resulting in altered brain structure and decreased cognitive function during adulthood. The Dutch famine in 1944/45 was a humanitarian disaster, now enabling studies of the effects of prenatal undernutrition during gestation on brain aging in late adulthood. We hypothesized that study participants prenatally exposed to maternal nutrient restriction (MNR) would demonstrate altered brain structure resembling premature brain aging in late adulthood, expecting the effect being stronger in men. Utilizing the Dutch famine birth cohort (n = 118; mean age: 67.5 ± 0.9 years), this study implements an innovative biomarker for individual brain aging, using structural neuroimaging. BrainAGE was calculated using state-of-the-art pattern recognition methods, trained on an independent healthy reference sample, then applied to the Dutch famine MRI sample, to evaluate the effects of prenatal undernutrition during early gestation on individual brain aging in late adulthood. Exposure to famine in early gestation was associated with BrainAGE scores indicative of an older-appearing brain in the male sample (mean difference to subjects born before famine: 4.3 years, p < 0.05). Furthermore, in explaining the observed variance in individual BrainAGE scores in the male sample, maternal age at birth, head circumference at birth, medical treatment of hypertension, history of cerebral incidences, actual heart rate, and current alcohol intake emerged to be the most influential variables (adjusted R 2  = 0.63, p < 0.01). The findings of our study on exposure to prenatal undernutrition being associated with a status of premature brain aging during late adulthood, as well as individual brain structure being shaped by birth- and late-life health characteristics, are strongly supporting the critical importance of sufficient nutrient supply during pregnancy. Interestingly, the status of premature brain aging in participants exposed to the Dutch famine during early gestation occurred in the absence of fetal growth restriction at birth as well as vascular pathology in late-life. Additionally, the neuroimaging brain aging biomarker presented in this study will further enable tracking effects of environmental influences or (preventive) treatments on individual brain maturation and aging in epidemiological and clinical studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Curtailing the high rate of late-stage attrition of investigational therapeutics against unprecedented targets in patients with lung and other malignancies.

PubMed

Rowinsky, Eric K

2004-06-15

A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.

Predictors of dropout from community clinic child CBT for anxiety disorders.

PubMed

Wergeland, Gro Janne H; Fjermestad, Krister W; Marin, Carla E; Haugland, Bente Storm-Mowatt; Silverman, Wendy K; Öst, Lars-Göran; Havik, Odd E; Heiervang, Einar R

2015-04-01

The aim was to investigate predictors of treatment dropout among 182 children (aged 8-15 years) participating in an effectiveness trial of manual-based 10-session individual and group cognitive behavior therapy (CBT) for anxiety disorders in community clinics. The dropout rate was 14.4%, with no significant difference between the two treatment conditions. We examined predictors for overall dropout (n=26), early (≤session 4, n=15), and late dropout (≥session 5, n=11). Overall dropout was predicted by low child and parent rated treatment credibility, and high parent self-rated internalizing symptoms. Low child rated treatment credibility predicted both early and late dropout. High parent self-rated internalizing symptoms predicted early dropout, whereas low parent rated treatment credibility predicted late dropout. These results highlight the importance of addressing treatment credibility, and to offer support for parents with internalizing symptoms, to help children and families remain in treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy.

PubMed

Hellwig, Birte; Madjar, Katrin; Edlund, Karolina; Marchan, Rosemarie; Cadenas, Cristina; Heimes, Anne-Sophie; Almstedt, Katrin; Lebrecht, Antje; Sicking, Isabel; Battista, Marco J; Micke, Patrick; Schmidt, Marcus; Hengstler, Jan G; Rahnenführer, Jörg

2016-01-01

In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery. Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer. Ten late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer. Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.

Development and external validation of a prediction rule for an unfavorable course of late-life depression: A multicenter cohort study.

PubMed

Maarsingh, O R; Heymans, M W; Verhaak, P F; Penninx, B W J H; Comijs, H C

2018-08-01

Given the poor prognosis of late-life depression, it is crucial to identify those at risk. Our objective was to construct and validate a prediction rule for an unfavourable course of late-life depression. For development and internal validation of the model, we used The Netherlands Study of Depression in Older Persons (NESDO) data. We included participants with a major depressive disorder (MDD) at baseline (n = 270; 60-90 years), assessed with the Composite International Diagnostic Interview (CIDI). For external validation of the model, we used The Netherlands Study of Depression and Anxiety (NESDA) data (n = 197; 50-66 years). The outcome was MDD after 2 years of follow-up, assessed with the CIDI. Candidate predictors concerned sociodemographics, psychopathology, physical symptoms, medication, psychological determinants, and healthcare setting. Model performance was assessed by calculating calibration and discrimination. 111 subjects (41.1%) had MDD after 2 years of follow-up. Independent predictors of MDD after 2 years were (older) age, (early) onset of depression, severity of depression, anxiety symptoms, comorbid anxiety disorder, fatigue, and loneliness. The final model showed good calibration and reasonable discrimination (AUC of 0.75; 0.70 after external validation). The strongest individual predictor was severity of depression (AUC of 0.69; 0.68 after external validation). The model was developed and validated in The Netherlands, which could affect the cross-country generalizability. Based on rather simple clinical indicators, it is possible to predict the 2-year course of MDD. The prediction rule can be used for monitoring MDD patients and identifying those at risk of an unfavourable outcome. Copyright © 2018 Elsevier B.V. All rights reserved.

Attention and Word Learning in Toddlers Who Are Late Talkers

ERIC Educational Resources Information Center

MacRoy-Higgins, Michelle; Montemarano, Elizabeth A.

2016-01-01

The purpose of this study was to examine attention allocation in toddlers who were late talkers and toddlers with typical language development while they were engaged in a word-learning task in order to determine if differences exist. Two-year-olds who were late talkers (11) and typically developing toddlers (11) were taught twelve novel…

Regulatory challenges for autologous tissue engineered products on their way from bench to bedside in Europe.

PubMed

Ram-Liebig, Gouya; Bednarz, Juergen; Stuerzebecher, Burkard; Fahlenkamp, Dirk; Barbagli, Guido; Romano, Giuseppe; Balsmeyer, Ulf; Spiegeler, Maria-Elsa; Liebig, Soeren; Knispel, Helmut

2015-03-01

Since the late eighties of last century the high potential of tissue engineered products (TEP)s has been shown for the treatment of various diseases and many scientific publications appeared in this field. However, only few products reached the market since. Development of TEPs is a promising but owing to its novelty a very challenging task that requires experts in this still developing field as well as ample financial resources. This paper summarises relevant regulatory challenges during quality, preclinical and clinical development of autologous TEPs in Europe. Selected strategies on how to manage major issues are presented, together with some examples from the development of an autologous TEP for urethroplasty. Considering these aspects may help other investigators with potential strategies during the development of novel TEPs. Copyright © 2014 Elsevier B.V. All rights reserved.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

PubMed

Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

2017-01-01

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na + and Ca 2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca 2+ -transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

Premorbid functioning of patients with first-episode nonaffective psychosis: a comparison of deterioration in academic and social performance, and clinical correlates of Premorbid Adjustment Scale scores.

PubMed

Monte, Ralph C; Goulding, Sandra M; Compton, Michael T

2008-09-01

Motivated by a previous study among male veterans [Allen, D.N., Frantom, L.V., Strauss, G.P., van Kammen, D.P., 2005. Differential patterns of premorbid academic and social deterioration in patients with schizophrenia. Schizophr. Res. 75, 389-397], the present analysis examined: (1) patterns of premorbid academic and social functioning during childhood, early adolescence, and late adolescence, and (2) associations between these premorbid functioning dimensions and a number of clinical variables. Data on premorbid functioning were collected using the Premorbid Adjustment Scale (PAS) in 95 hospitalized first-episode patients. Analyses were similar to those conducted by Allen and colleagues (2005). Deterioration was evident in both academic and social functioning from childhood to early adolescence, along with a pronounced/accelerated deterioration in academic functioning from early adolescence to late adolescence, occurring in both male and female patients. Age at onset of prodromal symptoms was predicted by childhood/early adolescent/late adolescent academic functioning scores, and age at onset of psychotic symptoms was significantly associated only with childhood academic functioning. Severity of negative symptoms was predicted by childhood and late adolescent social functioning scores, and severity of general psychopathology symptoms was predicted by late adolescent academic functioning, as well as childhood and late adolescent social functioning scores. Consistent with prior findings, deterioration in premorbid functioning appears to be more pronounced in the academic than social dimension of the PAS. Some PAS scores are predictive of ages at onset of prodrome/psychosis and severity of psychotic symptoms. Ongoing research on premorbid adjustment in schizophrenia may have implications for future prevention goals.

Effectiveness of two-year clopidogrel + aspirin in abolishing the risk of very late thrombosis after drug-eluting stent implantation (from the TYCOON [two-year ClOpidOgrel need] study).

PubMed

Tanzilli, Gaetano; Greco, Cesare; Pelliccia, Francesco; Pasceri, Vincenzo; Barillà, Francesco; Paravati, Vincenzo; Pannitteri, Gaetano; Gaudio, Carlo; Mangieri, Enrico

2009-11-15

It remains unclear whether dual antiplatelet therapy >12 months might carry a better prognosis after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). To address the hypothesis that in the real world the risk of very late thrombosis after PCI with DESs can be decreased by an extended use of clopidogrel, we set up the Two-Year ClOpidOgrel Need (TYCOON) registry and prospectively investigated the impact on very late thrombosis of 12- versus 24-month dual antiplatelet regimens in an unselected population. The registry enrolled 897 consecutive patients who underwent PCI with stenting from January 1, 2003, to December 31, 2004, and had dual antiplatelet therapy. All patients had a 4-year clinical follow-up. In the 447 patients with DES implantation, the dual antiplatelet regimen after PCI was given for 12 months in the 173 patients treated in 2003 (12-month group) and for 24 months in the 274 patients treated in 2004 (24-month group). Comparison between groups did not reveal any significant difference in baseline clinical characteristics, angiographic and procedural features, and major adverse cardiac events. During follow-up, there were 5 cases of stent thrombosis after PCI in the 12-month DES group and 1 case in the 24-month DES group (p = 0.02). Specifically, there were 2 cases of subacute thrombosis (1 in each group), no case of late thrombosis, and 4 cases of very late thrombosis occurring at 13, 15, 17, and 23 months after DES implantation in the 12-month group only. In conclusion, a 2-year dual antiplatelet regimen with aspirin and clopidogrel can prevent the occurrence of very late stent thrombosis after PCI with DESs.

Atrial ectopy predicts late recurrence of atrial fibrillation after pulmonary vein isolation.

PubMed

Gang, Uffe J O; Nalliah, Chrishan J; Lim, Toon Wei; Thiagalingam, Aravinda; Kovoor, Pramesh; Ross, David L; Thomas, Stuart P

2015-06-01

Late recurrence of atrial fibrillation (AF) after radiofrequency ablation remains significant. Asymptomatic recurrence poses a difficult clinical problem as it is associated with an equally increased risk of stroke and death compared with symptomatic AF events. Meta-analyses reveal that no single preablation patient characteristic efficiently predicts these AF recurrences. This study aimed to evaluate the prognostic value of premature atrial complex (PAC) occurrence with regard to the risk of late AF recurrence after radiofrequency ablation. The study cohort consisted of 124 patients with 7-day Holter recordings at 6 months post radiofrequency ablation for AF. No patients had AF recurrence before this time. Patients were followed-up every 6 months. Holter-detected PACs were defined as any supraventricular complexes occurring >30% earlier than expected. During a median follow-up of 4.2 years (first quartile to third quartile [Q1-Q3]=1.6-4.5), 32 patients (26%) had late recurrences of AF at a median of 462 days (Q1-Q3=319-1026) post radiofrequency ablation. The number of PACs per 24 hours was 248 (Q1-Q3=62-1026) in patients with and 77 (Q1-Q3=24-448) in patients without recurrence of AF (P=0.02). Multivariate analysis of the risk of late AF recurrence found ≥142 PACs per 24 hours to have a hazard ratio 2.84 (confidence interval, 1.26-6.43), P=0.01. This study showed that occurrence of ≥142 PACs per day at 6 months after PVI was independently associated with a significantly increased risk of late AF recurrence. These results could have important clinical implications for the design of post-PVI follow-up. URL: http://www.anzctr.org.au. Unique identifier: ACRTN12606000467538. © 2015 American Heart Association, Inc.

Effects of education on the progression of early- versus late-stage mild cognitive impairment.

PubMed

Ye, Byoung Seok; Seo, Sang Won; Cho, Hanna; Kim, Seong Yoon; Lee, Jung-Sun; Kim, Eun-Joo; Lee, Yunhwan; Back, Joung Hwan; Hong, Chang Hyung; Choi, Seong Hye; Park, Kyung Won; Ku, Bon D; Moon, So Young; Kim, Sangyun; Han, Seol-Heui; Lee, Jae-Hong; Cheong, Hae-Kwan; Na, Duk L

2013-04-01

Highly educated participants with normal cognition show lower incidence of Alzheimer's disease (AD) than poorly educated participants, whereas longitudinal studies involving AD have reported that higher education is associated with more rapid cognitive decline. We aimed to evaluate whether highly educated amnestic mild cognitive impairment (aMCI) participants show more rapid cognitive decline than those with lower levels of education. A total of 249 aMCI patients enrolled from 31 memory clinics using the standard assessment and diagnostic processes were followed with neuropsychological evaluation (duration 17.2 ± 8.8 months). According to baseline performances on memory tests, participants were divided into early-stage aMCI (-1.5 to -1.0 standard deviation (SD)) and late-stage aMCI (below -1.5 SD) groups. Risk of AD conversion and changes in neuropsychological performances according to the level of education were evaluated. Sixty-two patients converted to AD over a mean follow-up of 1.43 years. The risk of AD conversion was higher in late-stage aMCI than early-stage aMCI. Cox proportional hazard models showed that aMCI participants, and late-stage aMCI participants in particular, with higher levels of education had a higher risk of AD conversion than those with lower levels of education. Late-stage aMCI participants with higher education showed faster cognitive decline in language, memory, and Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores. On the contrary, early-stage aMCI participants with higher education showed slower cognitive decline in MMSE and CDR-SOB scores. Our findings suggest that the protective effects of education against cognitive decline remain in early-stage aMCI and disappear in late-stage aMCI.

Health and cost consequences of early versus late invasive strategy after thrombolysis for acute myocardial infarction.

PubMed

Bøhmer, Ellen; Kristiansen, Ivar Sønbø; Arnesen, Harald; Halvorsen, Sigrun

2011-10-01

The NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction showed an improved clinical outcome with early transfer for percutaneous coronary intervention (PCI) compared to a more conservative approach after thrombolysis. The aim of this substudy was to compare the 12-month quality-adjusted life years (QALYs) and costs of these alternative strategies. Patients with ST-elevation myocardial infarction <6 h duration and >90 min expected delay to PCI, received full-dose tenecteplase and were randomized to either early or late invasive strategy (n = 266). Detailed quality of life and resource use data were registered prospectively for a period of 12 months. Health outcomes were measured as quality of life using a generic instrument (15D). Quality of life scores were translated into QALYs. Unit costs were based on hospital accounts, fee schedules, and market prices. After 12 months of follow-up, patients in the early invasive group had 0.008 (95% CI -0.027 to 0.043) more QALYs compared to the late invasive group. The mean total costs were €18,201 in the early versus €17,643 in the late invasive group, with a mean difference of €558 (95% CI -2258 to 3484). Cost/QALY was €69,750 while cost/avoided clinical endpoint was €5636. Early and late invasive strategies after thrombolysis resulted in similar quality of life and similar costs in ST-elevation myocardial infarction patients living far from a PCI centre (NCT00161005).

Early- versus Late-Onset Dysthymia

PubMed Central

Sansone, Lori A.

2009-01-01

In the current Diagnostic and Statistical Manual of Mental Disorders, dysthymic disorder is categorized as either early-onset or late-onset, based upon the emergence of symptoms before or after the age of 21, respectively. Does this diagnostic distinction have any meaningful clinical implications? In this edition of The Interface, we present empirical studies that have, within a single study, compared individuals with early-versus late-onset dysthymia. In this review, we found that, compared to those with late-onset dysthymia, early-onset patients are more likely to harbor psychiatric comorbidity both on Axis I and II, exhibit less psychological resilience, and have more prominent family loadings for mood disorders. These findings suggest that this distinction is meaningful and that the early-onset subtype of dysthymia is more difficult to effectively treat. PMID:20049145

Building a sustainable clinical academic workforce to meet the future healthcare needs of Australia and New Zealand: report from the first summit meeting.

PubMed

Windsor, J; Searle, J; Hanney, R; Chapman, A; Grigg, M; Choong, P; Mackay, A; Smithers, B M; Churchill, J A; Carney, S; Smith, J A; Wainer, Z; Talley, N J; Gladman, M A

2015-09-01

The delivery of healthcare that meets the requirements for quality, safety and cost-effectiveness relies on a well-trained medical workforce, including clinical academics whose career includes a specific commitment to research, education and/or leadership. In 2011, the Medical Deans of Australia and New Zealand published a review on the clinical academic workforce and recommended the development of an integrated training pathway for clinical academics. A bi-national Summit on Clinical Academic Training was recently convened to bring together all relevant stakeholders to determine how best to do this. An important part understood the lessons learnt from the UK experience after 10 years since the introduction of an integrated training pathway. The outcome of the summit was to endorse strongly the recommendations of the medical deans. A steering committee has been established to identify further stakeholders, solicit more information from stakeholder organisations, convene a follow-up summit meeting in late 2015, recruit pilot host institutions and engage the government and future funders. © 2015 Royal Australasian College of Physicians.

Wearable sensor-based objective assessment of motor symptoms in Parkinson's disease.

PubMed

Ossig, Christiana; Antonini, Angelo; Buhmann, Carsten; Classen, Joseph; Csoti, Ilona; Falkenburger, Björn; Schwarz, Michael; Winkler, Jürgen; Storch, Alexander

2016-01-01

Effective management and development of new treatment strategies of motor symptoms in Parkinson's disease (PD) largely depend on clinical rating instruments like the Unified PD rating scale (UPDRS) and the modified abnormal involuntary movement scale (mAIMS). Regarding inter-rater variability and continuous monitoring, clinical rating scales have various limitations. Patient-administered questionnaires such as the PD home diary to assess motor stages and fluctuations in late-stage PD are frequently used in clinical routine and as clinical trial endpoints, but diary/questionnaire are tiring, and recall bias impacts on data quality, particularly in patients with cognitive dysfunction or depression. Consequently, there is a strong need for continuous and objective monitoring of motor symptoms in PD for improving therapeutic regimen and for usage in clinical trials. Recent advances in battery technology, movement sensors such as gyroscopes, accelerometers and information technology boosted the field of objective measurement of movement in everyday life and medicine using wearable sensors allowing continuous (long-term) monitoring. This systematic review summarizes the current wearable sensor-based devices to objectively assess the various motor symptoms of PD.

Hyperhidrosis Prevalence and Demographical Characteristics in Dermatology Outpatients in Shanghai and Vancouver.

PubMed

Liu, Yudan; Bahar, Rayeheh; Kalia, Sunil; Huang, Rachel Yuanshen; Phillips, Arlie; Su, Mingwan; Yang, Sen; Zhang, Xuejun; Zhou, Pingyu; Zhou, Youwen

2016-01-01

There is a wide variation in the reported prevalence of primary hyperhidrosis in the literature. Further, it is unknown if primary hyperhidrosis is a lifelong condition, or if demographical factors influence hyperhidrosis prevalence. This study aims to examine the prevalence of hyperhidrosis in multiple ethnic groups from two ethnically diverse cities and to determine if the prevalence of primary hyperhidrosis changes according to age, gender, ethnicity, body mass index, and geographical locations. In total, 1010 consecutive subjects attending dermatology outpatient clinics in Shanghai Skin Disease Hospital and 1018 subjects in Skin Care Center of Vancouver General Hospital were invited to fill out a questionnaire on their presenting concerns, demographical information, and sweating symptoms. The subjects were then classified to have primary hyperhidrosis using the criteria of International Hyperhidrosis Society, late-onset hyperhidrosis, or no-hyperhidrosis. The prevalence of primary HH and late-onset HH was calculated for the entire study population and in subgroups stratified according to age of examination, sex, ethnicity, presenting diagnosis, body mass index, and specific study cities. Multivariate logistic regression analyses were performed to assess the impact of these factors on HH prevalence. The prevalence of primary hyperhidrosis is very similar in Shanghai and in Vancouver, at 14.5% and 12.3% respectively. In addition, 4.0% of subjects in Shanghai and 4.4% subjects in Vancouver suffer from late-onset HH. Primary HH has highest prevalence in those younger than 30 years of age, decreasing dramatically in later years. Caucasian subjects are at least 2.5 times more likely to develop axillary hyperhidrosis compared to Chinese subjects. Obesity does not have much influence on primary HH presentation, although it does increase significantly the development of late-onset HH. Finally, there is no major difference of hyperhidrosis between Chinese subjects in Shanghai and Vancouver. The data were gathered according to patients' self-reports only and the sample size was relatively small in some groups after stratification for gender, ethnicity and age. Prevalence of primary HH and late-onset HH is similar in dermatology outpatients independent of geographical locations. However, certain specific HH subtypes can show great variations according to ethnicity, age, body mass index and sex.

Cost-effectiveness analysis of timely dialysis referral after renal transplant failure in Spain.

PubMed

Villa, Guillermo; Sánchez-Álvarez, Emilio; Cuervo, Jesús; Fernández-Ortiz, Lucía; Rebollo, Pablo; Ortega, Francisco

2012-08-16

A cost-effectiveness analysis of timely dialysis referral after renal transplant failure was undertaken from the perspective of the Public Administration. The current Spanish situation, where all the patients undergoing graft function loss are referred back to dialysis in a late manner, was compared to an ideal scenario where all the patients are timely referred. A Markov model was developed in which six health states were defined: hemodialysis, peritoneal dialysis, kidney transplantation, late referral hemodialysis, late referral peritoneal dialysis and death. The model carried out a simulation of the progression of renal disease for a hypothetical cohort of 1,000 patients aged 40, who were observed in a lifetime temporal horizon of 45 years. In depth sensitivity analyses were performed in order to ensure the robustness of the results obtained. Considering a discount rate of 3 %, timely referral showed an incremental cost of 211 €, compared to late referral. This cost increase was however a consequence of the incremental survival observed. The incremental effectiveness was 0.0087 quality-adjusted life years (QALY). When comparing both scenarios, an incremental cost-effectiveness ratio of 24,390 €/QALY was obtained, meaning that timely dialysis referral might be an efficient alternative if a willingness-to-pay threshold of 45,000 €/QALY is considered. This result proved to be independent of the proportion of late referral patients observed. The acceptance probability of timely referral was 61.90 %, while late referral was acceptable in 38.10 % of the simulations. If we however restrict the analysis to those situations not involving any loss of effectiveness, the acceptance probability of timely referral was 70.10 %, increasing twofold that of late referral (29.90 %). Timely dialysis referral after graft function loss might be an efficient alternative in Spain, improving both patients' survival rates and health-related quality of life at an affordable cost. Spanish Public Health authorities might therefore promote the inclusion of specific recommendations for this group of patients within the existing clinical guidelines.

The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9.

PubMed

Al-Holou, Shaza N; Tucker, William R; Agrón, Elvira; Clemons, Traci E; Cukras, Catherine; Ferris, Frederick L; Chew, Emily Y

2015-12-01

To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the majority of previous studies. Statins have been demonstrated to reduce the risk of cardiovascular disease, but our data do not provide evidence of a beneficial effect on slowing AMD progression. Published by Elsevier Inc.

Early versus late Gamma Knife radiosurgery following transsphenoidal surgery for nonfunctioning pituitary macroadenomas: a multicenter matched-cohort study.

PubMed

Pomeraniec, I Jonathan; Kano, Hideyuki; Xu, Zhiyuan; Nguyen, Brandon; Siddiqui, Zaid A; Silva, Danilo; Sharma, Mayur; Radwan, Hesham; Cohen, Jonathan A; Dallapiazza, Robert F; Iorio-Morin, Christian; Wolf, Amparo; Jane, John A; Grills, Inga S; Mathieu, David; Kondziolka, Douglas; Lee, Cheng-Chia; Wu, Chih-Chun; Cifarelli, Christopher P; Chytka, Tomas; Barnett, Gene H; Lunsford, L Dade; Sheehan, Jason P

2017-10-27

OBJECTIVE Gamma Knife radiosurgery (GKRS) is frequently used to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of imaging-defined progression of tumor. Given the high incidence of adenoma progression after subtotal resection over time, the present study intended to evaluate the effect of timing of radiosurgery on outcome. METHODS This is a multicenter retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS from 1987 to 2015 at 9 institutions affiliated with the International Gamma Knife Research Foundation. Patients were matched by adenoma and radiosurgical parameters and stratified based on the interval between last resection and radiosurgery. Operative results, imaging data, and clinical outcomes were compared across groups following early (≤ 6 months after resection) or late (> 6 months after resection) radiosurgery. RESULTS After matching, 222 patients met the authors' study criteria (from an initial collection of 496 patients) and were grouped based on early (n = 111) or late (n = 111) GKRS following transsphenoidal surgery. There was a greater risk of tumor progression after GKRS (p = 0.013) and residual tumor (p = 0.038) in the late radiosurgical group over a median imaging follow-up period of 68.5 months. No significant difference in the occurrence of post-GKRS endocrinopathy was observed (p = 0.68). Thirty percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 27% in the late cohort (p = 0.84). Fourteen percent of the patients in the early group and 25% of the patients in the late group experienced the resolution of endocrine dysfunction after original presentation (p = 0.32). CONCLUSIONS In this study, early GKRS was associated with a lower risk of radiological progression of subtotally resected nonfunctioning pituitary macroadenomas compared with expectant management followed by late radiosurgery. Delaying radiosurgery may increase patient risk for long-term adenoma progression. The timing of radiosurgery does not appear to significantly affect the rate of delayed endocrinopathy.

The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.

PubMed

Stanton, Kelly M; Ganigara, Madhusudan; Corte, Peter; Celermajer, David S; McGuire, Mark A; Torzillo, Paul J; Corte, Tamera J; Puranik, Rajesh

2017-11-01

Autopsy reports suggest that cardiac sarcoidosis occurs in 20 to 25% of patients with pulmonary sarcoidosis, yet the clinical ante-mortem diagnosis is made in only 5% of cases. Current diagnostic algorithms are complex and lack sensitivity. Cardiac Magnetic Resonance imaging (CMR) provides an opportunity to detect myocardial involvement in sarcoidosis. The aim of this study is to determine the prevalence and clinical significance of late gadolinium enhancement (LGE) on CMR in patients with sarcoidosis. Consecutive patients with biopsy-proven sarcoidosis undergoing CMR were retrospectively evaluated for cardiac sarcoidosis. Medical records were correlated with CMR. Forty-six patients were evaluated. Late gadolinium enhancement was present in 22%, indicating myocardial involvement, and 70% had corresponding hyper-intense T2 signal indicating active inflammation. Late gadolinium enhancement was 18%+/-9.7% of overall left ventricular (LV) mass and most commonly located in the basal to mid septum. There was no association between LGE and cardiovascular symptoms or pulmonary stage. Eighty per cent of patients with LGE did not fulfill conventional diagnostic criteria for cardiac sarcoidosis. However, LGE was associated with clinically significant arrhythmia (p<0.01) and a lower LVEF (p=0.04). Using CMR, we identified a higher prevalence of cardiac sarcoidosis than previously reported clinical studies, a prevalence which is more consistent with autopsy data. The presence of LGE was highly correlated with clinically significant arrhythmias and lower LVEF. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.

Longitudinal treatment of cleft lip and palate in developing countries: dentistry as part of a multidisciplinary endeavor.

PubMed

Lee, Cameron C Y; Jagtap, Rasika R; Deshpande, Gaurav S

2014-09-01

Cleft lip and palate affects roughly 1 in 600 children and predisposes patients to a lifetime of functional and esthetic discrepancies. Disparities in access as well as quality of care exist worldwide, with many children in developing countries unable to receive treatment. In the late 20th century, humanitarian medical missions emerged as a means of delivering surgical expertise to patients in resource-limited settings. These early missions took on a patient-centered approach focused solely on cleft repair, with little emphasis on treating the dental abnormalities that arose after the initial surgery. However, modern cleft care is characterized by a multidisciplinary, team-based approach with significant dental involvement. Recent cleft lip and palate endeavors have shifted from a mission-based approach to a developmental approach facilitating growth of an independent care center. This strategy focuses on creating an institution with expanded access to dental services, thus facilitating the long-term treatment inherent in modern cleft care. One clinic in a developing country that has experienced successful transitioning from a mission site to an independent craniofacial clinic is Operation Smile's Cleft Comprehensive Care Clinic in Guwahati, India. This article will summarize the rationale and planning of the clinic, underscore the team-based approach required in longitudinal treatment of cleft lip and palate, and demonstrate how treatment methodology may differ in resource-limited settings by outlining the therapeutic considerations of each provider in the Guwahati Clinic.

Assessment of anxiety in older adults: a review of self-report measures

PubMed Central

Balsamo, Michela; Cataldi, Fedele; Carlucci, Leonardo; Fairfield, Beth

2018-01-01

With increasing numbers of older adults in the general population, anxiety will become a widespread problem in late life and one of the major causes of health care access contributing to high societal and individual costs. Unfortunately, the detection of anxiety disorders in late life is complicated by a series of factors that make it different from assessment in younger cohorts, such as differential symptom presentation, high comorbidity with medical and mental disorders, the aging process, and newly emergent changes in life circumstances. This review covers commonly and currently used self-report inventories for assessing anxiety in older adults. For each tool, psychometric data is investigated in depth. In particular, information about reliability, validity evidence based on data from clinical and nonclinical samples of older adults, and availability of age-appropriate norms are provided. Finally, guidance for clinical evaluation and future research are proposed in an effort to highlight the importance of clinical assessment in the promotion of clinically relevant therapeutic choices. PMID:29670342

Linezolid in late-chronic prosthetic joint infection caused by gram-positive bacteria.

PubMed

Cobo, Javier; Lora-Tamayo, Jaime; Euba, Gorane; Jover-Sáenz, Alfredo; Palomino, Julián; del Toro, Ma Dolores; Rodríguez-Pardo, Dolors; Riera, Melchor; Ariza, Javier

2013-05-01

Linezolid may be an interesting alternative for prosthetic joint infection (PJI) due to its bioavailability and its antimicrobial spectrum. However, experience in this setting is scarce. The aim of the study was to assess linezolid's clinical and microbiological efficacy, and also its tolerance. This was a prospective, multicenter, open-label, non-comparative study of 25 patients with late-chronic PJI caused by Gram-positive bacteria managed with a two-step exchange procedure plus 6 weeks of linezolid. Twenty-two (88%) patients tolerated linezolid without major adverse effects, although a global decrease in the platelet count was observed. Three patients were withdrawn because of major toxicity, which reversed after linezolid stoppage. Among patients who completed treatment, 19 (86%) demonstrated clinical and microbiological cure. Two patients presented with clinical and microbiological failure, and one showed clinical cure and microbiological failure. In conclusion, linezolid showed good results in chronic PJI managed with a two-step exchange procedure. Tolerance seems acceptable, though close surveillance is required. Copyright © 2013 Elsevier Inc. All rights reserved.

Late onset Wilson's disease: therapeutic implications.

PubMed

Członkowska, Anna; Rodo, Maria; Gromadzka, Grazyna

2008-04-30

The clinical symptoms of Wilson's disease (WD) usually develop between 3 and 40 years of age and include signs of liver and/or neurologic and psychiatric disease. We report on an 84-year-old woman with WD. Despite the absence of treatment, the only symptom she presented with, until the age of 74 years, was Kayser-Fleisher rings. At the age of 74, she developed slightly abnormal liver function. This case raises the following issues: (a) Should WD be considered in all patients of all ages who manifest signs related to the disease? (b) Are ATP7B mutations fully penetrant? (c) Should all patients diagnosed presymptomatically receive anticopper therapy? (c) 2008 Movement Disorder Society.

No increase in toxicity of pelvic irradiation when intensity modulation is employed: clinical and dosimetric data of 208 patients treated with post-prostatectomy radiotherapy.

PubMed

Jereczek-Fossa, Barbara A; Ciardo, Delia; Ferrario, Silvia; Fossati, Piero; Fanetti, Giuseppe; Zerini, Dario; Zannoni, Davide; Fodor, Cristiana; Gerardi, Marianna A; Surgo, Alessia; Muto, Matteo; Cambria, Raffaella; De Cobelli, Ottavio; Orecchia, Roberto

2016-07-01

To compare the toxicity of image-guided intensity-modulated radiotherapy (IG-IMRT) to the pelvis or prostate bed (PB) only. To test the hypothesis that the potentially injurious effect of pelvic irradiation can be counterbalanced by reduced irradiated normal tissue volume using IG-IMRT. Between February 2010 and February 2012, 208 patients with prostate cancer were treated with adjuvant or salvage IG-IMRT to the PB (102 patients, Group PB) or the pelvis and prostate bed (P) (106 patients, Group P). The Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria were used to evaluate toxicity. Median follow-up was 27 months. Toxicity G ≥ 2 in Group PB: in the bowel acute and late toxicities were 11.8% and 10%, respectively; urinary acute and late toxicities were 10.8% and 15%, respectively. Toxicity G ≥ 2 in Group P: in the bowel acute and late toxicities were both 13.2%; urinary acute and late toxicities were 13.2% and 15.1%, respectively. No statistical difference in acute or late toxicity between the groups was found (bowel: p = 0.23 and p = 0.89 for acute and late toxicity, respectively; urinary: p = 0.39 and p = 0.66 for acute and late toxicity, respectively). Of the clinical variables, only previous abdominal surgery was correlated with acute bowel toxicity. Dosimetric parameters that correlated with bowel toxicity were identified. The toxicity rates were low and similar in both groups, suggesting that IG-IMRT allows for a safe post-operative irradiation of larger volumes. Further investigation is warranted to exclude bias owing to non-randomized character of the study. Our report shows that modern radiotherapy technology and careful planning allow maintaining the toxicity of pelvic lymph node treatment at the acceptable level, as it is in the case of PB radiotherapy.

The economic and clinical burden of early versus late initiation of celecoxib among patients with osteoarthritis

PubMed Central

Shelbaya, Ahmed; Solem, Caitlyn T; Walker, Chris; Wan, Yin; Johnson, Courtney; Cappelleri, Joseph C

2018-01-01

Objective This study aimed to evaluate the characteristics associated with early versus late initiation of celecoxib treatment after osteoarthritis (OA) diagnosis and whether economic and safety outcomes differ between patients with early versus late initiation of celecoxib. Methods Adults (≥18 years) with a confirmed OA diagnosis (International Classification of Diseases, 9th Edition, Clinical Modifications code: 715.XX), ≥12 months of continuous pre- and post-index enrollment, and ≥1 post-index claim for celecoxib were included from the MarketScan® Commercial Claims and Encounter Database (2009–2013). Index date was defined as initial OA diagnosis. Patients were categorized as initiating celecoxib early (within 6 months of index date) or late (≥6 months after index date). Logistic regressions were used to assess characteristics associated with early versus late celecoxib initiation. Key outcomes included health care resource utilization (HCRU) and costs post-index, and adverse event incidence post-celecoxib initiation. Unadjusted and adjusted comparisons (using generalized linear models with a gamma distribution for costs and Poisson distribution for event and resource utilization) were made between early and late celecoxib initiators. Results Of the 62,434 OA patients identified, 27,402 were early and 35,032 were late initiators. Post-index hospital admissions and length of stay did not differ statistically between early versus late initiators after controlling for pre-index event rates and covariates, but early patients had significantly fewer outpatient (incidence rate ratio [IRR]: 0.96; 95% confidence interval [CI]: 0.95, 0.97) and emergency room visits (IRR: 0.89; 95% CI: 0.84, 0.95). After adjustment for key covariates, early initiators (versus late initiators) had lower all-cause (US$12,909 versus US$13,781, P<0.001) and OA-related (US$4,988 versus US$5,178, P=0.015) costs per person-year. Early initiators had no statistically significant difference in the incidence of post-celecoxib cardiovascular (IRR: 0.92; 95% CI: 0.73, 1.14), gastrointestinal (IRR: 1.25; 95% CI: 0.81, 1.92), or renal (IRR: 1.19; 95% CI: 0.65, 2.18) events, controlling for pre-index event rates and covariates when compared to late initiators. Conclusion In this real-world cohort, patients initiated on celecoxib early (versus late) had significantly lower costs and HCRU; this may warrant consideration when making treatment decisions for OA patients. PMID:29670383

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib.

PubMed

Parrott, Neil J; Yu, Li J; Takano, Ryusuke; Nakamura, Mikiko; Morcos, Peter N

2016-11-01

Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus ™ software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.

Early intervention of negative pressure wound therapy using Vacuum-Assisted Closure in trauma patients: impact on hospital length of stay and cost.

PubMed

Kaplan, Mark; Daly, Darron; Stemkowski, Stephen

2009-03-01

The cost of treating complex traumatic wounds is substantial because of trauma severity, potential for infection, and delayed closure. Negative pressure wound therapy using reticulated open cell foam (NPWT/ROCF) as delivered by Vacuum-Assisted Closure* (KCI Licensing, Inc, San Antonio, Texas) is an established, viable option for treating traumatic wounds. The authors used retrospective data to study the clinical and cost-effective benefits of using NPWT/ROCF early on day 1 or day 2 of treatment for traumatic wounds as compared with using it late (on day 3 or later). Hospital data records from trauma wound patients treated with NPWT/ROCF were retrospectively analyzed. Data were subdivided into 2 groups based on start of treatment. The group of patients treated on day 1 or 2 of their hospital stay was referred to as the early group, and that composed of patients treated on day 3 or later as the late group. Clinical and cost-effective metrics were compared between the 2 groups. For the early group, 518 patient records were included; 1000 records were reviewed for the late group. Early-group patients had fewer hospital inpatient days (10.6 vs 20.6 days; P < .0001), fewer treatment days (5.1 vs 6.0 days; P = .0498), shorter intensive care unit (ICU) stays (5.3 vs 12.4 days; P < .0001), and higher ICU admission rates (51.5 vs 44.5%; P = .0091) than the late group. Compared with late-group patients, early-group patients had lower total and variable costs per patient discharge ($43,956 vs $32,175; P < .0001 and $22,891 vs $15,805; P < .0001, respectively). Acute-care trauma wound patients receiving early NPWT/ROCF demonstrated significant reductions in length of stay, treatment days, and ICU stay, which resulted in significant reduced patient treatment costs. These results indicate that early intervention with NPWT/ROCF has potential clinical and cost-effective benefits for the treatment of traumatic wounds.

Midlife Eriksonian Psychosocial Development: Setting the Stage for Cognitive and Emotional Health in Late Life

PubMed Central

Malone, Johanna C.; Liu, Sabrina R.; Vaillant, George E.; Rentz, Dorene M.; Waldinger, Robert J.

2017-01-01

Erikson’s (1950) model of adult psychosocial development outlines the significance of successful involvement within one’s relationships, work, and community for healthy aging. He theorized that the consequences of not meeting developmental challenges included stagnation and emotional despair. Drawing on this model, the present study uses prospective longitudinal data to examine how the quality of assessed Eriksonian psychosocial development in midlife relates to late-life cognitive and emotional functioning. In particular we were interested to see whether late-life depression mediated the relationship between Eriksonian development and specific domains of cognitive functioning (i.e., executive functioning and memory). Participants were 159 men from the over 75 year longitudinal Study of Adult Development. The sample was comprised of men from both higher and lower socio-economic strata. Eriksonian psychosocial development was coded from men’s narrative responses to interviews between the ages of 30–47 (Vaillant and Milofsky, 1980). In late life (ages 75–85) men completed a performance - based neuropsychological assessment measuring global cognitive status, executive functioning, and memory. In addition depressive symptomatology was assessed using the Geriatric Depression Scale. Our results indicated that higher midlife Eriksonian psychosocial development was associated with stronger global cognitive functioning and executive functioning, and lower levels of depression three to four decades later. There was no significant association between Eriksonian development and late-life memory. Late-life depression mediated the relationship between Eriksonian development and both global cognition and executive functioning. All of these results controlled for highest level of education and adolescent intelligence. Findings have important implications for understanding the lasting benefits of psychosocial engagement in mid-adulthood for late-life cognitive and emotional health. In addition, it may be that less successful psychosocial development increases levels of depression making individuals more vulnerable to specific areas of cognitive decline. PMID:26551530

Gonorrhoea in Greenland, incidence and previous preventive measures: a review to improve future strategies

PubMed Central

Berntsen, Sine; Karlsen, Anders Peder Højer; Pedersen, Michael Lynge; Mulvad, Gert

2017-01-01

ABSTRACT Gonorrhoea continues to be a significant health challenge in Greenland. The aim of this study was to describe the development of gonorrhoea in Greenland through time including incidence rates and previous measures taken to address the challenge. A systematic literature search in PubMed, Embase and The Cochrane Library was conducted. Furthermore, local archives were searched in the Health Clinic in Nuuk for relevant literature. From the 1940s the incidence of gonorrhoea increased steadily with a steep incline around 1970, possibly as a consequence of changes in living conditions and urbanisation. Significant declines in the incidence were seen the late 1970s and again in the late 1980s, most likely in the wake of an outbreak of ulcus molle/chancroid in the 1970s and as a result of focused education in venereology for Greenlandic nurses in the late 1980s combined with the stop-AIDS campaign. Since the early 1990s the incidence of gonorrhoea in Greenland has not risen to previously high levels. However, the incidence remains high and with a gradually increasing trend. Prevention intervention strategies such as peer-to-peer sexual education, storytelling and involvement of parent/guardian in sexual education of the youth could be appropriate approaches to improve sexual health in Greenland. PMID:28745556

Gonorrhoea in Greenland, incidence and previous preventive measures: a review to improve future strategies.

PubMed

Berntsen, Sine; Karlsen, Anders Peder Højer; Pedersen, Michael Lynge; Mulvad, Gert

2017-01-01

Gonorrhoea continues to be a significant health challenge in Greenland. The aim of this study was to describe the development of gonorrhoea in Greenland through time including incidence rates and previous measures taken to address the challenge. A systematic literature search in PubMed, Embase and The Cochrane Library was conducted. Furthermore, local archives were searched in the Health Clinic in Nuuk for relevant literature. From the 1940s the incidence of gonorrhoea increased steadily with a steep incline around 1970, possibly as a consequence of changes in living conditions and urbanisation. Significant declines in the incidence were seen the late 1970s and again in the late 1980s, most likely in the wake of an outbreak of ulcus molle/chancroid in the 1970s and as a result of focused education in venereology for Greenlandic nurses in the late 1980s combined with the stop-AIDS campaign. Since the early 1990s the incidence of gonorrhoea in Greenland has not risen to previously high levels. However, the incidence remains high and with a gradually increasing trend. Prevention intervention strategies such as peer-to-peer sexual education, storytelling and involvement of parent/guardian in sexual education of the youth could be appropriate approaches to improve sexual health in Greenland.

Preclinical and clinical data for factor Xa and “universal” reversal agents☆,☆☆,★

PubMed Central

Milling, Truman J.; Kaatz, Scott

2017-01-01

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoymolecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitoreassociated major hemorrhage. PMID:27697443

Preclinical and Clinical Data for Factor Xa and “Universal” Reversal Agents

PubMed Central

Milling, Truman J.; Kaatz, Scott

2017-01-01

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitor–associated major hemorrhage. PMID:27575436

[Treatment of testicular cancer].

PubMed

Droz, Jean-Pierre; Boyle, Helen; Culine, Stéphane; Fizazi, Karim; Fléchon, Aude; Massard, Christophe

2013-12-01

Germ-cell tumours (GCTs) are the most common type of cancer in young men. Since the late 1970s, disseminated GCT have been a paradigm for curable metastatic cancer and metastatic GCTs are highly curable with cisplatin-based chemotherapy followed by surgical resection of residual masses. Patients' prognosis is currently assessed using the International Germ-Cell Consensus Classification (IGCCC) and used to adapt the burden of chemotherapy. Approximately 20% of patients still do not achieve cure after first-line cisplatin-based chemotherapy, and need salvage chemotherapy (high dose or standard dose chemotherapy). Clinical stage I testicular cancer is the most common presentation and different strategies are proposed: adjuvant therapies, surgery or surveillance. During the last three decades, clinical trials and strong international collaborations lead to the development of a consensus in the management of GCTs.

Progress in BCL2 inhibition for patients with chronic lymphocytic leukemia.

PubMed

Tam, Constantine S; Seymour, John F; Roberts, Andrew W

2016-04-01

The prosurvival protein BCL2 is uniformly expressed in chronic lymphocytic leukemia (CLL), and enables leukemia cell survival in the face of cytotoxic treatment and increasing genomic, metabolic, and oxidative stresses. The therapeutic potential of BCL2 inhibition was first observed in the clinic following BCL2 antisense therapy. Subsequently, a number of small molecule inhibitors were developed to mimic the function of the pro-apoptotic BH3-only proteins (BH3-mimetics). These molecules are now in late-phase clinical trials and demonstrate potent activity, including the occurrence of acute tumor lysis syndrome in subjects with multiply relapsed, chemorefractory CLL. In this review, we discuss the history and summarize current knowledge regarding BCL2 inhibition as therapy of CLL. Copyright © 2016 Elsevier Inc. All rights reserved.

[Joint Prosthetic Infection: UpDate Approaches to Diagnosis and Treatment].

PubMed

Belov, B S; Makarov, S A; Byalik, E I

2015-01-01

At present endoprosthetics of the joints is considered as a progressive and ever developing method in the surgical treatment of patients with affection of the locomotor system of any genesis. Hence, increasing of the number of endoprosthetic results in increasing of the number of patients with periprosthetic infection. Polymorphism of the clinical picture and inspecificity of the diagnostic tests often cause a delay in the diagnosis of the joint prosthetic infection (JPI) and consequently the late treatment. The contemporary data on the etiology, epidemiology, clinical picture and diagnosis of JPI are presented. The importance of cooperated treatment of JPI, i.e. combination of the surgical management and etiotropic antibacterial therapy is indicated. The choice of the concrete treatment method is defined by the patient state, comorbid pathology, the infection severity and duration.

Late entry to HIV and AIDS care and treatment, Juba Teaching Hospital, Juba, South Sudan, 2013-2016.

PubMed

Johnson, Muki; Lemi, Benjamin L; Tonny, Hillary L; David, Adelina D; Boru, Waqo; Ransom, James

2018-05-10

Late diagnosis of HIV and enrolment to care are global public health challenges. This study aimed to characterise late HIV diagnoses and initiation of treatment among patients at Juba Teaching Hospital (JTH) in South Sudan. We conducted a retrospective review of lab-confirmed HIV patients at JTH, 2013-2016. Demographic, clinical, and laboratory data were entered into and descriptive statistics were calculated using Microsoft Excel. We identified 401 patients, with mean age 33.71±4.54 years, 235 (59%) were female, 307 (77%) were late entry, 64 (16%) were lost to follow-up, and 57 (14%) died within 12 months of diagnosis. Among patients who presented late, 122 (57%) were female, and 112 (53%) were <34 years old. Among patients who died, 33 (58%) were male, and 52 (91%) had CD4 counts <350 cells/mm3 and World Health Organization (WHO) stage >2 at diagnosis. Late diagnosis of HIV infection is a significant public health problem in South Sudan, particularly for younger and female patients.

Late onset MELAS with m.3243A > G mutation and its association with aneurysm formation.

PubMed

Zhu, Kun; Li, Shuang; Chen, Huan; Wang, Yao; Yu, Miao; Wang, Hongyan; Zhao, Weijie; Cao, Yunpeng

2017-08-01

We reported a 53-year-old with late-onset mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) accompanied by aneurysm and large vessel dilations. Most studies have focused on microangiopathy causing stroke-like episodes. We report a case to describe large vessel involvement in clinical considerations, and possible mechanisms of aneurysm formation. We recommended regular angiographic examination for patients with MELAS.

Toward late career transitioning: a proposal for academic surgeons.

PubMed

Richards, Robin; McLeod, Robin; Latter, David; Keshavjee, Shaf; Rotstein, Ori; Fehlings, Michael G; Ahmed, Najma; Nathens, Avery; Rutka, James

2017-09-01

In the absence of a defined retirement age, academic surgeons need to develop plans for transition as they approach the end of their academic surgical careers. The development of a plan for late career transition represents an opportunity for departments of surgery across Canada to initiate a constructive process in cooperation with the key stakeholders in the hospital or institution. The goal of the process is to develop an individual plan for each faculty member that is agreeable to the academic surgeon; informs the surgical leadership; and allows the late career surgeon, the hospital, the division and the department to make plans for the future. In this commentary, the literature on the science of aging is reviewed as it pertains to surgeons, and guidelines for late career transition planning are shared. It is hoped that these guidelines will be of some value to academic programs and surgeons across the country as late career transition models are developed and adopted.

Formulaic Language in Alzheimer’s Disease

PubMed Central

Bridges, Kelly Ann; Van Lancker Sidtis, Diana

2013-01-01

Background Studies of productive language in Alzheimer’s disease (AD) have focused on formal testing of syntax and semantics but have directed less attention to naturalistic discourse and formulaic language. Clinical observations suggest that individuals with AD retain the ability to produce formulaic language long after other cognitive abilities have deteriorated. Aims This study quantifies production of formulaic expressions in the spontaneous speech of individuals with AD. Persons with early- and late-onset forms of the disease were compared. Methods & Procedures Conversational language samples of individuals with early- (n = 5) and late-onset (n = 6) AD and healthy controls (n = 5) were analyzed to determine whether formulaic language, as measured by the number of words in formulaic expressions, differs between groups. Outcomes & Results Results indicate that individuals with AD, regardless of age of onset, used significantly more formulaic expressions than healthy controls. The early- and late-onset AD groups did not differ on formulaic language measures. Conclusions These findings contribute to a dual process model of cerebral function, which proposes differing processing principles for formulaic and novel expressions. In this model, subcortical areas, which remain intact into late in the progression of Alzheimer’s disease, play an important role in the production of formulaic language. Applications to clinical practice include identifying preserved formulaic language and providing informed counseling to patient and family. PMID:24187417

[A childhood and adolescence cancer survivors' association: Les Aguerris].

PubMed

Ly, Kai Yan; Vélius, Élodie; Pitot, Maxime; Rivieri, Lionel; Dupont, Morvan

2015-01-01

In France, we can estimate that 50,000 adults are childhood or adolescence cancer survivors. Not all of them will experience late effects but they should be informed about their previous disease and should get a detailed summary of treatment information including a personal plan for late effects screening. They also should have access to appropriate follow-up care including detection and treatment of late effects and provision of support and advice. From a follow-up clinic experience, the need of a survivor association has emerged and "Les Aguerris" has been created with several objectives: to improve the quality of life of survivors providing them information about the possible physical, social and psychological consequences of childhood cancer, to raise awareness of public authorities and other actors on questions regarding the need of long-term follow-up of the patients in dedicated clinics, to support researches about late effects of cancer and treatments and to create a network of adult survivors of childhood cancer in relation with other European survivors or parents associations. This paper describes the activities of the association to fulfill its objectives and the annual national meetings they are organizing. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Individual Differences in Lexical Processing at 18 Months Predict Vocabulary Growth in Typically Developing and Late-Talking Toddlers

ERIC Educational Resources Information Center

Fernald, Anne; Marchman, Virginia A.

2012-01-01

Using online measures of familiar word recognition in the looking-while-listening procedure, this prospective longitudinal study revealed robust links between processing efficiency and vocabulary growth from 18 to 30 months in children classified as typically developing (n = 46) and as "late talkers" (n = 36) at 18 months. Those late talkers who…

B cell expression of the inhibitory Fc gamma receptor is unchanged in early MS.

PubMed

Comabella, Manuel; Montalban, Xavier; Kakalacheva, Kristina; Osman, Deeqa; Nimmerjahn, Falk; Tintoré, Mar; Lünemann, Jan D

2010-06-01

Expression of the inhibitory Fcgamma receptor IIB (FcgammaRIIB) has emerged as a late checkpoint during peripheral B cell development which prevents autoreactive memory B lymphocytes from becoming long-lived plasma cells. Decreased expression of FcgammaRIIB or non-functional FcgammaRIIB variants are associated with the development of autoimmune tissue inflammation. We determined the expression profile of FcgammaRIIB in peripheral blood cells in treatment-naïve patients with early MS. Twenty-five patients with clinically isolated syndrome (CIS) who converted to clinically definite MS (CDMS) and 25 demographically matched healthy donors were included in the study. Frequencies of peripheral blood monocytes and B cell subsets as well as FcgammaRIIB expression profile was determined by flow cytometry. FcgammaRIIB expression levels were higher in B cells compared to monocytes (p<0.0001) and higher in memory B cells compared to their naïve counterparts (p<0.0001). However, FcgammaRIIB expression in naïve and memory B cells as well as monocytes was unchanged in patients with early MS at onset of symptoms as well as after conversion to CDMS compared to controls. No significant correlations were found between FcgammaRIIB expression levels and brain MRI-derived metrics or EDSS progression during follow-up. These data indicate that FcgammaRIIB expression, a critical late B cell differentiation checkpoint preventing the occurrence of autoreactive long-lived plasma cells, is not impaired in treatment-naïve patients with MS, at least in the early phases of the disease. Copyright 2010 Elsevier B.V. All rights reserved.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

PubMed

Khan, K A; Petrou, S; Dritsaki, M; Johnson, S J; Manktelow, B; Draper, E S; Smith, L K; Seaton, S E; Marlow, N; Dorling, J; Field, D J; Boyle, E M

2015-10-01

We sought to determine the economic costs associated with moderate and late preterm birth. An economic study was nested within a prospective cohort study. Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. Cumulative resource use and economic costs over the first two years of life. Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life. © 2015 Royal College of Obstetricians and Gynaecologists.

The DSM-5 Trait Measure in a Psychiatric Sample of Late Adolescents and Emerging Adults: Structure, Reliability, and Validity.

PubMed

De Caluwé, Elien; Verbeke, Lize; van Aken, Marcel; van der Heijden, Paul T; De Clercq, Barbara

2018-02-22

The inclusion of a dimensional trait model of personality pathology in DSM-5 creates new opportunities for research on developmental antecedents of personality pathology. The traits of this model can be measured with the Personality Inventory for DSM-5 (PID-5), initially developed for adults, but also demonstrating validity in adolescents. The present study adds to the growing body of literature on the psychometrics of the PID-5, by examining its structure, validity, and reliability in 187 psychiatric-referred late adolescents and emerging adults. PID-5, Big Five Inventory, and Kidscreen self-reports were provided, and 88 non-clinical matched controls completed the PID-5. Results confirm the PID-5's five-factor structure, indicate adequate psychometric properties, and underscore the construct and criterion validity, showing meaningful associations with adaptive traits and quality of life. Results are discussed in terms of the PID-5's applicability in vulnerable populations who are going through important developmental transition phases, such as the step towards early adulthood.

Adult onset Hallervorden-Spatz disease with psychotic symptoms.

PubMed

del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

2011-01-01

Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

Warfarin-induced toxic epidermal necrolysis in combination therapy of Henoch-Schönlein purpura nephritis: a case report.

PubMed

Kasahara, Katsuaki; Gotoh, Yoshimitsu; Kuroyanagi, Yoshiyuki; Nagano, China

2017-07-14

Toxic epidermal necrolysis (TEN) is a rare life-threatening condition almost exclusively attributed to drugs. The main etiologic factors for TEN are sulphonamides, anticonvulsants, and antibiotics; however, there are no published reports of warfarin causing TEN. We present the case of a 3-year-old patient who developed TEN while receiving treatment for Henoch-Schönlein purpura nephritis (HSPN). With multiple-drug therapy comprising prednisolone, mizoribine, dipyridamole, and warfarin, it is difficult to detect which drug is the causative agent. While in most cases, diagnosis of the causative drug is based on clinical history without a lymphocyte transformation test (LTT), we performed the test three times and identified the causative drug as warfarin at the late phase. We continued HSPN treatment without warfarin, and results showed good renal function without life-threatening complications. To our knowledge, this is the first report about TEN caused by warfarin. Repeated LTTs could be useful for identifying TEN-causative drugs even in the late phase.

Late gastrointestinal effects of pelvic radiation: a nurse-led service.

PubMed

Ludlow, Helen; Green, John; Turner, Jeff

2017-02-23

There are currently at least 2 million people in the UK living with and following a cancer diagnosis. Typically four out of every ten people with cancer will receive radiotherapy, but a large proportion of people who have pelvic radiotherapy may go on to develop gastrointestinal (GI) symptoms. This includes rectal bleeding and faecal incontinence, which can have a huge impact on quality of life. These problems often go under-reported by patients and are also under-recognised or under-treated by health professionals. Cancer survivorship is a growing topic that is likely to have a major impact on the NHS, with increasing numbers of patients presenting. A late GI effects of pelvic radiotherapy clinic was set up to address these growing needs of patients with GI symptoms following radiotherapy. This article also shares insights from a doctoral study that is underway looking at people's experiences of living with symptoms following their treatment, in order to improve awareness of the major impact that this can have.

Whole brain radiotherapy for brain metastasis

PubMed Central

McTyre, Emory; Scott, Jacob; Chinnaiyan, Prakash

2013-01-01

Whole brain radiotherapy (WBRT) is a mainstay of treatment in patients with both identifiable brain metastases and prophylaxis for microscopic disease. The use of WBRT has decreased somewhat in recent years due to both advances in radiation technology, allowing for a more localized delivery of radiation, and growing concerns regarding the late toxicity profile associated with WBRT. This has prompted the development of several recent and ongoing prospective studies designed to provide Level I evidence to guide optimal treatment approaches for patients with intracranial metastases. In addition to defining the role of WBRT in patients with brain metastases, identifying methods to improve WBRT is an active area of investigation, and can be classified into two general categories: Those designed to decrease the morbidity of WBRT, primarily by reducing late toxicity, and those designed to improve the efficacy of WBRT. Both of these areas of research show diversity and promise, and it seems feasible that in the near future, the efficacy/toxicity ratio may be improved, allowing for a more diverse clinical application of WBRT. PMID:23717795

Safinamide: A Review in Parkinson's Disease.

PubMed

Blair, Hannah A; Dhillon, Sohita

2017-02-01

Safinamide (Xadago ® ) is an orally active, selective, reversible monoamine oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic) properties. In the EU, safinamide is approved for the treatment of mid- to late-stage fluctuating Parkinson's disease (PD) as add-on therapy to a stable dose of levodopa alone or in combination with other PD medications. Safinamide 50-100 mg/day administered as a fixed or flexible dose significantly increased daily 'on' time without dyskinesia (primary endpoint) in patients with mid- to late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical trials. Other outcomes, including motor function, overall clinical status and health-related quality of life, were also generally improved with safinamide. Furthermore, in an 18-month extension of one study, although dyskinesia (primary endpoint) was not significantly improved with safinamide relative to placebo, treatment benefits in other outcomes were generally sustained over 24 months of treatment. Safinamide was generally well tolerated in clinical trials; dyskinesia was the most common adverse event. Although further studies are needed, including comparative and long-term studies, current evidence indicates that safinamide extends the treatment options available for use as add-on therapy to levodopa and other PD medications in patients with mid- to late-stage PD experiencing motor fluctuations.

Age of onset in social anxiety disorder: Relation to clinical variables and major depression comorbidity.

PubMed

Koyuncu, Ahmet; Ertekin, Erhan; Deveci, Erdem; Ertekin, Banu Aslanta; Yüksel, Çagrı; Çelebi, Fahri; Binbay, Zerrin; Demir, Esra Yancar; Tükel, Rasit

2015-05-01

The aim of this study was to determine the rates of early- and late-onset social anxiety disorder (SAD) and to investigate the effects of onset time on clinical characteristics and the course of SAD. A total of 377 patients with SAD were assessed using a sociodemographic data form, the Liebowitz Social Anxiety Scale (LSAS), Beck Depression Inventory (BDI), and the Global Assessment of Functioning (GAF). Three hundred patients with SAD onset before age 18 were classified as members of the early-onset group, whereas 77 patients with SAD onset at age ≥ 18 comprised the late-onset group. The 2 groups were compared in terms of sociodemographic and clinical characteristics, comorbidity, and scale scores. The rate of SAD onset before age 18 was 79.6%. Compared with the late-onset group, the early-onset group had a younger age at first depressive episode, higher rate of atypical depression, higher LSAS and BDI scores, and lower GAF scores. In cases of early onset of SAD, symptom severity of both SAD and comorbid depression increased and functionality decreased. It is important to assess and treat SAD patients at a younger age because early-onset SAD may be associated with a more severe course and higher rate of major depression comorbidity.

[Metaphylactic antibiotic treatment of footrot in sheep using Florfenicol].

PubMed

Strobel, Heinz; Stauch, Sieglinde

2014-01-01

A case report describes the metaphylactic antibiotic treatment of 520 sheep suffering from footrot (lameness prevalence > 60%) in late pregnancy (targeted selective treatment). Because of the lack of pharmaceuticals licensed for sheep and footrot in Germany in 2009, Florfenicol was used off label. Clinical recovery was observed a few days after a one shot application of florfenicol without any further treatment. The examination of all feet after weaning revealed no clinical symptoms in 96% of the sheep. Complete healing of almost all affected sheep was achieved. No transmission of footrot to lambs was noticed. Since the goal of the treatment was relief from pain and suffering under the particular conditions of late pregnancy and not a clinical study on efficacy no untreated control group was established for comparison. The suitability of the method for eliminating footrot in sheep flocks during the housing period in winter is discussed.

Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology.

PubMed

Jackson, Neville; Atar, Dan; Borentain, Maria; Breithardt, Günter; van Eickels, Martin; Endres, Matthias; Fraass, Uwe; Friede, Tim; Hannachi, Hakima; Janmohamed, Salim; Kreuzer, Jörg; Landray, Martin; Lautsch, Dominik; Le Floch, Chantal; Mol, Peter; Naci, Huseyin; Samani, Nilesh J; Svensson, Anders; Thorstensen, Cathrine; Tijssen, Jan; Vandzhura, Victoria; Zalewski, Andrew; Kirchhof, Paulus

2016-03-01

Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines. The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development. A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Test-Retest Reliability of the Self-Reported Impairments in Persons With Late Effects of Polio (SIPP) Rating Scale.

PubMed

Brogårdh, Christina; Lexell, Jan

2016-05-01

A new 13-item rating scale, the Self-Reported Impairments in Persons with Late Effects of Polio (SIPP), has been developed. The SIPP has been analyzed using the Rasch method and has shown good construct validity and internal consistency. To establish its clinical utility, further evaluation of its psychometric properties is needed. To evaluate the test-retest reliability of the SIPP and to define limits for the smallest change that indicates a real change, both for a group of persons and a single individual. A postal survey. University Hospital. Fifty-one persons (31 men and 20 women; mean age, 72 years) with clinically verified late effects of polio. Not applicable. The participants completed the SIPP twice, 2 weeks apart. The response frequencies at test occasion 1 (T1) and test occasion 2 (T2) were calculated. Test-retest reliability was analyzed using the percentage agreement of each item, the intraclass correlation coefficient, and the mean difference between the test occasions (đ), together with the 95% confidence intervals for đ, the standard error of measurement, the smallest real difference, and a Bland-Altman plot. The percentage agreement (ie, the same scoring at both test occasions) was >70% for 10 of 13 items. The mean score (standard deviation) was 27.9 (5.7) points at T1 and 28.2 (6.0) points at T2, with no systematic difference between the test occasions. The intraclass correlation coefficient was 0.88, the standard error of measurement (the smallest change for a group of persons) was 2.0 points, and the smallest real difference (the smallest change for a single individual) was 5.6 points, respectively. The SIPP is a reliable rating scale in persons with late effects of polio and can be used to evaluate effects of rehabilitation interventions and changes of perceived impairments over time both for a group of persons and for a single individual. Copyright © 2016 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays.

PubMed

Hamm, P C; Bakker, E J; van den Berg, A P; van den Aardweg, G J; Visser, A G; Levendag, P C

2000-07-01

An experimental brachytherapy model has been developed to study acute and late normal tissue reactions as a tool to examine the effects of clinically relevant multifractionation schedules. Pig skin was used as a model since its morphology, structure, cell kinetics and radiation-induced responses are similar to human skin. Brachytherapy was performed using a microSelectron high dose rate (HDR) afterloading machine with a single stepping source and a custom-made template. In this study the acute epidermal reactions of erythema and moist desquamation and the late dermal reactions of dusky mauve erythema and necrosis were evaluated after single doses of irradiation over a follow-up period of 16 weeks. The major aims of this work were: (a) to compare the effects of iridium-192 (192Ir) irradiation with effects after X-irradiation; (b) to compare the skin reactions in Yorkshire and Large White pigs; and (c) to standardize the methodology. For 192Ir irradiation with 100% isodose at the skin surface, the 95% isodose was estimated at the basal membrane, while the 80% isodose covered the dermal fat layers. After HDR 192Ir irradiation of Yorkshire pig skin the ED50 values (95% isodose) for moderate/severe erythema and moist desquamation were 24.8 Gy and 31.9 Gy, respectively. The associated mean latent period (+/- SD) was 39 +/- 7 days for both skin reactions. Late skin responses of dusky mauve erythema and dermal necrosis were characterized by ED50 values (80% isodose) of 16.3 Gy and 19.5 Gy, with latent periods of 58 +/- 7 days and 76 +/- 12 days, respectively. After X-irradiation, the incidence of the various skin reactions and their latent periods were similar. Acute and late reactions were well separated in time. The occurrence of skin reactions and the incidence of effects were comparable in Yorkshire and Large White pigs for both X-irradiation and HDR 192Ir brachytherapy. This pig skin model is feasible for future studies on clinically relevant multifractionation schedules in a brachytherapy setting.

Hypofractionated intensity modulated irradiation for localized prostate cancer, results from a phase I/II feasibility study

PubMed Central

Junius, Sara; Haustermans, Karin; Bussels, Barbara; Oyen, Raymond; Vanstraelen, Bianca; Depuydt, Tom; Verstraete, Jan; Joniau, Steven; Van Poppel, Hendrik

2007-01-01

Background To assess acute (primary endpoint) and late toxicity, quality of life (QOL), biochemical or clinical failure (secondary endpoints) of a hypofractionated IMRT schedule for prostate cancer (PC). Methods 38 men with localized PC received 66 Gy (2.64 Gy) to prostate,2 Gy to seminal vesicles (50 Gy total) using IMRT. Acute toxicity was evaluated weekly during radiotherapy (RT), at 1–3 months afterwards using RTOG acute scoring system. Late side effects were scored at 6, 9, 12, 16, 20, 24 and 36 months after RT using RTOG/EORTC criteria. Quality of life was assessed by EORTC-C30 questionnaire and PR25 prostate module. Biochemical failure was defined using ASTRO consensus and nadir+2 definition, clinical failure as local, regional or distant relapse. Results None experienced grade III-IV toxicity. 10% had no acute genito-urinary (GU) toxicity, 63% grade I; 26% grade II. Maximum acute gastrointestinal (GI) scores 0, I, II were 37%, 47% and 16%. Maximal acute toxicity was reached weeks 4–5 and resolved within 4 weeks after RT in 82%. Grade II rectal bleeding needing coagulation had a peak incidence of 18% at 16 months after RT but is 0% at 24–36 months. One developed a urethral stricture at 2 years (grade II late GU toxicity) successfully dilated until now. QOL urinary symptom scores reached a peak incidence 1 month after RT but normalized 6 months later. Bowel symptom scores before, at 1–6 months showed similar values but rose slowly 2–3 years after RT. Nadir of sexual symptom scores was reached 1–6 months after RT but improved 2–3 years later as well as physical, cognitive and role functional scales. Emotional, social functional scales were lowest before RT when diagnosis was given but improved later. Two years after RT global health status normalized. Conclusion This hypofractionated IMRT schedule for PC using 25 fractions of 2.64 Gy did not result in severe acute side effects. Until now late urethral, rectal toxicities seemed acceptable as well as failure rates. Detailed analysis of QOL questionnaires resulted in the same conclusion. PMID:17686162

Admixture analysis of age of onset in generalized anxiety disorder.

PubMed

Rhebergen, Didi; Aderka, Idan M; van der Steenstraten, Ira M; van Balkom, Anton J L M; van Oppen, Patricia; Stek, Max L; Comijs, Hannie C; Batelaan, Neeltje M

2017-08-01

Age of onset is a marker of clinically relevant subtypes in various medical and psychiatric disorders. Past research has also reported that age of onset in generalized anxiety disorder (GAD) is clinically significant; but, in research to date, arbitrary cut-off ages have been used. In the present study, admixture analysis was used to determine the best fitting model for age of onset distribution in GAD. Data were derived from 459 adults with a diagnosis of GAD who took part in the Netherlands Study of Depression and Anxiety (NESDA). Associations between age of onset subtypes, identified by admixture analysis, and sociodemographic, clinical, and vulnerability factors were examined using univariate tests and multivariate logistic regression analyses. Two age of onset distributions were identified: an early-onset group (24 years of age and younger) and a late-onset group (greater than 24 years of age). Multivariate analysis revealed that early-onset GAD was associated with female gender (OR 2.1 (95%CI 1.4-3.2)), higher education (OR 1.1 (95%CI 1.0-1.2)), and higher neuroticism (OR 1.4 (95%CI 1.1-1.7)), while late-onset GAD was associated with physical illnesses (OR 1.3 (95%CI 1.1-1.7)). Study limitations include the possibility of recall bias given that age of onset was assessed retrospectively, and an inability to detect a possible very-late-onset GAD subtype. Collectively, the results of the study indicate that GAD is characterized by a bimodal age of onset distribution with an objectively determined early cut-off at 24 years of age. Early-onset GAD is associated with unique factors that may contribute to its aetiology; but, it does not constitute a more severe subtype compared to late-onset GAD. Future research should use 24 years of age as the cut-off for early-onset GAD to when examining the clinical relevance of age of onset for treatment efficacy and illness course. Copyright © 2017 Elsevier Ltd. All rights reserved.

Does the concept of borderline personality features have clinical utility in childhood?

PubMed

Hawes, David J

2014-01-01

Phenotypic features of borderline personality disorder may first emerge during childhood, alongside symptoms of common externalizing and internalizing disorders. Children with these borderline personality features (BPF) are, therefore, likely to come into contact with clinical services prior to adolescence. This raises the question of whether BPF may be clinically informative with respect to the formulation and treatment of childhood psychopathology. BPF in late childhood appear to be highly heritable, while also predicted by environmental risk factors that overlap with those related to both externalizing and internalizing disorders. These risk factors include hostile parenting, maternal insensitivity to infant attachment cues, and early peer victimization, thereby implicating both family and peer processes that play out across early development. Children with BPF appear to be further characterized by social-cognitive factors including social perspective coordination deficits, a shame-prone self-concept, and hypermentalizing, which may represent potential therapeutic targets. Clinical research into the implications of BPF for the treatment of childhood psychopathology is a current priority. It is proposed that the research designs that have contributed to recent evidence for the clinical utility of childhood psychopathic traits may likewise aid in understanding the potential clinical utility of BPF in children.

Clinical dimensions of a 'biological concept': transsexualism and the interplay between etiological theory and clinical therapy.

PubMed

Lea, Andrew S

2016-09-01

In 1966, the Johns Hopkins University School of Medicine became the first American medical institution to perform sex reassignment surgeries. This article interrogates the relationship between the emergence of this clinical therapy in the United States and the changing medical understandings of the contemporaneous condition it was intended to address - 'transsexualism.' I argue that, during the mid-to-late twentieth century, therapeutic practices and theories about the etiology of transsexualism were mutually constitutive. On one hand, the clinical development of sex reassignment surgery precipitated a newfound interest in the possible biological, as opposed to psychopathological, underpinnings of transsexualism. At the same time, different theories about etiology were marshaled by both advocates and critics of sex reassignment in their efforts to secure or undercut the medical legitimacy and clinical presence of competing therapeutic practices. Debates surrounding transsexualism's etiology were therefore about much more than the causes of this condition: these etiological conversations also intervened in fundamental debates about the ethics of medical care and the therapeutic identity of different clinical practices (that is, whether sex reassignment and psychotherapy were to be considered primarily symptomatic or curative). Copyright © 2016 Elsevier Ltd. All rights reserved.

Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature.

PubMed

Mahmood, Asif; Berry, Jay; Wenger, David A; Escolar, Maria; Sobeih, Magdi; Raymond, Gerald; Eichler, Florian S

2010-05-01

Metachromatic leukodystrophy is a rare disorder with great clinical variability. We report the first case of triplets with the late infantile form of the disease and their systematic progression of symptoms. We reviewed the literature and identified all human studies that reported new cases since 1921. We analyzed survival by decade to assess the impact of historical changes in the management of care. Mean age at death and the 5-year survival from onset of symptoms for late infantile, juvenile, and adult phenotypes were 4.2 years and 24.9%, 17.4 years and 70.3%, and 43.1 years and 88.6%, respectively. The 5-year survival of cases reported after 1990 was significantly better than cases reported before 1970 in all subtypes of metachromatic leukodystrophy (late infantile: 52% vs 14%, juvenile: 100% vs 46%, adult: 95% vs 67%). Survival in the late infantile subtype was worse than that in other subtypes. Survival significantly improved over time in all subtypes.

Experimental Modelling of the Consequences of Brief Late Gestation Asphyxia on Newborn Lamb Behaviour and Brain Structure

PubMed Central

Yawno, Tamara; Witjaksono, Anissa; Miller, Suzie L.; Walker, David W.

2013-01-01

Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle - compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies. PMID:24223120

Association of Crossword Puzzle Participation with Memory Decline in Persons Who Develop Dementia

PubMed Central

Pillai, Jagan A.; Hall, Charles B.; Dickson, Dennis W.; Buschke, Herman; Lipton, Richard B.; Verghese, Joe

2013-01-01

Participation in cognitively stimulating leisure activities such as crossword puzzles may delay onset of the memory decline in the preclinical stages of dementia, possibly via its effect on improving cognitive reserve. We followed 488 initially cognitively intact community residing individuals with clinical and cognitive assessments every 12–18 months in the Bronx Aging Study. We assessed the influence of crossword puzzle participation on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model. Crossword puzzle participation at baseline delayed onset of accelerated memory decline by 2.54 years. Inclusion of education or participation in other cognitively stimulating activities did not significantly add to the fit of the model beyond the effect of puzzles. Our findings show that late life crossword puzzle participation, independent of education, was associated with delayed onset of memory decline in persons who developed dementia. Given the wide availability and accessibility of crossword puzzles, their role in preventing cognitive decline should be validated in future clinical trials. PMID:22040899

Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks.

PubMed

Mallikarjun, Venkatesh; Swift, Joe

2016-12-01

Ageing is a leading risk factor for many debilitating diseases. While age-related diseases have been the subject of over a century of intense investigation, until recently, physiological ageing was considered unavoidable. Pharmacological and genetic studies have since shown that ageing is a malleable process and that its abrogation can prevent its associated diseases. This review summarises a sample of the most promising efforts to deliver the products of ageing research to the clinic. Current efforts include the use of clinically approved drugs that have since been repurposed, as well as the development of novel therapeutics, to target ageing. Furthermore, ongoing research has sought reliable biomarkers of ageing that will accelerate the development of such therapeutics. Development of these technologies will improve quality of late-life and help relieve the enormous stress placed on state healthcare systems by a rapidly ageing global population. Thus, for both medical and socioeconomic reasons, it is imperative that ageing is made to yield to intervention. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Designing new collaborative learning spaces in clinical environments: experiences from a children's hospital in Australia.

PubMed

Bines, Julie E; Jamieson, Peter

2013-09-01

Hospitals are complex places that provide a rich learning environment for students, staff, patients and their families, professional groups and the community. The "new" Royal Children's Hospital opened in late 2011. Its mission is focused on improving health and well-being of children and adolescents through leadership in healthcare, research and education. Addressing the need to create "responsive learning environments" aligned with the shift to student-centred pedagogy, two distinct learning environments were developed within the new Royal Children's Hospital; (i) a dedicated education precinct providing a suite of physical environments to promote a more active, collaborative and social learning experience for education and training programs conducted on the Royal Children's Hospital campus and (ii) a suite of learning spaces embedded within clinical areas so that learning becomes an integral part of the daily activities of this busy Hospital environment. The aim of this article is to present the overarching educational principles that lead the design of these learning spaces and describe the opportunities and obstacles encountered in the development of collaborative learning spaces within a large hospital development.

Vaccine Pipeline Has Grown During The Past Two Decades With More Early-Stage Trials From Small And Medium-Size Companies.

PubMed

Hwang, Thomas J; Kesselheim, Aaron S

2016-02-01

Many serious diseases lack safe and effective vaccines. Using a large commercial database, we examined trends in global vaccine research and development and found that the proportion of new vaccine candidates entering all stages of clinical development increased by 3-5 percentage points over the past two decades. Small and medium-size companies accounted for nearly twice as many new Phase I vaccine trials compared to large companies, but late-stage (Phase III) vaccine trials were dominated by large companies. There were no significant differences between vaccines and drugs in the probability of success in clinical trials or in profitability. Small and medium-size companies, including spin-outs from academic research centers, play an important role in innovative research and discovery. Our findings suggest that policy making targeted at smaller companies, such as prizes or opportunities for public-private partnerships, could support the development of new vaccines, particularly those targeting unmet medical needs and emerging public health threats. Project HOPE—The People-to-People Health Foundation, Inc.

A reproductive screening test of hawthorn.

PubMed

Yao, Mei; Ritchie, Helen E; Brown-Woodman, Patricia D

2008-06-19

Hawthorn (Crataegus) has a long history as a medicine. The current clinical use of hawthorn as a heart medicine dates back to the late 19th century. It is well tolerated clinically yet contraindicated in pregnancy. To determine the safety of hawthorn to the developing fetus, pregnant rats were dosed daily by gavage using 56 times the human dose of hawthorn on either gestation days (GD) 1-8 or GD 8-15. On GD 20, fetuses were weighed and examined for signs of external, internal or skeletal malformations. Rat fetuses were also explanted on GD 10.5 and cultured with hawthorn extract for 26 h. Hawthorn did not have an adverse effect on embryonic development in vivo or in vitro. While the results suggest that hawthorn, taken at the recommended dose would have no adverse effects on embryonic development this may be due to the low bioavailability of some hawthorn constituents when taken orally. Pharmacokinetic studies are required to determine the extent of absorption of hawthorn from the small intestine in healthy adults in order to verify its safety.

Features of asthma which provide meaningful insights for understanding the disease heterogeneity.

PubMed

Deliu, M; Yavuz, T S; Sperrin, M; Belgrave, D; Sahiner, U M; Sackesen, C; Kalayci, O; Custovic, A

2018-01-01

Data-driven methods such as hierarchical clustering (HC) and principal component analysis (PCA) have been used to identify asthma subtypes, with inconsistent results. To develop a framework for the discovery of stable and clinically meaningful asthma subtypes. We performed HC in a rich data set from 613 asthmatic children, using 45 clinical variables (Model 1), and after PCA dimensionality reduction (Model 2). Clinical experts then identified a set of asthma features/domains which informed clusters in the two analyses. In Model 3, we reclustered the data using these features to ascertain whether this improved the discovery process. Cluster stability was poor in Models 1 and 2. Clinical experts highlighted four asthma features/domains which differentiated the clusters in two models: age of onset, allergic sensitization, severity, and recent exacerbations. In Model 3 (HC using these four features), cluster stability improved substantially. The cluster assignment changed, providing more clinically interpretable results. In a 5-cluster model, we labelled the clusters as: "Difficult asthma" (n = 132); "Early-onset mild atopic" (n = 210); "Early-onset mild non-atopic: (n = 153); "Late-onset" (n = 105); and "Exacerbation-prone asthma" (n = 13). Multinomial regression demonstrated that lung function was significantly diminished among children with "Difficult asthma"; blood eosinophilia was a significant feature of "Difficult," "Early-onset mild atopic," and "Late-onset asthma." Children with moderate-to-severe asthma were present in each cluster. An integrative approach of blending the data with clinical expert domain knowledge identified four features, which may be informative for ascertaining asthma endotypes. These findings suggest that variables which are key determinants of asthma presence, severity, or control may not be the most informative for determining asthma subtypes. Our results indicate that exacerbation-prone asthma may be a separate asthma endotype and that severe asthma is not a single entity, but an extreme end of the spectrum of several different asthma endotypes. © 2017 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

Ovation Pharmaceuticals, Inc.

PubMed

Deutsch, Barry

2002-11-01

Ovation Pharmaceuticals, Inc. is a privately held specialty pharmaceutical company that focuses on products in central nervous system (CNS) disorders, oncology and other therapeutic areas where a small number of specialized physicians treat patients. Ovation serves unmet medical needs by acquiring underpromoted branded pharmaceutical products and promising late-stage development products no longer being actively promoted or developed by larger companies. Ovation supports acquired products through active sales and marketing activities and a clinical development program focused on new formulations, new indications and other product improvements. In April 2002, Ovation received a US$150 million commitment in private equity financing, believed to be the largest private equity investment received to date by an early-stage specialty pharmaceutical firm. Ovation used a portion of those funds to purchase its first two products from a major pharmaceutical company in August 2002.

Implementing Dementia Care Models in Primary Care Settings: The Aging Brain Care Medical Home (Special Supplement)

PubMed Central

Callahan, Christopher M.; Boustani, Malaz A.; Weiner, Michael; Beck, Robin A.; Livin, Lee R.; Kellams, Jeffrey J.; Willis, Deanna R.; Hendrie, Hugh C.

2010-01-01

Objectives The purpose of this paper is to describe our experience in implementing a primary care-based dementia and depression care program focused on providing collaborative care for dementia and late-life depression. Methods Capitalizing on the substantial interest in the US on the patient-centered medical home concept, the Aging Brain Care Medical Home targets older adults with dementia and/or late life depression in the primary care setting. We describe a structured set of activities that laid the foundation for a new partnership with the primary care practice and the lessons learned in implementing this new care model. We also provide a description of the core components of this innovative memory care program. Results Findings from three recent randomized clinical trials provided the rationale and basic components for implementing the new memory care program. We used the reflective adaptive process as a relationship building framework that recognizes primary care practices as complex adaptive systems. This framework allows for local adaptation of the protocols and procedures developed in the clinical trials. Tailored care for individual patients is facilitated through a care manager working in collaboration with a primary care physician and supported by specialists in a memory care clinic as well as by information technology resources. Conclusions We have successfully overcome many system-level barriers in implementing a collaborative care program for dementia and depression in primary care. Spontaneous adoption of new models of care is unlikely without specific attention to the complexities and resource constraints of health care systems. PMID:20945236

Treatment initiation and dropout from prolonged exposure and cognitive processing therapy in a VA outpatient clinic.

PubMed

Kehle-Forbes, Shannon M; Meis, Laura A; Spoont, Michele R; Polusny, Melissa A

2016-01-01

Emerging data suggest that few veterans are initiating prolonged exposure (PE) and cognitive processing therapy (CPT) and dropout levels are high among those who do start the therapies. The goal of this study was to use a large sample of veterans seen in routine clinical care to 1) report the percent of eligible and referred veterans who (a) initiated PE/CPT, (b) dropped out of PE/CPT, (c) were early PE/CPT dropouts, 2) examine predictors of PE/CPT initiation, and 3) examine predictors of early and late PE/CPT dropout. We extracted data from the medical records of 427 veterans who were offered PE/CPT following an intake at a Veterans Health Administration (VHA) PTSD Clinical Team. Eighty-two percent (n = 351) of veterans initiated treatment by attending Session 1 of PE/CPT; among those veterans, 38.5% (n = 135) dropped out of treatment. About one quarter of veterans who dropped out were categorized as early dropouts (dropout before Session 3). No significant predictors of initiation were identified. Age was a significant predictor of treatment dropout; younger veterans were more likely to drop out of treatment than older veterans. Therapy type was also a significant predictor of dropout; veterans receiving PE were more likely to drop out late than veterans receiving CPT. Findings demonstrate that dropout from PE/CPT is a serious problem and highlight the need for additional research that can guide the development of interventions to improve PE/CPT engagement and adherence. (c) 2016 APA, all rights reserved).

Tolerance of canine anastomoses to intraoperative radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tepper, J.E.; Sindelar, W.; Travis, E.L.

1983-07-01

Radiation has been given intraoperatively to various abdominal structures in dogs, using a fixed horizontal 11 MeV electron beam at the Armed Forces Radiobiologic Research Institute. Animals were irradiated with single doses of 2000, 3000 and 4500 rad to a field which extended from the bifurcation of the aorta to the rib cage. All animals were irradiated during laparotomy under general anesthesia. Because the clinical use of intraoperative radiotherapy in cancer treatment will occasionally require irradiation of anastomosed large vessels and blind loops of bowel, the tolerance of aortic anastomoses and the suture lines of blind loops of jejunum tomore » irradiation were studied. Responses in these experiments were scored at times up to one year after irradiation. In separate experiments both aortic and intestinal anastomoses were performed on each animal for evaluation of short term response. The dogs with aortic anastomoses showed adequate healing at all doses with no evidence of suture line weakening. On long-term follow-up one animal (2000 rad) had stenosis at the anastomosis and one animal (4500 rad) developed an arteriovenous fistula. Three of the animals that had an intestinal blind loop irradiated subsequently developed intussusception, with the irradiated loop acting as the lead point. One week after irradiation, bursting pressure of an intestinal blind loop was normal at 3000 rad, but markedly decreased at 4500 rad. No late complications were noted after the irradiation of the intestinal anastomosis. No late complicatons were observed after irradiation of intestinal anastomoses, but one needs to be cautious with regards to possible late stenosis at the site of an irradiated vascular anastomosis.« less

A common challenge in older adults: Classification, overlap, and therapy of depression and dementia.

PubMed

Leyhe, Thomas; Reynolds, Charles F; Melcher, Tobias; Linnemann, Christoph; Klöppel, Stefan; Blennow, Kaj; Zetterberg, Henrik; Dubois, Bruno; Lista, Simone; Hampel, Harald

2017-01-01

Late-life depression is frequently associated with cognitive impairment. Depressive symptoms are often associated with or even precede a dementia syndrome. Moreover, depressive disorders increase the risk of persistence for mild cognitive impairment and dementia. Here, we present both the current state of evidence and future perspectives regarding the integration and value of clinical assessments, neuropsychological, neurochemical, and neuroimaging biomarkers for the etiological classification of the dementia versus the depression syndrome and for the prognosis of depression relating to dementia risk. Finally, we summarize the existing evidence for both pharmacotherapy and psychotherapy of depression in demented patients. There is an urgent need for large-scale collaborative research to elucidate the role and interplay of clinical and biological features in elderly individuals with depressive disorders who are at elevated risk for developing dementia. To overcome barriers for successful drug development, we propose the introduction of the precision medicine paradigm to this research field. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Child neurology: Past, present, and future: part 1: history.

PubMed

Millichap, John J; Millichap, J Gordon

2009-08-18

The founding period of child neurology occurred in 3 phases: 1) early individual contributory phase, 2) organized training phase, and 3) expansion phase. In the late 19th and early 20th centuries, individuals in pediatrics, neurology, and psychiatry established clinics and made important contributions to the literature on childhood epilepsy, cerebral palsy, and pediatric neurology. The latter half of the 20th century saw the organization of training programs in pediatric neurology, with fellowships supported by the NIH. This development was followed by a rapid expansion in the number of trainees certified in child neurology and their appointment to divisions of neurology in children's hospitals. In recent years, referrals of children with neurologic disorders have increased, and disorders previously managed by pediatricians are often seen in neurology clinics. The era of subspecialization is embraced by the practicing physician. The present day status of pediatric neurology and suggestions for the future development of the specialty are subjects for further discussion.

Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers

PubMed Central

DeKosky, Steven T.; Blennow, Kaj; Ikonomovic, Milos D.; Gandy, Sam

2014-01-01

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)—which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression—has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. PMID:23558985

Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers.

PubMed

DeKosky, Steven T; Blennow, Kaj; Ikonomovic, Milos D; Gandy, Sam

2013-04-01

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)--which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression--has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE.

Accumulation of Mutant Neuroserpin Precedes Development of Clinical Symptoms in Familial Encephalopathy with Neuroserpin Inclusion Bodies

PubMed Central

Galliciotti, Giovanna; Glatzel, Markus; Kinter, Jochen; Kozlov, Serguei V.; Cinelli, Paolo; Rülicke, Thomas; Sonderegger, Peter

2007-01-01

Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson’s disease, tauopathies, Huntington’s disease, and familial encephalopathy with neuroserpin inclusion bodies. The latter is an autosomal dominant disorder caused by point mutations in neuroserpin resulting in its destabilization. Mutant neuroserpin polymerizes and forms intracellular aggregates that eventually lead to neurodegeneration. We generated genetically modified mice expressing the late-onset S49P-Syracuse or the early-onset S52R-Portland mutation of neuroserpin in central nervous system neurons. Mice exhibited morphological, biochemical, and clinical features resembling those found in the human disease. Analysis of brains revealed large intraneuronal inclusions composed exclusively of mutant neuroserpin, accumulating long before the development of clinical symptoms in a time-dependent manner. Clinical symptoms and amount of neuroserpin inclusions correlated with the predicted instability of the protein. The presence of inclusion bodies in subclinical mice indicates that in humans the prevalence of the disease could be higher than anticipated. In addition to shedding light on the pathophysiology of the human disorder, these mice provide an excellent model to study mechanisms of neurodegeneration or establish novel therapies for familial encephalopathy with neuroserpin inclusion bodies and other neurodegenerative diseases with intracellular protein deposition. PMID:17392169

Background on Establishing a Working Group to Create Home Clinical Cases for Education.

PubMed

Yoshitake, Taketo

2017-01-01

In Japan there are concerns that there will be a surge in social insurance costs such as medical and nursing care expenses as a result of the baby boom generation reaching the late stages of old age (75 years old and beyond) around 2025 ("The 2025 Problem"). In 2012, the "Outline on Social Insurance and Tax Reform" was approved by the Japanese cabinet and government, including "construction of regional comprehensive care". To promote participation in home medical care by pharmacists, this article presents the roles demanded of pharmacists in regional comprehensive care from the standpoint of physicians, and the discussion of case studies bridging the gap from knowledge learned in lectures to practical applications. In the field of medical education, "The 2023 Problem", regarding standards of education on a global level, caused medical schools across Japan to scramble for curriculum reform, specifically in the demand for increased time spent in clinical training and the expansion of community-based medical education. The current state of community-based medical education will be reviewed. In light of these developments, "the working group to create home clinical cases for education" was developed by clinical pharmacists in the field and university faculty members at Daiichi University of Pharmacy.

Nanomedicine for the molecular diagnosis of cardiovascular pathologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juenet, Maya; Varna, Mariana; Aid-Launais, Rachida

Predicting acute clinical events caused by atherosclerotic plaque rupture remains a clinical challenge. Anatomic mapping of the vascular tree provided by standard imaging technologies is not always sufficient for a robust diagnosis. Yet biological mechanisms leading to unstable plaques have been identified and corresponding biomarkers have been described. Nanosystems charged with contrast agents and targeted towards these specific biomarkers have been developed for several types of imaging modalities. The first systems that have reached the clinic are ultrasmall superparamagnetic iron oxides for Magnetic Resonance Imaging. Their potential relies on their passive accumulation by predominant physiological mechanisms in rupture-prone plaques. Activemore » targeting strategies are under development to improve their specificity and set up other types of nanoplatforms. Preclinical results show a huge potential of nanomedicine for cardiovascular diagnosis, as long as the safety of these nanosystems in the body is studied in depth. - Highlights: • Ischemic stroke and myocardial infarction are the main causes of death in the world. • Their prevalence is related to late detection of high-risk atherosclerotic plaques. • Biomarkers of atherosclerosis evolution and potential ligands have been identified. • Nanosystems based on these ligands appear promising for early molecular diagnosis. • Preclinical and clinical nanosystems for common imaging modalities are described.« less