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Sample records for doses predict poorer

  1. Somatic Complaints in Children with Anxiety Disorders and Their Unique Prediction of Poorer Academic Performance

    ERIC Educational Resources Information Center

    Hughes, Alicia A.; Lourea-Waddell, Brittany; Kendall, Philip C.

    2008-01-01

    The present study aimed to examine somatic complaints in children with anxiety disorders compared to non-anxious control children and whether somatic complaints predict poorer academic performance. The sample consisted of 108 children and adolescents (aged 8-14 years) assessed by a structured diagnostic interview: 69 with a principal (i.e., most…

  2. Age-related reduction of BOLD modulation to cognitive difficulty predicts poorer task accuracy and poorer fluid reasoning ability.

    PubMed

    Rieck, Jenny R; Rodrigue, Karen M; Boylan, Maria A; Kennedy, Kristen M

    2017-02-15

    Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20-94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right-lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age-related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Somatic complaints in children with anxiety disorders and their unique prediction of poorer academic performance.

    PubMed

    Hughes, Alicia A; Lourea-Waddell, Brittany; Kendall, Philip C

    2008-06-01

    The present study aimed to examine somatic complaints in children with anxiety disorders compared to non-anxious control children and whether somatic complaints predict poorer academic performance. The sample consisted of 108 children and adolescents (aged 8-14 years) assessed by a structured diagnostic interview: 69 with a principal (i.e., most severe and/or interfering) anxiety disorder diagnosis and 39 non-anxious community controls. Established child and parent report measure of somatic complaints, anxiety, and internalizing symptoms were completed. The participants' primary teacher was used to assess academic performance. Findings indicated that children with anxiety disorders reported more somatic complaints than the non-anxious community controls. Furthermore, a greater frequency of somatic complaints uniquely predicted poorer academic performance beyond that accounted for by anxiety and internalizing symptoms based on both child and parent report measures. Knowledge about somatic complaints in children with anxiety disorders and their relation to academic functioning may allow for early identification and prevent academic problems.

  4. Increased Marijuana Use and Gender Predict Poorer Cognitive Functioning in Adolescents and Emerging Adults

    PubMed Central

    Lisdahl, Krista M.; Price, Jenessa S.

    2014-01-01

    This study sought to characterize neuropsychological functioning in MJ-using adolescents and emerging adults (ages 18–26) and to investigate whether gender moderated these effects. Data were collected from 59 teens and emerging adults including MJ users (n = 23, 56% female) and controls (n = 35, 50% female) aged 18–26 (M = 21 years). Exclusionary criteria included independent Axis I disorders (besides SUD), and medical and neurologic disorders. After controlling for reading ability, gender, subclinical depressive symptoms, body mass index, and alcohol and other drug use, increased MJ use was associated with slower psychomotor speed/sequencing ability (p< .01), less efficient sustained attention (p< .05), and increased cognitive inhibition errors (p< .03). Gender significantly moderated the effects of MJ on psychomotor speed/sequencing ability (p< .003) in that males had a more robust negative relationship. The current study demonstrated that MJ exposure was associated with poorer psychomotor speed, sustained attention and cognitive inhibition in a dose-dependent manner in young adults, findings that are consistent with other samples of adolescent MJ users. Male MJ users demonstrated greater cognitive slowing than females. Future studies need to examine the neural substrates underlying with these cognitive deficits and whether cognitive rehabilitation or exercise interventions may serve as a viable treatments of cognitive deficits in emerging adult MJ users. PMID:22613255

  5. Increased marijuana use and gender predict poorer cognitive functioning in adolescents and emerging adults.

    PubMed

    Lisdahl, Krista M; Price, Jenessa S

    2012-07-01

    This study sought to characterize neuropsychological functioning in MJ-using adolescents and emerging adults (ages 18-26) and to investigate whether gender moderated these effects. Data were collected from 59 teens and emerging adults including MJ users (n = 23, 56% female) and controls (n = 35, 50% female) aged 18-26 (M = 21 years). Exclusionary criteria included independent Axis I disorders (besides SUD), and medical and neurologic disorders. After controlling for reading ability, gender, subclinical depressive symptoms, body mass index, and alcohol and other drug use, increased MJ use was associated with slower psychomotor speed/sequencing ability (p < .01), less efficient sustained attention (p < .05), and increased cognitive inhibition errors (p < .03). Gender significantly moderated the effects of MJ on psychomotor speed/sequencing ability (p < .003) in that males had a more robust negative relationship. The current study demonstrated that MJ exposure was associated with poorer psychomotor speed, sustained attention and cognitive inhibition in a dose-dependent manner in young adults, findings that are consistent with other samples of adolescent MJ users. Male MJ users demonstrated greater cognitive slowing than females. Future studies need to examine the neural substrates underlying with these cognitive deficits and whether cognitive rehabilitation or exercise interventions may serve as a viable treatments of cognitive deficits in emerging adult MJ users.

  6. Sustain talk predicts poorer outcomes among mandated college student drinkers receiving a brief motivational intervention.

    PubMed

    Apodaca, Timothy R; Borsari, Brian; Jackson, Kristina M; Magill, Molly; Longabaugh, Richard; Mastroleo, Nadine R; Barnett, Nancy P

    2014-09-01

    Within-session client language that represents a movement toward behavior change (change talk) has been linked to better treatment outcomes in the literature on motivational interviewing (MI). There has been somewhat less study of the impact of client language against change (sustain talk) on outcomes following an MI session. This study examined the role of both client change talk and sustain talk, as well as therapist language, occurring during a brief motivational intervention (BMI) session with college students who had violated college alcohol policy (N = 92). Audiotapes of these sessions were coded using a therapy process coding system. A series of hierarchical regressions were used to examine the relationships among therapist MI-consistent and MI-inconsistent language, client change talk and sustain talk, as well as global measures of relational variables, and drinking outcomes. Contrary to prior research, sustain talk, but not change talk, predicted poorer alcohol use outcomes following the BMI at 3- and 12-month follow-up assessments. Higher levels of client self-exploration during the session also predicted improved drinking outcomes. Therapist measures of MI-consistent and MI-inconsistent language, and global measures of therapist acceptance and MI spirit were unrelated to client drinking outcomes. Results suggest that client sustain talk and self-exploration during the session play an important role in determining drinking outcomes among mandated college students receiving a BMI addressing alcohol use.

  7. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor-Treatment Resistant Depression

    PubMed Central

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective To identify symptom dimensions of depression that predict recovery among SSRI-treatment resistant adolescents undergoing second-step treatment. Method The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI-treatment resistant youth randomized to a medication switch, or a medication switch plus CBT. This study examined five established symptom dimensions (Child Depression Rating Scale-Revised) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment. The two indices of recovery that were evaluated were time to remission and number of depression-free days. Results Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that Anhedonia was the only dimension to predict a longer time to remission, and also the only dimension to predict fewer depression-free days. In addition, when Anhedonia and CDRS-total score were evaluated simultaneously, Anhedonia continued to uniquely predict longer time to remission and fewer depression-free days. Conclusions Anhedonia may represent an important negative prognostic indicator among treatment resistant depressed adolescents. Further research is needed to elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression. PMID:22449646

  8. Greater attention problems during childhood predict poorer executive functioning in late adolescence.

    PubMed

    Friedman, Naomi P; Haberstick, Brett C; Willcutt, Erik G; Miyake, Akira; Young, Susan E; Corley, Robin P; Hewitt, John K

    2007-10-01

    Attention problems (behavior problems including inattention, disorganization, impulsivity, and hyperactivity) are widely thought to reflect deficits in executive functions (EFs). However, it is unclear whether attention problems differentially relate to distinct EFs and how developmental stability and change predict levels of EFs in late adolescence. We investigated, in an unselected sample, how teacher-rated attention problems from ages 7 to 14 years related to three correlated but separable EFs, measured as latent variables at age 17. Attention problems at all ages significantly predicted later levels of response inhibition and working memory updating, and to some extent set shifting; the relation to inhibiting was stronger than the relations to the other EFs or IQ. Growth models indicated that attention problems were quite stable in this age range, and it was the initial levels of problems, rather than their changes across time, that predicted later EFs. These results support the hypothesis that attention problems primarily reflect difficulties with response inhibition.

  9. Peer Victimization, Depressive Symptoms, and High Salivary Cortisol Predict Poorer Memory in Children

    ERIC Educational Resources Information Center

    Vaillancourt, Tracy; Duku, Eric; Becker, Suzanna; Schmidt, Louis A.; Nicol, Jeffrey; Muir, Cameron; MacMillan, Harriet

    2011-01-01

    The predictive relations of peer victimization, depressive symptoms, and salivary cortisol on memory in 168 children aged 12 at Time 1 (T1) were examined using a longitudinal design in which data were collected on four occasions over a 2-year period. Results indicated that: (1) peer victimization, depressive symptoms, and evening cortisol were…

  10. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    ERIC Educational Resources Information Center

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  11. Peer Victimization, Depressive Symptoms, and High Salivary Cortisol Predict Poorer Memory in Children

    ERIC Educational Resources Information Center

    Vaillancourt, Tracy; Duku, Eric; Becker, Suzanna; Schmidt, Louis A.; Nicol, Jeffrey; Muir, Cameron; MacMillan, Harriet

    2011-01-01

    The predictive relations of peer victimization, depressive symptoms, and salivary cortisol on memory in 168 children aged 12 at Time 1 (T1) were examined using a longitudinal design in which data were collected on four occasions over a 2-year period. Results indicated that: (1) peer victimization, depressive symptoms, and evening cortisol were…

  12. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    ERIC Educational Resources Information Center

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  13. Characteristics of Fibromyalgia Independently Predict Poorer Long‐Term Analgesic Outcomes Following Total Knee and Hip Arthroplasty

    PubMed Central

    Urquhart, Andrew G.; Hassett, Afton L.; Tsodikov, Alex; Hallstrom, Brian R.; Wood, Nathan I.; Williams, David A.; Clauw, Daniel J.

    2015-01-01

    Objective While psychosocial factors have been associated with poorer outcomes after knee and hip arthroplasty, we hypothesized that augmented pain perception, as occurs in conditions such as fibromyalgia, may account for decreased responsiveness to primary knee and hip arthroplasty. Methods A prospective, observational cohort study was conducted. Preoperative phenotyping was conducted using validated questionnaires to assess pain, function, depression, anxiety, and catastrophizing. Participants also completed the 2011 fibromyalgia survey questionnaire, which addresses the widespread body pain and comorbid symptoms associated with characteristics of fibromyalgia. Results Of the 665 participants, 464 were retained 6 months after surgery. Since individuals who met criteria for being classified as having fibromyalgia were expected to respond less favorably, all primary analyses excluded these individuals (6% of the cohort). In the multivariate linear regression model predicting change in knee/hip pain (primary outcome), a higher fibromyalgia survey score was independently predictive of less improvement in pain (estimate −0.25, SE 0.044; P < 0.00001). Lower baseline joint pain scores and knee (versus hip) arthroplasty were also predictive of less improvement (R2 = 0.58). The same covariates were predictive in the multivariate logistic regression model for change in knee/hip pain, with a 17.8% increase in the odds of failure to meet the threshold of 50% improvement for every 1‐point increase in fibromyalgia survey score (P = 0.00032). The fibromyalgia survey score was also independently predictive of change in overall pain and patient global impression of change. Conclusion Our findings indicate that the fibromyalgia survey score is a robust predictor of poorer arthroplasty outcomes, even among individuals whose score falls well below the threshold for the categorical diagnosis of fibromyalgia. PMID:25772388

  14. Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York

    PubMed Central

    Mendiola, Jaime; Stahlhut, Richard W.; Jørgensen, Niels; Liu, Fan

    2011-01-01

    Background: In male rodents, anogenital distance (AGD) provides a sensitive and continuous correlate of androgen exposure in the intrauterine environment and predicts later reproductive success. Some endocrine-disrupting chemicals can alter male reproductive tract development, including shortening AGD, in both rodents and humans. Whether AGD is related to semen quality in human is unknown. Objective: We examined associations between AGD and semen parameters in adult males. Methods: We used multiple regression analyses to model the relationships between sperm parameters and two alternative measures of AGD [from the anus to the posterior base of the scrotum (AGDAS) and to the cephalad insertion of the penis (AGDAP)] in 126 volunteers in Rochester, New York. Results: AGDAS, but not AGDAP, was associated with sperm concentration, motility, morphology, total sperm count, and total motile count (p-values, 0.002–0.048). Men with AGDAS below (vs. above) the median were 7.3 times more likely (95% confidence interval, 2.5–21.6) to have a low sperm concentration (< 20 × 106/mL). For a typical study participant, sperm concentrations were 34.7 × 106/mL and 51.6 × 106/mL at the 25th and 75th percentiles of (adjusted) AGDAS. Conclusions: In our population, AGDAS was a strong correlate of all semen parameters and a predictor of low sperm concentration. In animals, male AGD at birth reflects androgen levels during the masculinization programming window and predicts adult AGD and reproductive function. Our results suggest, therefore, that the androgenic environment during early fetal life exerts a fundamental influence on both AGD and adult sperm counts in humans, as demonstrated in rodents. PMID:21377950

  15. Atrophy of spared grey matter tissue predicts poorer motor recovery and rehabilitation response in chronic stroke

    PubMed Central

    Gauthier, Lynne V.; Taub, Edward; Mark, Victor W.; Barghi, Ameen; Uswatte, Gitendra

    2011-01-01

    Background and Purpose Although the motor deficit following stroke is clearly due to the structural brain damage that has been sustained, this relationship is attenuated from the acute to chronic phases. We investigated the possibility that motor impairment and response to Constraint-Induced Movement therapy (CI therapy) in chronic stroke patients may relate more strongly to the structural integrity of brain structures remote from the lesion than to measures of overt tissue damage. Methods Voxel-based morphometry (VBM) analysis was performed on MRI scans from 80 chronic stroke patients to investigate whether variations in grey matter density were correlated with extent of residual motor impairment or with CI therapy-induced motor recovery. Results Decreased grey matter density in non-infarcted motor regions was significantly correlated with magnitude of residual motor deficit. In addition, reduced grey matter density in multiple remote brain regions predicted a lesser extent of motor improvement from CI therapy. Conclusions Atrophy in seemingly healthy parts of the brain that are distant from the infarct accounts for at least a portion of the sustained motor deficit in chronic stroke. PMID:22096036

  16. Greater pre-operative anxiety, pain and poorer function predict a worse outcome of a total knee arthroplasty.

    PubMed

    Alattas, Sharifah Adla; Smith, Toby; Bhatti, Maria; Wilson-Nunn, Daniel; Donell, Simon

    2016-10-12

    Around 10-30 % of patients are dissatisfied with the results of their total knee arthroplasty (TKA). This review aimed to identify and evaluate the predictors of outcome measured by the three domains of health-related quality of life (pain, stiffness and function). The focus was on pre-operative psychological factors as related to other patient-related variables. A systematic search was performed using the following databases: MEDLINE, PubMed, AMED, CINAHL, PsychINFO, SciFinder, Scopus, EMBASE, Cochrane, Lilacs, Web of Science and ScienceDirect. The quality of identified studies was assessed using the Critical Appraisal Skills Programme Cohort checklist. Ten studies met the eligibility criteria. From these, nine patient-related predictors of outcome were identified (depression, anxiety, age at surgery, gender (being female), medical co-morbidities, BMI, level of education, pre-operative pain severity and pre-operative knee function). Greater anxiety, pre-operative pain and function were the most significant factors to predict a poorer outcome of a TKA. The results of depression, gender (female), medical co-morbidities, BMI and level of education were variable among the included studies. There was very little evidence to support older age at operation as a predictor of poorer outcome. Patients experiencing high levels of pain before surgery should be informed of the chances of improvement by having a TKA. A validated psychological screening tool that separates depression and anxiety is recommended as part of the pre-operative assessment stage. Patients presenting with symptoms of depression and anxiety should be identified and consulted before a TKA. II.

  17. Low baseline pCO2 predicts poorer outcome from behavioral treatment: evidence from a mixed anxiety disorders sample.

    PubMed

    Davies, Carolyn D; Craske, Michelle G

    2014-10-30

    Low levels of end-tidal partial pressure of carbon dioxide (pCO2)-the amount of carbon dioxide measured from expired air-are commonly found in individuals with anxiety disorders but have not been examined as predictors of outcome from anxiety treatment. The current study examined pre-treatment baseline pCO2 as a predictor of outcome from cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT) for anxiety disorders. Sixty-one individuals with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defined principal anxiety disorder diagnosis completed 12 sessions of either CBT or ACT. Baseline pCO2 was measured prior to entering treatment. Self-reported anxiety symptoms and quality of life were assessed at pre-treatment, post-treatment, and 6- and 12-month follow-up from baseline. Low baseline pCO2 was associated with higher anxiety symptoms and lower quality of life across follow-up timepoints, above and beyond baseline symptom severity. These results suggest that low baseline pCO2 predicts poorer outcome from CBT and ACT for anxiety and may warrant treatment that directly addresses respiratory dysregulation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD).

    PubMed

    Sagvolden, Terje

    2011-03-30

    ADHD is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms. There is no biological marker, but there is considerable evidence to suggest that ADHD behavior is associated with poor dopaminergic and noradrenergic modulation of neuronal circuits that involve the frontal lobes. The best validated animal model of ADHD, the Spontaneously Hypertensive Rat (SHR), shows pronounced overactivity, impulsiveness, and deficient sustained attention. The primary objective of the present research was to investigate behavioral effects of a range of doses of chronic l-amphetamine on ADHD-like symptoms in the SHR. The present study tested the behavioral effects of 0.75 and 2.2 mg l-amphetamine base/kg i.p. in male SHRs and their controls, the Wistar Kyoto rat (WKY). ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. The striking impulsiveness, overactivity, and poorer sustained attention seen during baseline conditions in the SHR were improved by chronic treatment with l-amphetamine. The dose-response curves were, however, different for the different behaviors. Most significantly, the 0.75 mg/kg dose of l-amphetamine improved sustained attention without reducing overactivity and impulsiveness. The 2.2 mg/kg dose improved sustained attention as well as reduced SHR overactivity and impulsiveness. The effects of l-amphetamine to reduce the behavioral symptoms of ADHD in the SHR were maintained over the 14 days of daily dosing with no evidence of tolerance developing.

  19. Acute, low-dose methamphetamine administration improves attention/information processing speed and working memory in methamphetamine-dependent individuals displaying poorer cognitive performance at baseline.

    PubMed

    Mahoney, James J; Jackson, Brian J; Kalechstein, Ari D; De La Garza, Richard; Newton, Thomas F

    2011-03-30

    Abstinent methamphetamine (Meth) dependent individuals demonstrate poorer performance on tests sensitive to attention/information processing speed, learning and memory, and working memory when compared to non-Meth dependent individuals. The poorer performance on these tests may contribute to the morbidity associated with Meth-dependence. In light of this, we sought to determine the effects of acute, low-dose Meth administration on attention, working memory, and verbal learning and memory in 19 non-treatment seeking, Meth-dependent individuals. Participants were predominantly male (89%), Caucasian (63%), and cigarette smokers (63%). Following a four day, drug-free washout period, participants were given a single-blind intravenous infusion of saline, followed the next day by 30 mg of Meth. A battery of neurocognitive tasks was administered before and after each infusion, and performance on measures of accuracy and reaction time were compared between conditions. While acute Meth exposure did not affect test performance for the entire sample, participants who demonstrated relatively poor performance on these tests at baseline, identified using a median split on each test, showed significant improvement on measures of attention/information processing speed and working memory when administered Meth. Improved performance was seen on the following measures of working memory: choice reaction time task (p≤0.04), a 1-back task (p≤0.01), and a 2-back task (p≤0.04). In addition, those participants demonstrating high neurocognitive performance at baseline experienced similar or decreased performance following Meth exposure. These findings suggest that acute administration of Meth may temporarily improve Meth-associated neurocognitive performance in those individuals experiencing lower cognitive performance at baseline. As a result, stimulants may serve as a successful treatment for improving cognitive functioning in those Meth-dependent individuals experiencing

  20. C-C motif chemokine ligand 5 (CCL5) levels in gastric cancer patient sera predict occult peritoneal metastasis and a poorer prognosis.

    PubMed

    Wang, Tie; Wei, Yuzhe; Tian, Lining; Song, Hongjiang; Ma, Yan; Yao, Qian; Feng, Meiyan; Wang, Yanying; Gao, Meizhuo; Xue, Yingwei

    2016-08-01

    Gastric cancer is one of the most common cancers and the third leading cause of cancer death worldwide. A number of chemokines and cytokines play important roles in the progress of gastric cancer. The roles of C-C motif chemokine ligand 5 (CCL5) in gastric cancer remain unclear. Here, we retrospectively report an analysis of 105 patients with gastric cancer. Increased levels of CCL5 in circulation were correlated with more advanced T and N stages, poorly- or un-differentiated histological types, peritoneal metastasis, higher rates of residual tumor, and shorter survivals. Patients in the CCL5 High Group had stronger CCL5 immunohistochemistry (IHC) staining in tumor beds. Circulating CCL5 concentrations before surgery are a good biomarker for occult peritoneal metastasis. Elevated levels of serum CCL5, along with strong IHC CCL5 staining and poorly- or un-differentiated cancer are predictors for poorer outcomes. In conclusion, increased serum levels of CCL5 can be used to predict peritoneal dissemination and a poorer prognosis.

  1. An increased neutrophil-to-lymphocyte ratio predicts poorer survival following recurrence for patients with breast cancer

    PubMed Central

    Iwase, Toshiaki; Sangai, Takafumi; Sakakibara, Masahiro; Sakakibara, Junta; Ishigami, Emi; Hayama, Shouko; Nakagawa, Ayako; Masuda, Takahito; Tabe, Shunsuke; Nagashima, Takeshi

    2017-01-01

    The aim of the present study was to evaluate the association between changes in the neutrophil-to-lymphocyte ratio and the survival rate, as well as tumor subtype, in recurrent breast cancer. Patients with recurrent breast cancer following surgery were included in this study. NLR was calculated and compared between two time points: Pre-treatment and recurrence. The associations between the longitudinal NLR change, the NLR at the time of recurrence and overall survival following recurrence (OSrec) were evaluated. A total of 89 patients were evaluated. NLR increased by 0.59 at recurrence, as compared with the initial treatment (P<0.05). The triple negative (TN) type demonstrated 4.59 in NLR, which was the highest among the four subtypes at the time of recurrence (P<0.05). The highest change (an increase of 2.0) was observed in TN type cancer (P<0.05). Patients with high NLR upon recurrence demonstrated significantly shorter OSrec rates (P<0.05). On the other hand, patients with an NLR increased by more than a third quartile demonstrated a shorter OSrec rate (P=0.06). When adjusted by covariates, the NLR and tumor subtype were determined to be associated with OSrec (P<0.05). Therefore, an increased NLR predicts survival, even in patients with recurrent breast cancer, and the NLR is potentially useful as an inflammation marker for TN breast cancer.

  2. Self-Assessed Hearing Handicap in Older Adults With Poorer-Than-Predicted Speech Recognition in Noise

    PubMed Central

    Matthews, Lois J.; Dubno, Judy R.

    2017-01-01

    Purpose Even older adults with relatively mild hearing loss report hearing handicap, suggesting that hearing handicap is not completely explained by reduced speech audibility. Method We examined the extent to which self-assessed ratings of hearing handicap using the Hearing Handicap Inventory for the Elderly (HHIE; Ventry & Weinstein, 1982) were significantly associated with measures of speech recognition in noise that controlled for differences in speech audibility. Results One hundred sixty-two middle-aged and older adults had HHIE total scores that were significantly associated with audibility-adjusted measures of speech recognition for low-context but not high-context sentences. These findings were driven by HHIE items involving negative feelings related to communication difficulties that also captured variance in subjective ratings of effort and frustration that predicted speech recognition. The average pure-tone threshold accounted for some of the variance in the association between the HHIE and audibility-adjusted speech recognition, suggesting an effect of central and peripheral auditory system decline related to elevated thresholds. Conclusion The accumulation of difficult listening experiences appears to produce a self-assessment of hearing handicap resulting from (a) reduced audibility of stimuli, (b) declines in the central and peripheral auditory system function, and (c) additional individual variation in central nervous system function. PMID:28060993

  3. Self-Assessed Hearing Handicap in Older Adults With Poorer-Than-Predicted Speech Recognition in Noise.

    PubMed

    Eckert, Mark A; Matthews, Lois J; Dubno, Judy R

    2017-01-01

    Even older adults with relatively mild hearing loss report hearing handicap, suggesting that hearing handicap is not completely explained by reduced speech audibility. We examined the extent to which self-assessed ratings of hearing handicap using the Hearing Handicap Inventory for the Elderly (HHIE; Ventry & Weinstein, 1982) were significantly associated with measures of speech recognition in noise that controlled for differences in speech audibility. One hundred sixty-two middle-aged and older adults had HHIE total scores that were significantly associated with audibility-adjusted measures of speech recognition for low-context but not high-context sentences. These findings were driven by HHIE items involving negative feelings related to communication difficulties that also captured variance in subjective ratings of effort and frustration that predicted speech recognition. The average pure-tone threshold accounted for some of the variance in the association between the HHIE and audibility-adjusted speech recognition, suggesting an effect of central and peripheral auditory system decline related to elevated thresholds. The accumulation of difficult listening experiences appears to produce a self-assessment of hearing handicap resulting from (a) reduced audibility of stimuli, (b) declines in the central and peripheral auditory system function, and (c) additional individual variation in central nervous system function.

  4. Can digoxin dose requirements be predicted?

    PubMed

    Dobbs, S M; Mawer, G E; Rodgers, M; Woodcock, B G; Lucas, S B

    1976-04-01

    A search for patient variables relevant to digoxin dose requirements was made in fourty-three patients with a wide range of renal and hepatic function. The daily dose of digoxin to achieve a mean serum concentration of 1.5 ng/ml, the standardized dose, was calculated for each patient. The standardized dose correlated significantly with the following variables, in descending order of correlation coefficient; creatinine clearance, serum creatinine concentration, body weight and serum albumin concentration. An equation containing the two independent variables, creatinine clearance and serum albumin concentration, had a significantly stronger correlation with standardized dose than creatinine clearance alone. Attempts were made in each patient to predict the standardized dose using both empirical prescribing methods and the published nomograms. Although a maximum of 70% of the variance of the standardized dose was explained, this corresponded approximately to one patient in three having a predicted dose outside the 95% confidnece limits for the standardized dose. There remain important sources of individual variation in digoxin dose requirements yet to be identified. Future application of empirical prescribing methods, such as multiple linear regression and Bayes' theorem, to prescription for large, defined patient groups may improve dose prediction for individual patients.

  5. Can digoxin dose requirements be predicted?

    PubMed Central

    Dobbs, S M; Mawer, G E; Rodgers, M; Woodcock, B G; Lucas, S B

    1976-01-01

    A search for patient variables relevant to digoxin dose requirements was made in fourty-three patients with a wide range of renal and hepatic function. The daily dose of digoxin to achieve a mean serum concentration of 1.5 ng/ml, the standardized dose, was calculated for each patient. The standardized dose correlated significantly with the following variables, in descending order of correlation coefficient; creatinine clearance, serum creatinine concentration, body weight and serum albumin concentration. An equation containing the two independent variables, creatinine clearance and serum albumin concentration, had a significantly stronger correlation with standardized dose than creatinine clearance alone. Attempts were made in each patient to predict the standardized dose using both empirical prescribing methods and the published nomograms. Although a maximum of 70% of the variance of the standardized dose was explained, this corresponded approximately to one patient in three having a predicted dose outside the 95% confidnece limits for the standardized dose. There remain important sources of individual variation in digoxin dose requirements yet to be identified. Future application of empirical prescribing methods, such as multiple linear regression and Bayes' theorem, to prescription for large, defined patient groups may improve dose prediction for individual patients. PMID:973957

  6. Comparing dose prediction software used to manage gentamicin dosing.

    PubMed

    Wong, C; Kumar, S S; Graham, G G; Begg, E J; Chin, P K L; Brett, J; Ray, J E; Marriott, D J E; Williams, K M; Day, R O

    2013-05-01

    Current Australian guidelines recommend initiating directed therapy of gentamicin if administration exceeds 48 h. Directed doses of gentamicin require the monitoring of plasma concentrations of gentamicin to determine the 24-h area under the time course of plasma gentamicin concentrations (AUC) and a dosage prediction program, for example TCIWorks or Aladdin. However, doses calculated by such programs have not been compared with an established program. To compare the directed dosage of gentamicin calculated by TCIWorks, Aladdin and an Excel-based program, with an established program, Abbottbase. Peak and trough plasma concentrations after the first and second administered doses of gentamicin were available from three patient groups (n = 20-23) with varying creatinine clearances (<40, 40-80, >80 mL/min). The directed dose needed to produce 24-h AUC values of 80 mg.h/L was calculated using each program. There was a strong correlation between the directed doses predicted by each of the three programs compared with Abbottbase, following the first administered dose (r(2) > 0.97, P < 0.0001). The mean ratio (90% confidence intervals) of these directed doses of the gentamicin were: TCIWorks/Abbottbase 106% (105-107%), Aladdin/Abbottbase 102% (101-103%) and Excel/Abbottbase 108% (106-109%). The correlations and dose ratios were also similar when comparisons were made following the second administered dose. For each of the three renal function groups, all programs yielded similar directed doses. The four programs used in the calculation of directed doses of gentamicin yielded similar results. Any would be suitable for use in clinical practice. © 2012 The Authors; Internal Medicine Journal © 2012 Royal Australasian College of Physicians.

  7. Higher Leptin and Adiponectin Concentrations Predict Poorer Performance-based Physical Functioning in Midlife Women: the Michigan Study of Women’s Health Across the Nation

    PubMed Central

    Zheng, Huiyong; Mancuso, Peter; Harlow, Siobán D.

    2016-01-01

    Background. Excess fat mass is a greater contributor to functional limitations than is reduced lean mass or the presence of obesity-related conditions. The impact of fat mass on physical functioning may be due to adipokines, adipose-derived proteins that have pro- or anti-inflammatory properties. Methods. Serum samples from 1996 to 2003 that were assayed for leptin, adiponectin, and resistin were provided by 511 participants from the Michigan site of the Study of Women’s Health Across the Nation. Physical functioning performance was assessed annually during study visits from 1996 to 2003. Results. Among this population of Black and White women (mean baseline age = 45.6 years, SD = 2.7 years), all of whom were premenopausal at baseline, higher baseline leptin concentrations predicted longer stair climb, sit-to-rise, and 2-pound lift times and shorter forward reach distance (all p < .01). This relationship persisted after adjustment for age, BMI, percent skeletal muscle mass, race/ethnicity, economic strain, bodily pain, diabetes, knee osteoarthritis, and C-reactive protein. Baseline total adiponectin concentrations did not predict any mobility measures but did predict quadriceps strength; a 1 µg/mL higher adiponectin concentration was associated with 0.64 Nm lower quadriceps strength (p = .02). Resistin was not associated with any of the physical functioning performance measures. Change in the adipokines was not associated with physical functioning. Conclusion. In this population of middle-aged women, higher baseline leptin concentrations predicted poorer mobility-based functioning, whereas higher adiponectin concentrations predicted reduced quadriceps strength. These findings suggest that the relationship between the adipokines and physical functioning performance is independent of other known correlates of poor functioning. PMID:26302979

  8. Predictions of dose from electrons in space

    NASA Technical Reports Server (NTRS)

    Seltzer, Stephen M.

    1992-01-01

    The objective of the project is to develop a general-purpose, user-friendly computerized database and code package, for the PC as well as larger computers, which can be used for the routine prediction of the absorbed dose from incident electrons and their secondary bremsstrahlung (and from incident protons) as functions of the thickness of aluminum shielding in space. The assumption of homogeneous aluminum shields and of isotropic incident fluxes (at least in a time-averaged sense) allows for the rather reliable conversion of doses in slabs to those in other simple bodies, such as spherical and cylindrical solids and shells. On such a basis, depth-dose data for monoenergetic incident radiation can be generated once-and-for-all from accurate transport calculations, and this database can then be used repeatedly in rapid dose predictions for arbitrary radiation spectra and for a variety of spacecraft sizes and shapes, without recourse to the very time-consuming Monte Carlo calculations. This project entails a thorough updating, extension, and refinement of our earlier SHIELDOSE package, with the goal of a more reliable, fool-proof, and general system.

  9. Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance.

    PubMed

    Foster, Chris M; Kennedy, Kristen M; Rodrigue, Karen M

    2017-07-19

    The present study was designed to investigate the effect of a genetic risk factor for Alzheimer's disease (AD), ApolipoproteinE ε4 (APOEε4), on the ability of the brain to modulate activation in response to cognitive challenge in a lifespan sample of healthy human adults. A community-based sample of 181 cognitively intact, healthy adults were recruited from the Dallas-Fort Worth metroplex. Thirty-one APOEε4+ individuals (48% women), derived from the parent sample, were matched based on sex, age, and years of education to 31 individuals who were APOEε4-negative (APOEε4-). Ages ranged from 20 to 86 years of age. Blood oxygen level-dependent functional magnetic resonance imaging was collected during the performance of a visuospatial distance judgment task with three parametric levels of difficulty. Multiple regression was used in a whole-brain analysis with age, APOE group, and their interaction predicting functional brain modulation in response to difficulty. Results revealed an interaction between age and APOE in a large cluster localized primarily to the bilateral precuneus. APOEε4- individuals exhibited age-invariant modulation in response to task difficulty, whereas APOEε4+ individuals showed age-related reduction of modulation in response to increasing task difficulty compared with ε4- individuals. Decreased modulation in response to cognitive challenge was associated with reduced task accuracy as well as poorer name-face associative memory performance. Findings suggest that APOEε4 is associated with a reduction in the ability of the brain to dynamically modulate in response to cognitive challenge. Coupled with a significant genetic risk factor for AD, changes in modulation may provide additional information toward identifying individuals potentially at risk for cognitive decline associated with preclinical AD.SIGNIFICANCE STATEMENT Understanding how risk factors for Alzheimer's disease (AD) affect brain function and cognition in healthy adult samples

  10. Dose-volume histogram prediction using density estimation.

    PubMed

    Skarpman Munter, Johanna; Sjölund, Jens

    2015-09-07

    Knowledge of what dose-volume histograms can be expected for a previously unseen patient could increase consistency and quality in radiotherapy treatment planning. We propose a machine learning method that uses previous treatment plans to predict such dose-volume histograms. The key to the approach is the framing of dose-volume histograms in a probabilistic setting.The training consists of estimating, from the patients in the training set, the joint probability distribution of some predictive features and the dose. The joint distribution immediately provides an estimate of the conditional probability of the dose given the values of the predictive features. The prediction consists of estimating, from the new patient, the distribution of the predictive features and marginalizing the conditional probability from the training over this. Integrating the resulting probability distribution for the dose yields an estimate of the dose-volume histogram.To illustrate how the proposed method relates to previously proposed methods, we use the signed distance to the target boundary as a single predictive feature. As a proof-of-concept, we predicted dose-volume histograms for the brainstems of 22 acoustic schwannoma patients treated with stereotactic radiosurgery, and for the lungs of 9 lung cancer patients treated with stereotactic body radiation therapy. Comparing with two previous attempts at dose-volume histogram prediction we find that, given the same input data, the predictions are similar.In summary, we propose a method for dose-volume histogram prediction that exploits the intrinsic probabilistic properties of dose-volume histograms. We argue that the proposed method makes up for some deficiencies in previously proposed methods, thereby potentially increasing ease of use, flexibility and ability to perform well with small amounts of training data.

  11. Influence of Genotype on Warfarin Maintenance Dose Predictions Produced Using a Bayesian Dose Individualization Tool.

    PubMed

    Saffian, Shamin M; Duffull, Stephen B; Roberts, Rebecca L; Tait, Robert C; Black, Leanne; Lund, Kirstin A; Thomson, Alison H; Wright, Daniel F B

    2016-12-01

    A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values. The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations. Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.

  12. Vancomycin dosing: assessment of time to therapeutic concentration and predictive accuracy of pharmacokinetic modeling software.

    PubMed

    Nunn, Maya O; Corallo, Carmela E; Aubron, Cecile; Poole, Susan; Dooley, Michael J; Cheng, Allen C

    2011-06-01

    Therapeutic drug monitoring is usually required for safe and effective administration of vancomycin. However, dosing recommendations from published guidelines are not suitable in achieving therapeutic vancomycin concentrations in a timely manner in patients with normal renal function. To audit vancomycin dosing and concentrations at our institution and evaluate the predictive accuracy of a pharmacokinetic simulation program, with a view to implementing a pharmacy-based pharmacokinetic service for vancomycin monitoring. Patients receiving vancomycin were identified prospectively through the therapeutic drug monitoring archives. Patient information was obtained from medication charts and medical records that were located on wards. Data were entered into the MM-USC*Pack program (Jelliffe R, University of Southern California, 2008, version 12.10). This software was used to predict initial and subsequent concentrations of vancomycin based on patient parameters. The predictive accuracy of this software was evaluated by comparing the predicted concentrations to the observed concentrations. During a 6-week period, 204 concentrations were measured in 77 patients. The most common dosing regimen was 1 g every 12 hours. Overall, initial trough concentrations were subtherapeutic (<10 mg/L) in 58% of patients and trough concentrations did not become therapeutic at any stage throughout therapy in 25% of patients. The pharmacokinetic modeling software demonstrated little systematic bias (-3.1%), but the precision (median prediction error) was 23% (interquartile range, 11-45%). Predictions were poorer in obese patients (body mass index >35 kg/m(2)) and in patients with unstable renal function. A delay in attaining target trough concentrations was observed in a significant proportion of patients. Pharmacokinetic modeling software is a potential tool to improve the timeliness of achieving adequate dosing by allowing concentrations to be determined prior to steady-state. The program

  13. Why are older pensioners poorer?

    PubMed

    Johnson, P; Stears, G

    1998-08-01

    "We show that older [UK] male pensioners have substantially lower incomes than younger pensioners.... We find that cohort differences more than account for the lower incomes of older pensioners in the sense that the mean income of older pensioners is actually higher than the mean income of the same cohort of pensioners when they were younger. We explore a number of possible reasons for this and conclude that it is driven by differential mortality between richer and poorer pensioners. We show how this manifests itself in a long time series of cross-sectional datasets." excerpt

  14. Prediction of the mortality dose-response relationship in man

    SciTech Connect

    Morris, M.D.; Jones, T.D.

    1987-01-01

    Based upon an extensive data base including 100 separate animal studies, an estimate of the mortality dose-response relationship due to continuous photon radiation is predicted for 70 kg man. The model used in this prediction exercise includes fixed terms accounting for effects of body weight and dose rate, and random terms accounting for inter- and intra-species variation and experimental error. Point predictions and 95% prediction intervals are given for the LD/sub 05/, LD/sub 10/, LD/sub 25/, LD/sub 50/, LD/sub 75/, LD/sub 90/, and LD/sub 95/, for dose rates ranging from 1 to 50 R/min. 6 refs., 5 tabs.

  15. Quantifying and Communicating Uncertainty in Preclinical Human Dose-Prediction

    PubMed Central

    Sundqvist, M; Lundahl, A; Någård, MB; Bredberg, U; Gennemark, P

    2015-01-01

    Human dose-prediction is fundamental for ranking lead-optimization compounds in drug discovery and to inform design of early clinical trials. This tutorial describes how uncertainty in such predictions can be quantified and efficiently communicated to facilitate decision-making. Using three drug-discovery case studies, we show how several uncertain pieces of input information can be integrated into one single uncomplicated plot with key predictions, including their uncertainties, for many compounds or for many scenarios, or both. PMID:26225248

  16. Evaluation of Genetic Factors for Warfarin Dose Prediction

    PubMed Central

    Caldwell, Michael D.; Berg, Richard L.; Zhang, Kai Qi; Glurich, Ingrid; Schmelzer, John R.; Yale, Steven H.; Vidaillet, Humberto J.; Burmester, James K.

    2007-01-01

    Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors. Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes. Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability. Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose. PMID:17456829

  17. Predicting prolonged dose titration in patients starting warfarin.

    PubMed

    Finkelman, Brian S; French, Benjamin; Bershaw, Luanne; Brensinger, Colleen M; Streiff, Michael B; Epstein, Andrew E; Kimmel, Stephen E

    2016-11-01

    Patients initiating warfarin therapy generally experience a dose-titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration. A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting. The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross-validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction. Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Comprehensive fluence model for absolute portal dose image prediction.

    PubMed

    Chytyk, K; McCurdy, B M C

    2009-04-01

    Amorphous silicon (a-Si) electronic portal imaging devices (EPIDs) continue to be investigated as treatment verification tools, with a particular focus on intensity modulated radiation therapy (IMRT). This verification could be accomplished through a comparison of measured portal images to predicted portal dose images. A general fluence determination tailored to portal dose image prediction would be a great asset in order to model the complex modulation of IMRT. A proposed physics-based parameter fluence model was commissioned by matching predicted EPID images to corresponding measured EPID images of multileaf collimator (MLC) defined fields. The two-source fluence model was composed of a focal Gaussian and an extrafocal Gaussian-like source. Specific aspects of the MLC and secondary collimators were also modeled (e.g., jaw and MLC transmission factors, MLC rounded leaf tips, tongue and groove effect, interleaf leakage, and leaf offsets). Several unique aspects of the model were developed based on the results of detailed Monte Carlo simulations of the linear accelerator including (1) use of a non-Gaussian extrafocal fluence source function, (2) separate energy spectra used for focal and extrafocal fluence, and (3) different off-axis energy spectra softening used for focal and extrafocal fluences. The predicted energy fluence was then convolved with Monte Carlo generated, EPID-specific dose kernels to convert incident fluence to dose delivered to the EPID. Measured EPID data were obtained with an a-Si EPID for various MLC-defined fields (from 1 x 1 to 20 x 20 cm2) over a range of source-to-detector distances. These measured profiles were used to determine the fluence model parameters in a process analogous to the commissioning of a treatment planning system. The resulting model was tested on 20 clinical IMRT plans, including ten prostate and ten oropharyngeal cases. The model predicted the open-field profiles within 2%, 2 mm, while a mean of 96.6% of pixels over all

  19. Fully automated treatment planning for head and neck radiotherapy using a voxel-based dose prediction and dose mimicking method

    NASA Astrophysics Data System (ADS)

    McIntosh, Chris; Welch, Mattea; McNiven, Andrea; Jaffray, David A.; Purdie, Thomas G.

    2017-08-01

    Recent works in automated radiotherapy treatment planning have used machine learning based on historical treatment plans to infer the spatial dose distribution for a novel patient directly from the planning image. We present a probabilistic, atlas-based approach which predicts the dose for novel patients using a set of automatically selected most similar patients (atlases). The output is a spatial dose objective, which specifies the desired dose-per-voxel, and therefore replaces the need to specify and tune dose-volume objectives. Voxel-based dose mimicking optimization then converts the predicted dose distribution to a complete treatment plan with dose calculation using a collapsed cone convolution dose engine. In this study, we investigated automated planning for right-sided oropharaynx head and neck patients treated with IMRT and VMAT. We compare four versions of our dose prediction pipeline using a database of 54 training and 12 independent testing patients by evaluating 14 clinical dose evaluation criteria. Our preliminary results are promising and demonstrate that automated methods can generate comparable dose distributions to clinical. Overall, automated plans achieved an average of 0.6% higher dose for target coverage evaluation criteria, and 2.4% lower dose at the organs at risk criteria levels evaluated compared with clinical. There was no statistically significant difference detected in high-dose conformity between automated and clinical plans as measured by the conformation number. Automated plans achieved nine more unique criteria than clinical across the 12 patients tested and automated plans scored a significantly higher dose at the evaluation limit for two high-risk target coverage criteria and a significantly lower dose in one critical organ maximum dose. The novel dose prediction method with dose mimicking can generate complete treatment plans in 12-13 min without user interaction. It is a promising approach for fully automated treatment

  20. Predicting Pneumonitis Risk: A Dosimetric Alternative to Mean Lung Dose

    SciTech Connect

    Tucker, Susan L.; Mohan, Radhe; Liengsawangwong, Raweewan; Martel, Mary K.; Liao Zhongxing

    2013-02-01

    Purpose: To determine whether the association between mean lung dose (MLD) and risk of severe (grade {>=}3) radiation pneumonitis (RP) depends on the dose distribution pattern to normal lung among patients receiving 3-dimensional conformal radiation therapy for non-small-cell lung cancer. Methods and Materials: Three cohorts treated with different beam arrangements were identified. One cohort (2-field boost [2FB]) received 2 parallel-opposed (anteroposterior-posteroanterior) fields per fraction initially, followed by a sequential boost delivered using 2 oblique beams. The other 2 cohorts received 3 or 4 straight fields (3FS and 4FS, respectively), ie, all fields were irradiated every day. The incidence of severe RP was plotted against MLD in each cohort, and data were analyzed using the Lyman-Kutcher-Burman (LKB) model. Results: The incidence of grade {>=}3 RP rose more steeply as a function of MLD in the 2FB cohort (N=120) than in the 4FS cohort (N=138), with an intermediate slope for the 3FS group (N=99). The estimated volume parameter from the LKB model was n=0.41 (95% confidence interval, 0.15-1.0) and led to a significant improvement in fit (P=.05) compared to a fit with volume parameter fixed at n=1 (the MLD model). Unlike the MLD model, the LKB model with n=0.41 provided a consistent description of the risk of severe RP in all three cohorts (2FB, 3FS, 4FS) simultaneously. Conclusions: When predicting risk of grade {>=}3 RP, the mean lung dose does not adequately take into account the effects of high doses. Instead, the effective dose, computed from the LKB model using volume parameter n=0.41, may provide a better dosimetric parameter for predicting RP risk. If confirmed, these findings support the conclusion that for the same MLD, high doses to small lung volumes ('a lot to a little') are worse than low doses to large volumes ('a little to a lot').

  1. Predicting dose-time profiles of solar energetic particle events using Bayesian forecasting methods.

    PubMed

    Neal, J S; Townsend, L W

    2001-12-01

    Bayesian inference techniques, coupled with Markov chain Monte Carlo sampling methods, are used to predict dose-time profiles for energetic solar particle events. Inputs into the predictive methodology are dose and dose-rate measurements obtained early in the event. Surrogate dose values are grouped in hierarchical models to express relationships among similar solar particle events. Models assume nonlinear, sigmoidal growth for dose throughout an event. Markov chain Monte Carlo methods are used to sample from Bayesian posterior predictive distributions for dose and dose rate. Example predictions are provided for the November 8, 2000, and August 12, 1989, solar particle events.

  2. Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients.

    PubMed

    Shuker, Nauras; de Man, Femke M; de Weerd, Annelies E; van Agteren, Madelon; Weimar, Willem; Betjes, Michiel G H; van Gelder, Teun; Hesselink, Dennis A

    2016-04-01

    The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes.

  3. Oral morphine dosing predictions based on single dose in healthy children undergoing surgery.

    PubMed

    Dawes, Joy M; Cooke, Erin M; Hannam, Jacqueline A; Brand, Katherine A; Winton, Pamela; Jimenez-Mendez, Ricardo; Aleksa, Katarina; Lauder, Gillian R; Carleton, Bruce C; Koren, Gideon; Rieder, Michael J; Anderson, Brian J; Montgomery, Carolyne J

    2017-01-01

    Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens. Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg(-1) , 200 mcg·kg(-1) , 300 mcg·kg(-1) ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG ), and absorption half-time (TABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg(-1) ) at different dosing intervals (3, 4, 5, 6, 8, 12 h). The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg(-1) achieved a mean CMAX 10 mcg·l(-1) . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l(-1) ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l(-1) at steady state. Oral morphine 200 mcg·kg(-1) then 100 mcg·kg(-1) 4 h or 150 mcg·kg(-1) 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these

  4. Health literacy predicts pediatric dosing accuracy for liquid zidovudine.

    PubMed

    Howard, Leigh M; Tique, José A; Gaveta, Sandra; Sidat, Mohsin; Rothman, Russell L; Vermund, Sten H; Ciampa, Philip J

    2014-04-24

    Little is known about adult caregivers' ability to accurately dose pediatric antiretroviral medications. We aimed to characterize the frequency of dosing errors for liquid zidovudine using two dosing devices and to evaluate the association between HIV literacy and dosing errors in adults living with HIV infection. Cross-sectional study enrolling 316 adults receiving combination antiretroviral therapy (cART) for HIV infection in Maputo Province, Mozambique. Participants were administered the HIV Literacy Test (HIV-LT) and asked to measure 2.5 ml of liquid zidovudine using both a cup and syringe. Dosing measurement errors for liquid zidovudine were defined as 'any error' (≥ 20% deviation from reference dose) and 'major error' (≥ 40% deviation from reference dose). Dosing errors were common using the cup (any error: 50%, major error: 28%) and syringe (any error: 48% of participants, major error: 28%). There were no significant differences in proportions of any dosing error (P=0.61) or major dosing errors (P=0.82) between dosing instruments. In multivariable models, associations (P ≤ 0.03) were found between higher HIV-LT score and dosing errors for both the cup [any error adjusted odds ratio, AOR: 0.91 (0.84-0.99), major error AOR: 0.84 (0.75-0.92)] and syringe [any error AOR: 0.82 (0.75-0.90), major error AOR: 0.88 (0.80-0.97)]. Liquid antiretroviral medications are critical for prevention and treatment of pediatric HIV infections, yet dosing errors were exceedingly common in this population and were significantly associated with lower HIV literacy levels. Targeted interventions are needed to improve HIV knowledge and skills for pediatric medication dosing, particularly for caregivers with limited literacy.

  5. Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

    PubMed Central

    Grover, Anita; Benet, Leslie Z.

    2013-01-01

    Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

  6. Predicting Heart Dose in Breast Cancer Patients Who Received 3D Conformal Radiation Therapy.

    PubMed

    Wollschläger, Daniel; Karle, Heiko; Stockinger, Marcus; Bartkowiak, Detlef; Bührdel, Sandra; Merzenich, Hiltrud; Wiegel, Thomas; Schmidberger, Heinz; Blettner, Maria

    2017-01-01

    Cardiac late effects are a major health concern for long-term survivors after radiotherapy for breast cancer. Large cohort studies to better understand the exact dose-response relationship require individual estimates of radiation dose to the heart. To predict individual cardiac dose from information that is typically available for all members of a retrospective epidemiological cohort study, 774 female breast cancer patients treated with megavoltage tangential field radiotherapy in 1998-2008 were examined. All dose distributions were calculated using Eclipse with the anisotropic analytical algorithm (AAA) for photon fields and the electron Monte Carlo algorithm for electron boost fields. Based on individual dose volume histograms, the authors calculated absorbed dose in the complete heart as well as in six functional substructures. Statistical models were developed to predict absorbed dose using only covariate information from patients' clinical records on tumor location, patient anatomy and radiotherapy prescription. The out-of-sample prediction error for mean heart dose was 54% (coefficient of variation). The prediction error in functional substructures ranged from 49-68% for mean dose and from 52-86% for extreme dose. The authors conclude that based on a patient sample with exact heart dosimetry, it is possible to use clinical information alone to predict absorbed heart dose in the remaining cohort with a quantified error suitable for dose-response analyses of cardiac late effects.

  7. Detailed dose distribution prediction of Cf-252 brachytherapy source with boron loading dose enhancement.

    PubMed

    Ghassoun, J; Mostacci, D; Molinari, V; Jehouani, A

    2010-02-01

    The purpose of this work is to evaluate the dose rate distribution and to determine the boron effect on dose rate distribution for (252)Cf brachytherapy source. This study was carried out using a Monte Carlo simulation. To validate the Monte Carlo computer code, the dosimetric parameters were determined following the updated TG-43 formalism and compared with current literature data. The validated computer code was then applied to evaluate the neutron and photon dose distribution and to illustrate the boron loading effect.

  8. Can point doses predict volumetric dose to rectum and bladder: a CT-based planning study in high dose rate intracavitary brachytherapy of cervical carcinoma?

    PubMed Central

    Patil, V M; Patel, F D; Chakraborty, S; Oinam, A S; Sharma, S C

    2011-01-01

    Objective Point doses, as defined by the International Commission on Radiation Units and Measurements (ICRU), are classically used to evaluate doses to the rectum and bladder in high dose rate intracavitary brachytherapy (HDR-ICBT) in cervical cancer. Several studies have shown good correlation between the ICRU point doses and the volumetric doses to these organs. In the present study we attempted to evaluate whether this correlation could be used to predict the volumetric doses to these organs. Methods A total of 150 HDR-ICBT insertions performed between December 2006 and June 2008 were randomly divided into two groups. Group A (n=50) was used to derive the correlation between the point and volumetric doses using regression analysis. This was tested in Group B (n=100) insertions using studentised residuals and Bland–Altman plots. Results Significant correlations were obtained for all volumetric doses and ICRU point doses for rectum and bladder in Group A insertions. The strongest correlation was found for the dose to 2 cc volumes (D2cc). The correlation coefficients for bladder and rectal D2cc versus the respective ICRU point doses were 0.82 and 0.77, respectively (p<0.001). Statistical validation of equations generated in Group B showed mean studentised residual values of 0.001 and 0.000 for the bladder and rectum. However, Bland–Altman analysis showed that the error range for these equations for bladder and rectum were ±64% and ±41% of the point A dose, respectively, which makes these equations unreliable for clinical use. Conclusion Volumetric imaging is essential to obtain proper information about volumetric doses. PMID:21511749

  9. Absorbed dose measurements on LDEF and comparisons with predictions.

    PubMed

    Benton, E V; Frank, A L; Benton, E R; Armstrong, T W; Colborn, B L

    1996-11-01

    The radiation environment on LDEF was monitored by cumulative absorbed dose measurements made with TLDs at different locations and shielding depths. The TLDs were included in four experiments: A0015(a) Biostack, P0004 Seeds in Space and P0006 Linear Energy Transfer Spectrum Measurements at the trailing edge (west side) of the satellite; M0004 Fiber Optics Data Link at the leading edge (east side); and A0015(b) Biostack at the Earth side. The shielding depths varied between 0.48 and 15.4 g/cm2, Al equivalent. Both the directional dependence of trapped protons incident on the satellite and the shielding thickness were reflected in absorbed dose values. The trapped proton anisotropy was measured by TLDs at the east and west sides of LDEF. At the east side doses ranged from 2.10 to 2.58 Gy under shielding of 2.90 to 1.37 g/cm2 (M0004) while on the west side doses ranged from 2.66 to 6.48 Gy under shielding of 15.4 to 0.48 g/cm2 (P0006). The west side doses were more than a factor of two higher, where the vertical shielding thicknesses to space were equal. Other west side doses of 3.04 to 4.49 Gy under shielding of 11.7 to 3.85 g/cm2 (A0015(a)) and 2.91 to 6.64 Gy under shielding of 11.1 to 0.48 g/cm2 (P0004) generally agreed with the P0006 results. The Earth side doses of 2.41 to 3.93 Gy under shielding of 10.0 to 1.66 g cm2 (A0015(b)) were intermediate between the east side and west side doses. Calculations utilizing a model of trapped proton spectra were performed by Watts et al. (1993) and comparisons of dose measurement and calculations may be found in a companion paper (Armstrong et al., 1996).

  10. Absorbed dose measurements on LDEF and comparisons with predictions

    NASA Technical Reports Server (NTRS)

    Benton, E. V.; Frank, A. L.; Benton, E. R.; Armstrong, T. W.; Colborn, B. L.

    1996-01-01

    The radiation environment on LDEF was monitored by cumulative absorbed dose measurements made with TLDs at different locations and shielding depths. The TLDs were included in four experiments: A0015(a) Biostack, P0004 Seeds in Space and P0006 Linear Energy Transfer Spectrum Measurements at the trailing edge (west side) of the satellite; M0004 Fiber Optics Data Link at the leading edge (east side); and A0015(b) Biostack at the Earth side. The shielding depths varied between 0.48 and 15.4 g/cm2, Al equivalent. Both the directional dependence of trapped protons incident on the satellite and the shielding thickness were reflected in absorbed dose values. The trapped proton anisotropy was measured by TLDs at the east and west sides of LDEF. At the east side doses ranged from 2.10 to 2.58 Gy under shielding of 2.90 to 1.37 g/cm2 (M0004) while on the west side doses ranged from 2.66 to 6.48 Gy under shielding of 15.4 to 0.48 g/cm2 (P0006). The west side doses were more than a factor of two higher, where the vertical shielding thicknesses to space were equal. Other west side doses of 3.04 to 4.49 Gy under shielding of 11.7 to 3.85 g/cm2 (A0015(a)) and 2.91 to 6.64 Gy under shielding of 11.1 to 0.48 g/cm2 (P0004) generally agreed with the P0006 results. The Earth side doses of 2.41 to 3.93 Gy under shielding of 10.0 to 1.66 g cm2 (A0015(b)) were intermediate between the east side and west side doses. Calculations utilizing a model of trapped proton spectra were performed by Watts et al. (1993) and comparisons of dose measurement and calculations may be found in a companion paper (Armstrong et al., 1996).

  11. Predicting Maintenance Doses of Vancomycin for Hospitalized Patients Undergoing Hemodialysis

    PubMed Central

    El Nekidy, Wasim S; El-Masri, Maher M; Umstead, Greg S; Dehoorne-Smith, Michelle

    2016-01-01

    Background Methicillin-resistant Staphylococcus aureus is a leading cause of death in patients undergoing hemodialysis. However, controversy exists about the optimal dose of vancomycin that will yield the recommended pre-hemodialysis serum concentration of 15–20 mg/L. Objective To develop a data-driven model to optimize the accuracy of maintenance dosing of vancomycin for patients undergoing hemodialysis. Methods A prospective observational cohort study was performed with 164 observations obtained from a convenience sample of 63 patients undergoing hemodialysis. All vancomycin doses were given on the floor after completion of a hemodialysis session. Multivariate linear generalized estimating equation analysis was used to examine independent predictors of pre-hemodialysis serum vancomycin concentration. Results Pre-hemodialysis serum vancomycin concentration was independently associated with maintenance dose (B = 0.658, p < 0.001), baseline pre-hemodialysis serum concentration of the drug (B = 0.492, p < 0.001), and interdialytic interval (B = −2.133, p < 0.001). According to the best of 4 models that were developed, the maintenance dose of vancomycin required to achieve a pre-hemodialysis serum concentration of 15–20 mg/L, if the baseline serum concentration of the drug was also 15–20 mg/L, was 5.9 mg/kg with interdialytic interval of 48 h and 7.1 mg/kg with interdialytic interval of 72 h. However, if the baseline pre-hemodialysis serum concentration was 10–14.99 mg/L, the required dose increased to 9.2 mg/kg with an interdialytic interval of 48 h and 10.0 mg/kg with an interdialytic interval of 72 h. Conclusions The maintenance dose of vancomycin varied according to baseline pre-hemodialysis serum concentration of the drug and interdialytic interval. The current practice of targeting a pre-hemodialysis concentration of 15–20 mg/L may be difficult to achieve for the majority of patients undergoing hemodialysis. PMID:27826151

  12. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control

    PubMed Central

    Brorsson, Caroline A.; Nielsen, Lotte B.; Andersen, Marie Louise; Kaur, Simranjeet; Bergholdt, Regine; Hansen, Lars; Mortensen, Henrik B.; Pociot, Flemming; Størling, Joachim; Hvidoere Study Group on Childhood Diabetes

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment. PMID:26904692

  13. SU-E-T-802: Verification of Implanted Cardiac Pacemaker Doses in Intensity-Modulated Radiation Therapy: Dose Prediction Accuracy and Reduction Effect of a Lead Sheet

    SciTech Connect

    Lee, J; Chung, J

    2015-06-15

    Purpose: To verify delivered doses on the implanted cardiac pacemaker, predicted doses with and without dose reduction method were verified using the MOSFET detectors in terms of beam delivery and dose calculation techniques in intensity-modulated radiation therapy (IMRT). Methods: The pacemaker doses for a patient with a tongue cancer were predicted according to the beam delivery methods [step-and-shoot (SS) and sliding window (SW)], intensity levels for dose optimization, and dose calculation algorithms. Dosimetric effects on the pacemaker were calculated three dose engines: pencil-beam convolution (PBC), analytical anisotropic algorithm (AAA), and Acuros-XB. A lead shield of 2 mm thickness was designed for minimizing irradiated doses to the pacemaker. Dose variations affected by the heterogeneous material properties of the pacemaker and effectiveness of the lead shield were predicted by the Acuros-XB. Dose prediction accuracy and the feasibility of the dose reduction strategy were verified based on the measured skin doses right above the pacemaker using mosfet detectors during the radiation treatment. Results: The Acuros-XB showed underestimated skin doses and overestimated doses by the lead-shield effect, even though the lower dose disagreement was observed. It led to improved dose prediction with higher intensity level of dose optimization in IMRT. The dedicated tertiary lead sheet effectively achieved reduction of pacemaker dose up to 60%. Conclusion: The current SS technique could deliver lower scattered doses than recommendation criteria, however, use of the lead sheet contributed to reduce scattered doses.Thin lead plate can be a useful tertiary shielder and it could not acuse malfunction or electrical damage of the implanted pacemaker in IMRT. It is required to estimate more accurate scattered doses of the patient with medical device to design proper dose reduction strategy.

  14. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups.

    PubMed

    Limdi, Nita A; Wadelius, Mia; Cavallari, Larisa; Eriksson, Niclas; Crawford, Dana C; Lee, Ming-Ta M; Chen, Chien-Hsiun; Motsinger-Reif, Alison; Sagreiya, Hersh; Liu, Nianjun; Wu, Alan H B; Gage, Brian F; Jorgensen, Andrea; Pirmohamed, Munir; Shin, Jae-Gook; Suarez-Kurtz, Guilherme; Kimmel, Stephen E; Johnson, Julie A; Klein, Teri E; Wagner, Michael J

    2010-05-06

    Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

  15. Estimating the predictive quality of dose-response after model selection.

    PubMed

    Hu, Chuanpu; Dong, Yingwen

    2007-07-20

    Prediction of dose-response is important in dose selection in drug development. As the true dose-response shape is generally unknown, model selection is frequently used, and predictions based on the final selected model. Correctly assessing the quality of the predictions requires accounting for the uncertainties caused by the model selection process, which has been difficult. Recently, a new approach called data perturbation has emerged. It allows important predictive characteristics be computed while taking model selection into consideration. We study, through simulation, the performance of data perturbation in estimating standard error of parameter estimates and prediction errors. Data perturbation was found to give excellent prediction error estimates, although at times large Monte Carlo sizes were needed to obtain good standard error estimates. Overall, it is a useful tool to characterize uncertainties in dose-response predictions, with the potential of allowing more accurate dose selection in drug development. We also look at the influence of model selection on estimation bias. This leads to insights into candidate model choices that enable good dose-response prediction.

  16. Extrapolation of the dna fragment-size distribution after high-dose irradiation to predict effects at low doses

    NASA Technical Reports Server (NTRS)

    Ponomarev, A. L.; Cucinotta, F. A.; Sachs, R. K.; Brenner, D. J.; Peterson, L. E.

    2001-01-01

    The patterns of DSBs induced in the genome are different for sparsely and densely ionizing radiations: In the former case, the patterns are well described by a random-breakage model; in the latter, a more sophisticated tool is needed. We used a Monte Carlo algorithm with a random-walk geometry of chromatin, and a track structure defined by the radial distribution of energy deposition from an incident ion, to fit the PFGE data for fragment-size distribution after high-dose irradiation. These fits determined the unknown parameters of the model, enabling the extrapolation of data for high-dose irradiation to the low doses that are relevant for NASA space radiation research. The randomly-located-clusters formalism was used to speed the simulations. It was shown that only one adjustable parameter, Q, the track efficiency parameter, was necessary to predict DNA fragment sizes for wide ranges of doses. This parameter was determined for a variety of radiations and LETs and was used to predict the DSB patterns at the HPRT locus of the human X chromosome after low-dose irradiation. It was found that high-LET radiation would be more likely than low-LET radiation to induce additional DSBs within the HPRT gene if this gene already contained one DSB.

  17. Extrapolation of the dna fragment-size distribution after high-dose irradiation to predict effects at low doses

    NASA Technical Reports Server (NTRS)

    Ponomarev, A. L.; Cucinotta, F. A.; Sachs, R. K.; Brenner, D. J.; Peterson, L. E.

    2001-01-01

    The patterns of DSBs induced in the genome are different for sparsely and densely ionizing radiations: In the former case, the patterns are well described by a random-breakage model; in the latter, a more sophisticated tool is needed. We used a Monte Carlo algorithm with a random-walk geometry of chromatin, and a track structure defined by the radial distribution of energy deposition from an incident ion, to fit the PFGE data for fragment-size distribution after high-dose irradiation. These fits determined the unknown parameters of the model, enabling the extrapolation of data for high-dose irradiation to the low doses that are relevant for NASA space radiation research. The randomly-located-clusters formalism was used to speed the simulations. It was shown that only one adjustable parameter, Q, the track efficiency parameter, was necessary to predict DNA fragment sizes for wide ranges of doses. This parameter was determined for a variety of radiations and LETs and was used to predict the DSB patterns at the HPRT locus of the human X chromosome after low-dose irradiation. It was found that high-LET radiation would be more likely than low-LET radiation to induce additional DSBs within the HPRT gene if this gene already contained one DSB.

  18. TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

    SciTech Connect

    Liu, J; Wu, Q.J.; Yin, F; Kirkpatrick, J; Cabrera, A; Ge, Y

    2014-06-15

    Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into five groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant

  19. Imprecision in predicted dose from /sup 137/Cs resulting from biological variability

    SciTech Connect

    Dunning, D.E. Jr.; Schwarz, G.

    1981-01-01

    The variability of observed values of human metabolic and physiological characteristics which influence estimates of dose from ingestion of a unit of Cesium-137 activity, and the subsequent predicted total-body dose commitment is analyzed. The analysis is based on extensive literature review and statistical comparison of parameter variability, correlation and reliability. (PSB)

  20. NEUTRON GENERATOR FACILITY AT SFU: GEANT4 DOSE RATE PREDICTION AND VERIFICATION.

    PubMed

    Williams, J; Chester, A; Domingo, T; Rizwan, U; Starosta, K; Voss, P

    2016-11-01

    Detailed dose rate maps for a neutron generator facility at Simon Fraser University were produced via the GEANT4 Monte Carlo framework. Predicted neutron dose rates throughout the facility were compared with radiation survey measurements made during the facility commissioning process. When accounting for thermal neutrons, the prediction and measurement agree within a factor of 2 or better in most survey locations, and within 10 % inside the vault housing the neutron generator.

  1. Voxel-based dose prediction with multi-patient atlas selection for automated radiotherapy treatment planning

    NASA Astrophysics Data System (ADS)

    McIntosh, Chris; Purdie, Thomas G.

    2017-01-01

    Automating the radiotherapy treatment planning process is a technically challenging problem. The majority of automated approaches have focused on customizing and inferring dose volume objectives to be used in plan optimization. In this work we outline a multi-patient atlas-based dose prediction approach that learns to predict the dose-per-voxel for a novel patient directly from the computed tomography planning scan without the requirement of specifying any objectives. Our method learns to automatically select the most effective atlases for a novel patient, and then map the dose from those atlases onto the novel patient. We extend our previous work to include a conditional random field for the optimization of a joint distribution prior that matches the complementary goals of an accurately spatially distributed dose distribution while still adhering to the desired dose volume histograms. The resulting distribution can then be used for inverse-planning with a new spatial dose objective, or to create typical dose volume objectives for the canonical optimization pipeline. We investigated six treatment sites (633 patients for training and 113 patients for testing) and evaluated the mean absolute difference in all DVHs for the clinical and predicted dose distribution. The results on average are favorable in comparison to our previous approach (1.91 versus 2.57). Comparing our method with and without atlas-selection further validates that atlas-selection improved dose prediction on average in whole breast (0.64 versus 1.59), prostate (2.13 versus 4.07), and rectum (1.46 versus 3.29) while it is less important in breast cavity (0.79 versus 0.92) and lung (1.33 versus 1.27) for which there is high conformity and minimal dose shaping. In CNS brain, atlas-selection has the potential to be impactful (3.65 versus 5.09), but selecting the ideal atlas is the most challenging.

  2. Prediction of human efficacious antidepressant doses using the mouse forced swim test.

    PubMed

    Yuen, Eunice; Swanson, Steven; Witkin, Jeffrey M

    2017-09-06

    The forced swim test (FST) is a commonly used preclinical animal behavioural model for prediction of antidepressant activity in humans. While the FST may qualitatively predict efficacy, less is known about the quantitative translation of FST data to human efficacious doses. Assessing quantitative translation allows better predictions of human efficacious doses and a higher chance of success in the drug development process. Dose-response and time-course FST experiments were carried out on mice using four marketed antidepressants (citalopram, desipramine, bupropion, desvenlafaxine) in addition to ketamine, all with varying mechanisms of action. Population pharmacokinetic (PK)/pharmacodynamic (PD) analysis methods were applied to analyse the PK and immobility data, and the accuracy of the translation of FST data to human doses was evaluated using both area under the curve (AUC) and concentration-based approaches. The results showed that for the five antidepressants, average human AUC at clinically relevant doses were up to 38-fold higher than mouse AUC at doses associated with 50% of maximal efficacy in the FST (ED50). Using a concentration approach, human peak and trough drug concentrations at clinically relevant doses were generally associated with concentrations of at least 65% (EC65) and 20% (EC20) of maximal effect in mice, respectively. The FST is a useful tool to predict antidepressant efficacy across a variety of drugs with different mechanisms of actions. However, human doses can be over-or under-predicted many fold when using the traditional approach of estimating based upon ED50 AUC in mice. It is recommended that a concentration approach be used, where concentrations associated with 80% (EC80) and 30% (EC30) of maximal effect in the mouse are used as general targets for human maximum and trough concentrations, respectively, in the prediction of clinically efficacious doses of new, potential antidepressant agents. Copyright © 2017 Elsevier Inc. All rights

  3. Knowledge-based prediction of three-dimensional dose distributions for external beam radiotherapy

    SciTech Connect

    Shiraishi, Satomi; Moore, Kevin L.

    2016-01-15

    Purpose: To demonstrate knowledge-based 3D dose prediction for external beam radiotherapy. Methods: Using previously treated plans as training data, an artificial neural network (ANN) was trained to predict a dose matrix based on patient-specific geometric and planning parameters, such as the closest distance (r) to planning target volume (PTV) and organ-at-risks (OARs). Twenty-three prostate and 43 stereotactic radiosurgery/radiotherapy (SRS/SRT) cases with at least one nearby OAR were studied. All were planned with volumetric-modulated arc therapy to prescription doses of 81 Gy for prostate and 12–30 Gy for SRS. Using these clinically approved plans, ANNs were trained to predict dose matrix and the predictive accuracy was evaluated using the dose difference between the clinical plan and prediction, δD = D{sub clin} − D{sub pred}. The mean (〈δD{sub r}〉), standard deviation (σ{sub δD{sub r}}), and their interquartile range (IQR) for the training plans were evaluated at a 2–3 mm interval from the PTV boundary (r{sub PTV}) to assess prediction bias and precision. Initially, unfiltered models which were trained using all plans in the cohorts were created for each treatment site. The models predict approximately the average quality of OAR sparing. Emphasizing a subset of plans that exhibited superior to the average OAR sparing during training, refined models were created to predict high-quality rectum sparing for prostate and brainstem sparing for SRS. Using the refined model, potentially suboptimal plans were identified where the model predicted further sparing of the OARs was achievable. Replans were performed to test if the OAR sparing could be improved as predicted by the model. Results: The refined models demonstrated highly accurate dose distribution prediction. For prostate cases, the average prediction bias for all voxels irrespective of organ delineation ranged from −1% to 0% with maximum IQR of 3% over r{sub PTV} ∈ [ − 6, 30] mm. The

  4. Overweight predicts poorer exercise capacity in congenital heart disease patients.

    PubMed

    Kuehl, Karen; Tucker, Alicia; Khan, Munziba; Goldberg, Paula; Anne Greene, E; Smith, Megan

    2015-12-07

    Overweight (OW) and obesity (OB) are endemic in the United States and affect adolescents and adults with congenital heart disease (ACHD). Defining the burden of excess weight on the cardiovascular system in ACHD is the goal of this study. Limitation of exercise capacity due to overweight or obesity might be reversible with weight loss and improve quality of life for ACHD adults. Exercise tests performed using a Bruce protocol and measurement of maximum oxygen consumption were retrospectively reviewed on 418 CHD patients. OW and OB were defined as the 85-95 or > 95 percentile respectively for age and gender or by adult criteria. Severity of CHD was assigned based on criteria published in standard guidelines. 63 patients had mild, 198 moderate, and 157 severe heart disease. Each ACHD group was 32 to 34% OW or OB. Measured exercise time (ET) of CHD patients with moderate or severe heart disease was less than that of controls in each weight categories. However, OB or OW people have shorter ET than their normal weight peers with CHD. Multiple regression using ET as the dependent variable finds that female sex, relative BMI, and VE/VCO2 at peak exercise are all associated with lesser ET with high significance. Peak heart rate is associated with greater ET, with borderline significance. Severity of heart disease is not independently associated with ET. OW and OB are strongly associated with reduced ET in persons with congenital heart disease. Losing weight may improve exercise capacity in ACHD.

  5. Contextual Atlas Regression Forests: Multiple-Atlas-Based Automated Dose Prediction in Radiation Therapy.

    PubMed

    McIntosh, Chris; Purdie, Thomas G

    2016-04-01

    Radiation therapy is an integral part of cancer treatment, but to date it remains highly manual. Plans are created through optimization of dose volume objectives that specify intent to minimize, maximize, or achieve a prescribed dose level to clinical targets and organs. Optimization is NP-hard, requiring highly iterative and manual initialization procedures. We present a proof-of-concept for a method to automatically infer the radiation dose directly from the patient's treatment planning image based on a database of previous patients with corresponding clinical treatment plans. Our method uses regression forests augmented with density estimation over the most informative features to learn an automatic atlas-selection metric that is tailored to dose prediction. We validate our approach on 276 patients from 3 clinical treatment plan sites (whole breast, breast cavity, and prostate), with an overall dose prediction accuracies of 78.68%, 64.76%, 86.83% under the Gamma metric.

  6. Can radiation therapy treatment planning system accurately predict surface doses in postmastectomy radiation therapy patients?

    SciTech Connect

    Wong, Sharon; Back, Michael; Tan, Poh Wee; Lee, Khai Mun; Baggarley, Shaun; Lu, Jaide Jay

    2012-07-01

    Skin doses have been an important factor in the dose prescription for breast radiotherapy. Recent advances in radiotherapy treatment techniques, such as intensity-modulated radiation therapy (IMRT) and new treatment schemes such as hypofractionated breast therapy have made the precise determination of the surface dose necessary. Detailed information of the dose at various depths of the skin is also critical in designing new treatment strategies. The purpose of this work was to assess the accuracy of surface dose calculation by a clinically used treatment planning system and those measured by thermoluminescence dosimeters (TLDs) in a customized chest wall phantom. This study involved the construction of a chest wall phantom for skin dose assessment. Seven TLDs were distributed throughout each right chest wall phantom to give adequate representation of measured radiation doses. Point doses from the CMS Xio Registered-Sign treatment planning system (TPS) were calculated for each relevant TLD positions and results correlated. There were no significant difference between measured absorbed dose by TLD and calculated doses by the TPS (p > 0.05 (1-tailed). Dose accuracy of up to 2.21% was found. The deviations from the calculated absorbed doses were overall larger (3.4%) when wedges and bolus were used. 3D radiotherapy TPS is a useful and accurate tool to assess the accuracy of surface dose. Our studies have shown that radiation treatment accuracy expressed as a comparison between calculated doses (by TPS) and measured doses (by TLD dosimetry) can be accurately predicted for tangential treatment of the chest wall after mastectomy.

  7. Evaluation of uncertainty predictions and dose output for model-based dose calculations for megavoltage photon beams

    SciTech Connect

    Olofsson, Joergen; Nyholm, Tufve; Georg, Dietmar; Ahnesjoe, Anders; Karlsson, Mikael

    2006-07-15

    In many radiotherapy clinics an independent verification of the number of monitor units (MU) used to deliver the prescribed dose to the target volume is performed prior to the treatment start. Traditionally this has been done by using methods mainly based on empirical factors which, at least to some extent, try to separate the influence from input parameters such as field size, depth, distance, etc. The growing complexity of modern treatment techniques does however make this approach increasingly difficult, both in terms of practical application and in terms of the reliability of the results. In the present work the performance of a model-based approach, describing the influence from different input parameters through actual modeling of the physical effects, has been investigated in detail. The investigated model is based on two components related to megavoltage photon beams; one describing the exiting energy fluence per delivered MU, and a second component describing the dose deposition through a pencil kernel algorithm solely based on a measured beam quality index. Together with the output calculations, the basis of a method aiming to predict the inherent calculation uncertainties in individual treatment setups has been developed. This has all emerged from the intention of creating a clinical dose/MU verification tool that requires an absolute minimum of commissioned input data. This evaluation was focused on irregular field shapes and performed through comparison with output factors measured at 5, 10, and 20 cm depth in ten multileaf collimated fields on four different linear accelerators with varying multileaf collimator designs. The measurements were performed both in air and in water and the results of the two components of the model were evaluated separately and combined. When compared with the corresponding measurements the resulting deviations in the calculated output factors were in most cases smaller than 1% and in all cases smaller than 1.7%. The

  8. SU-E-T-196: Comparative Analysis of Surface Dose Measurements Using MOSFET Detector and Dose Predicted by Eclipse - AAA with Varying Dose Calculation Grid Size

    SciTech Connect

    Badkul, R; Nejaiman, S; Pokhrel, D; Jiang, H; Kumar, P

    2015-06-15

    Purpose: Skin dose can be the limiting factor and fairly common reason to interrupt the treatment, especially for treating head-and-neck with Intensity-modulated-radiation-therapy(IMRT) or Volumetrically-modulated - arc-therapy (VMAT) and breast with tangentially-directed-beams. Aim of this study was to investigate accuracy of near-surface dose predicted by Eclipse treatment-planning-system (TPS) using Anisotropic-Analytic Algorithm (AAA)with varying calculation grid-size and comparing with metal-oxide-semiconductor-field-effect-transistors(MOSFETs)measurements for a range of clinical-conditions (open-field,dynamic-wedge, physical-wedge, IMRT,VMAT). Methods: QUASAR™-Body-Phantom was used in this study with oval curved-surfaces to mimic breast, chest wall and head-and-neck sites.A CT-scan was obtained with five radio-opaque markers(ROM) placed on the surface of phantom to mimic the range of incident angles for measurements and dose prediction using 2mm slice thickness.At each ROM, small structure(1mmx2mm) were contoured to obtain mean-doses from TPS.Calculations were performed for open-field,dynamic-wedge,physical-wedge,IMRT and VMAT using Varian-21EX,6&15MV photons using twogrid-sizes:2.5mm and 1mm.Calibration checks were performed to ensure that MOSFETs response were within ±5%.Surface-doses were measured at five locations and compared with TPS calculations. Results: For 6MV: 2.5mm grid-size,mean calculated doses(MCD)were higher by 10%(±7.6),10%(±7.6),20%(±8.5),40%(±7.5),30%(±6.9) and for 1mm grid-size MCD were higher by 0%(±5.7),0%(±4.2),0%(±5.5),1.2%(±5.0),1.1% (±7.8) for open-field,dynamic-wedge,physical-wedge,IMRT,VMAT respectively.For 15MV: 2.5mm grid-size,MCD were higher by 30%(±14.6),30%(±14.6),30%(±14.0),40%(±11.0),30%(±3.5)and for 1mm grid-size MCD were higher by 10% (±10.6), 10%(±9.8),10%(±8.0),30%(±7.8),10%(±3.8) for open-field, dynamic-wedge, physical-wedge, IMRT, VMAT respectively.For 6MV, 86% and 56% of all measured values

  9. A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin-mediated Photodynamic Therapy.

    PubMed

    Qiu, Haixia; Kim, Michele M; Penjweini, Rozhin; Finlay, Jarod C; Busch, Theresa M; Wang, Tianhao; Guo, Wensheng; Cengel, Keith A; Simone, Charles B; Glatstein, Eli; Zhu, Timothy C

    2017-01-13

    This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [(1) O2 ]rx , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm(-2) ) and in-air fluence rates (50-150 mW cm(-2) ) at Photofrin dosages of 5 and 15 mg kg(-1) and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [(1) O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [(1) O2 ]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [(1) O2 ]rx ≥ 1.1 mm or PDT dose ≥1200 μm J cm(-2) but cannot be predicted with fluence alone. LCR increases with increasing [(1) O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [(1) O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.

  10. Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution

    SciTech Connect

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yoshikawa, Nobuhiko; Yamada, Yuji; Suzuki, Osamu; Seo, Yuji; Isohashi, Fumiaki; Yoshioka, Yasuo; Ogawa, Kazuhiko

    2015-07-15

    Purpose: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). Methods and Materials: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV, spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. Results: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03–.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. Conclusions: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution.

  11. Early childhood electronic media use as a predictor of poorer well-being: a prospective cohort study.

    PubMed

    Hinkley, Trina; Verbestel, Vera; Ahrens, Wolfgang; Lissner, Lauren; Molnár, Dénes; Moreno, Luis A; Pigeot, Iris; Pohlabeln, Hermann; Reisch, Lucia A; Russo, Paola; Veidebaum, Toomas; Tornaritis, Michael; Williams, Garrath; De Henauw, Stefaan; De Bourdeaudhuij, Ilse

    2014-05-01

    Identifying associations between preschool-aged children's electronic media use and their later well-being is essential to supporting positive long-term outcomes. To investigate possible dose-response associations of young children's electronic media use with their later well-being. The IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) study is a prospective cohort study with an intervention component. Data were collected at baseline from September 1, 2007, through June 30, 2008, and at follow-up from September 1, 2009, through May 31, 2010, in 8 European countries participating in the IDEFICS study. This investigation is based on 3604 children aged 2 to 6 years who participated in the longitudinal component of the IDEFICS study only and not in the intervention. Early childhood electronic media use. The following 6 indicators of well-being from 2 validated instruments were used as outcomes at follow-up: Peer problems and Emotional problems subscales from the Strengths and Difficulties Questionnaire and Emotional well-being, Self-esteem, Family functioning, and Social networks subscales from the KINDLR (Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents-Revised Version). Each scale was dichotomized to identify those children at risk for poorer outcomes. Indicators of electronic media use (weekday and weekend television and electronic game [e-game]/computer use) from baseline were used as predictors. Associations varied between boys and girls; however, associations suggested that increased levels of electronic media use predicted poorer well-being outcomes. Television viewing on weekdays or weekends was more consistently associated with poorer outcomes than e-game/computer use. Across associations, the likelihood of adverse outcomes in children ranged from a 1.2- to 2.0-fold increase for emotional problems and poorer family functioning for each additional hour of

  12. Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium.

    PubMed

    Haney, J

    2015-02-01

    The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose-specific adjustment factor of at least an order of magnitude to be less over-predictive of risk at more environmentally-relevant doses.

  13. MO-FG-303-03: Demonstration of Universal Knowledge-Based 3D Dose Prediction

    SciTech Connect

    Shiraishi, S; Moore, K L

    2015-06-15

    Purpose: To demonstrate a knowledge-based 3D dose prediction methodology that can accurately predict achievable radiotherapy distributions. Methods: Using previously treated plans as input, an artificial neural network (ANN) was trained to predict 3D dose distributions based on 14 patient-specific anatomical parameters including the distance (r) to planning target volume (PTV) boundary, organ-at-risk (OAR) boundary distances, and angular position ( θ,φ). 23 prostate and 49 stereotactic radiosurgery (SRS) cases with ≥1 nearby OARs were studied. All were planned with volumetric-modulated arc therapy (VMAT) to prescription doses of 81Gy for prostate and 12–30Gy for SRS. Site-specific ANNs were trained using all prostate 23 plans and using a 24 randomly-selected subset for the SRS model. The remaining 25 SRS plans were used to validate the model. To quantify predictive accuracy, the dose difference between the clinical plan and prediction were calculated on a voxel-by-voxel basis δD(r,θ,φ)=Dclin(r,θ,φ)-Dpred(r, θ,φ). Grouping voxels by boundary distance, the mean <δ Dr>=(1/N)Σ -θ,φ D(r,θ,φ) and inter-quartile range (IQR) quantified the accuracy of this method for deriving DVH estimations. The standard deviation (σ) of δ D quantified the 3D dose prediction error on a voxel-by-voxel basis. Results: The ANNs were highly accurate in predictive ability for both prostate and SRS plans. For prostate, <δDr> ranged from −0.8% to +0.6% (max IQR=3.8%) over r=0–32mm, while 3D dose prediction accuracy averaged from σ=5–8% across the same range. For SRS, from r=0–34mm the training set <δDr> ranged from −3.7% to +1.5% (max IQR=4.4%) while the validation set <δDr> ranged from −2.2% to +5.8% (max IQR=5.3%). 3D dose prediction accuracy averaged σ=2.5% for the training set and σ=4.0% over the same interval. Conclusion: The study demonstrates this technique’s ability to predict achievable 3D dose distributions for VMAT SRS and prostate. Future

  14. Radiation Dose Predicts for Biochemical Control in Intermediate-Risk Prostate Cancer Patients Treated With Low-Dose-Rate Brachytherapy

    SciTech Connect

    Ho, Alice Y.; Burri, Ryan J.; Cesaretti, Jamie A.; Stone, Nelson N.; Stock, Richard G.

    2009-09-01

    Purpose: To evaluate the influence of patient- and treatment-related factors on freedom from biochemical failure (FFbF) in patients with intermediate-risk prostate cancer. Methods and Materials: From a prospectively collected database of 2250 men treated at Mount Sinai Hospital from 1990 to 2004 with low-dose-rate brachytherapy for prostate cancer, 558 men with either one or more intermediate-risk features (prostate-specific antigen [PSA] level 10-20 ng/mL, Gleason score 7, or Stage T2b) were identified who had a minimum follow-up of 24 months and postimplant CT-based dosimetric analysis. Biologically effective dose (BED) values were calculated to compare doses from different isotopes and treatment regimens. Patients were treated with brachytherapy with or without hormone therapy and/or external-beam radiotherapy. Patient- and treatment-related factors were analyzed with respect to FFbF. The median follow-up was 60 months (range, 24-167 months). Biochemical failure was defined according to the Phoenix definition. Univariate analyses were used to determine whether any variable was predictive of FFbF. A two-sided p value of <0.05 was considered significant. Results: Overall, the actuarial FFbF at 10 years was 86%. Dose (BED <150 Gy{sub 2} vs. {>=}150 Gy{sub 2}) was the only significant predictor of FFbF (p < 0.001). None of the other variables (PSA, external-beam radiotherapy, Gleason score, treatment type, hormones, stage, and number of risk factors) was found to be a statistically significant predictor of 10-year FFbF. Conclusions: Radiation dose is an important predictor of FFbF in intermediate-risk prostate cancer. Treatment should continue to be individualized according to presenting disease characteristics until results from Radiation Therapy Oncology Group trial 0232 become available.

  15. Prediction of multidimensional drug dose responses based on measurements of drug pairs

    PubMed Central

    Zimmer, Anat; Katzir, Itay; Dekel, Erez; Alon, Uri

    2016-01-01

    Finding potent multidrug combinations against cancer and infections is a pressing therapeutic challenge; however, screening all combinations is difficult because the number of experiments grows exponentially with the number of drugs and doses. To address this, we present a mathematical model that predicts the effects of three or more antibiotics or anticancer drugs at all doses based only on measurements of drug pairs at a few doses, without need for mechanistic information. The model provides accurate predictions on available data for antibiotic combinations, and on experiments presented here on the response matrix of three cancer drugs at eight doses per drug. This approach offers a way to search for effective multidrug combinations using a small number of experiments. PMID:27562164

  16. Prediction of multidimensional drug dose responses based on measurements of drug pairs.

    PubMed

    Zimmer, Anat; Katzir, Itay; Dekel, Erez; Mayo, Avraham E; Alon, Uri

    2016-09-13

    Finding potent multidrug combinations against cancer and infections is a pressing therapeutic challenge; however, screening all combinations is difficult because the number of experiments grows exponentially with the number of drugs and doses. To address this, we present a mathematical model that predicts the effects of three or more antibiotics or anticancer drugs at all doses based only on measurements of drug pairs at a few doses, without need for mechanistic information. The model provides accurate predictions on available data for antibiotic combinations, and on experiments presented here on the response matrix of three cancer drugs at eight doses per drug. This approach offers a way to search for effective multidrug combinations using a small number of experiments.

  17. Estimation of Maximum Recommended Therapeutic Dose Using Predicted Promiscuity and Potency

    PubMed Central

    Liu, T; Oprea, T; Ursu, O; Hasselgren, C

    2016-01-01

    We report a simple model that predicts the maximum recommended therapeutic dose (MRTD) of small molecule drugs based on an assessment of likely protein–drug interactions. Previously, we reported methods for computational estimation of drug promiscuity and potency. We used these concepts to build a linear model derived from 238 small molecular drugs to predict MRTD. We applied this model successfully to predict MRTDs for 16 nonsteroidal antiinflammatory drugs (NSAIDs) and 14 antiretroviral drugs. Of note, based on the estimated promiscuity of low‐dose drugs (and active chemicals), we identified 83 proteins as “high‐risk off‐targets” (HROTs) that are often associated with low doses; the evaluation of interactions with HROTs may be useful during early phases of drug discovery. Our model helps explain the MRTD for drugs with severe adverse reactions caused by interactions with HROTs. PMID:27736015

  18. Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy

    PubMed Central

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Yagi, Masashi; Ogawa, Kazuhiko

    2015-01-01

    Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal. PMID:25742866

  19. A review of a priori regression models for warfarin maintenance dose prediction.

    PubMed

    Francis, Ben; Lane, Steven; Pirmohamed, Munir; Jorgensen, Andrea

    2014-01-01

    A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed.

  20. Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy.

    PubMed

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Yagi, Masashi; Ogawa, Kazuhiko

    2015-05-01

    Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal.

  1. Improving the Accuracy of a Heliocentric Potential (HCP) Prediction Model for the Aviation Radiation Dose

    NASA Astrophysics Data System (ADS)

    Hwang, Junga; Yoon, Kyoung-Won; Jo, Gyeongbok; Noh, Sung-Jun

    2016-12-01

    The space radiation dose over air routes including polar routes should be carefully considered, especially when space weather shows sudden disturbances such as coronal mass ejections (CMEs), flares, and accompanying solar energetic particle events. We recently established a heliocentric potential (HCP) prediction model for real-time operation of the CARI-6 and CARI-6M programs. Specifically, the HCP value is used as a critical input value in the CARI-6/6M programs, which estimate the aviation route dose based on the effective dose rate. The CARI-6/6M approach is the most widely used technique, and the programs can be obtained from the U.S. Federal Aviation Administration (FAA). However, HCP values are given at a one month delay on the FAA official webpage, which makes it difficult to obtain real-time information on the aviation route dose. In order to overcome this critical limitation regarding the time delay for space weather customers, we developed a HCP prediction model based on sunspot number variations (Hwang et al. 2015). In this paper, we focus on improvements to our HCP prediction model and update it with neutron monitoring data. We found that the most accurate method to derive the HCP value involves (1) real-time daily sunspot assessments, (2) predictions of the daily HCP by our prediction algorithm, and (3) calculations of the resultant daily effective dose rate. Additionally, we also derived the HCP prediction algorithm in this paper by using ground neutron counts. With the compensation stemming from the use of ground neutron count data, the newly developed HCP prediction model was improved.

  2. MO-G-304-02: Knowledge Based DVH Prediction Using a Geometric Dose Transform

    SciTech Connect

    Staub, D; Wang, J; Jiang, S

    2015-06-15

    Purpose: To demonstrate a novel method for predicting patient dose-volume histograms (DVHs) using a prior database of optimized radiotherapy treatment plans. Such predicted DVHs could be useful for automating treatment planning. Methods: Our initial demonstration utilized a database of 100 prostate intensity-modulated radiotherapy (IMRT) data-sets. Each data-set contained a CT image with contours of the planning target volume (PTV), rectum, and bladder, the parameters of a clinically approved IMRT plan, and a corresponding simulated dose distribution. We applied a novel geometric transformation to remove the influence of the PTV size, shape, and location on the dose distribution. We termed the transformed distribution the geometrically normalized dose distribution (GNDD). This normalization transform was applied to 80 data-sets randomly selected from the database, and a population GNDD was computed as the average. Next, the population GNDD was mapped onto each of the remaining 20 patient datasets using the reverse of the geometric normalization transform, and predicted DVHs were calculated from the reverse transformed dose distributions (GNDD-DVHs). In addition, a state of the art machine learning based method from the literature was tested for comparison. Results: DVH prediction accuracy was quantified by calculating the relative root mean squared error (rRMSE) on predicted DVHs for the 20 test patients using their known DVHs. For bladder, rectum, and PTV average rRMSEs for the GNDD method were 9.7 ± 4.2%, 13.9 ± 6.0%, and 2.3 ± 0.5% respectively. Prediction results using GNDD were roughly equivalent to that from the machine learning method. Conclusion: We developed a new method for predicting DVH curves from a database of prior patient plans. We demonstrated that our simple approach achieves accuracy comparable to a method using a complicated machine learning based approach.

  3. Cellular response of the rat brain to single doses of (137)Cs γ rays does not predict its response to prolonged 'biologically equivalent' fractionated doses.

    PubMed

    Greene-Schloesser, Dana M; Kooshki, Mitra; Payne, Valerie; D'Agostino, Ralph B; Wheeler, Kenneth T; Metheny-Barlow, Linda J; Robbins, Mike E

    2014-09-01

    To determine if the brain's response to single doses predicts its response to 'biologically equivalent' fractionated doses. Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of (137)Cs γ rays or their 'biologically equivalent' 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 μm sections of the dentate gyrus (DG). Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). These data demonstrate that the rat brain's cellular response to single doses often does not predict its cellular response to 'biologically equivalent' fWBI doses.

  4. Cytokinesis-block micronucleus assay by manual and automated scoring: calibration curves and dose prediction.

    PubMed

    De Sanctis, S; De Amicis, A; Di Cristofaro, S; Franchini, V; Regalbuto, E; Mammana, G; Lista, F

    2014-06-01

    The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is one of the best standardized and validated techniques for individual radiation dose assessment. This method has been proposed as an alternative to the dicentric chromosome assay, which is considered the "gold standard" in biological dosimetry because it requires less time and cytogenetic expertise. Nevertheless, for application as a biodosimetry tool in large-scale nuclear or radiological accidents, the manually performed cytokinesis-block micronucleus assay needs further strategies (e.g., the automation of micronucleus scoring) to speed up the analysis. An essential prerequisite for radiation dose assessment is to establish a dose-effect curve. In this study, blood samples of one healthy subject were irradiated with seven increasing doses of x-ray (240 kVp, 1 Gy min⁻¹) ranging from 0.25-4.0 Gy to generate calibration curves based on manual as well as on automated scoring mode. The quality of the calibration curves was evaluated by determination of the dose prediction accuracy after the analysis of 10 blood samples from the same donor exposed to unknown radiation doses. The micronucleus frequencies in binucleated cells were scored manually as well as automatically and were used to assess the absorbed radiation doses with reference to the respective calibration curve. The accuracy of the dose assessment based on manual and automatic scoring mode was compared.

  5. Predicting astronaut radiation doses from major solar particle events using artificial intelligence

    NASA Astrophysics Data System (ADS)

    Tehrani, Nazila H.

    1998-06-01

    Space radiation is an important issue for manned space flight. For long missions outside of the Earth's magnetosphere, there are two major sources of exposure. Large Solar Particle Events (SPEs) consisting of numerous energetic protons and other heavy ions emitted by the Sun, and the Galactic Cosmic Rays (GCRs) that constitute an isotropic radiation field of low flux and high energy. In deep-space missions both SPEs and GCRs can be hazardous to the space crew. SPEs can provide an acute dose, which is a large dose over a short period of time. The acute doses from a large SPE that could be received by an astronaut with shielding as thick as a spacesuit maybe as large as 500 cGy. GCRs will not provide acute doses, but may increase the lifetime risk of cancer from prolonged exposures in a range of 40-50 cSv/yr. In this research, we are using artificial intelligence to model the dose-time profiles during a major solar particle event. Artificial neural networks are reliable approximators for nonlinear functions. In this study we design a dynamic network. This network has the ability to update its dose predictions as new input dose data is received while the event is occurring. To accomplish this temporal behavior of the system we use an innovative Sliding Time-Delay Neural Network (STDNN). By using a STDNN one can predict doses received from large SPEs while the event is happening. The parametric fits and actual calculated doses for the skin, eye and bone marrow are used. The parametric data set obtained by fitting the Weibull functional forms to the calculated dose points has been divided into two subsets. The STDNN has been trained using some of these parametric events. The other subset of parametric data and the actual doses are used for testing with the resulting weights and biases of the first set. This is done to show that the network can generalize. Results of this testing indicate that the STDNN is capable of predicting doses from events that it has not seen

  6. Predicting standard-dose PET image from low-dose PET and multimodal MR images using mapping-based sparse representation

    NASA Astrophysics Data System (ADS)

    Wang, Yan; Zhang, Pei; An, Le; Ma, Guangkai; Kang, Jiayin; Shi, Feng; Wu, Xi; Zhou, Jiliu; Lalush, David S.; Lin, Weili; Shen, Dinggang

    2016-01-01

    Positron emission tomography (PET) has been widely used in clinical diagnosis for diseases and disorders. To obtain high-quality PET images requires a standard-dose radionuclide (tracer) injection into the human body, which inevitably increases risk of radiation exposure. One possible solution to this problem is to predict the standard-dose PET image from its low-dose counterpart and its corresponding multimodal magnetic resonance (MR) images. Inspired by the success of patch-based sparse representation (SR) in super-resolution image reconstruction, we propose a mapping-based SR (m-SR) framework for standard-dose PET image prediction. Compared with the conventional patch-based SR, our method uses a mapping strategy to ensure that the sparse coefficients, estimated from the multimodal MR images and low-dose PET image, can be applied directly to the prediction of standard-dose PET image. As the mapping between multimodal MR images (or low-dose PET image) and standard-dose PET images can be particularly complex, one step of mapping is often insufficient. To this end, an incremental refinement framework is therefore proposed. Specifically, the predicted standard-dose PET image is further mapped to the target standard-dose PET image, and then the SR is performed again to predict a new standard-dose PET image. This procedure can be repeated for prediction refinement of the iterations. Also, a patch selection based dictionary construction method is further used to speed up the prediction process. The proposed method is validated on a human brain dataset. The experimental results show that our method can outperform benchmark methods in both qualitative and quantitative measures.

  7. Prediction of standard-dose brain PET image by using MRI and low-dose brain [{sup 18}F]FDG PET images

    SciTech Connect

    Kang, Jiayin; Gao, Yaozong; Shi, Feng; Lalush, David S.; Lin, Weili; Shen, Dinggang

    2015-09-15

    Purpose: Positron emission tomography (PET) is a nuclear medical imaging technology that produces 3D images reflecting tissue metabolic activity in human body. PET has been widely used in various clinical applications, such as in diagnosis of brain disorders. High-quality PET images play an essential role in diagnosing brain diseases/disorders. In practice, in order to obtain high-quality PET images, a standard-dose radionuclide (tracer) needs to be used and injected into a living body. As a result, it will inevitably increase the patient’s exposure to radiation. One solution to solve this problem is predicting standard-dose PET images using low-dose PET images. As yet, no previous studies with this approach have been reported. Accordingly, in this paper, the authors propose a regression forest based framework for predicting a standard-dose brain [{sup 18}F]FDG PET image by using a low-dose brain [{sup 18}F]FDG PET image and its corresponding magnetic resonance imaging (MRI) image. Methods: The authors employ a regression forest for predicting the standard-dose brain [{sup 18}F]FDG PET image by low-dose brain [{sup 18}F]FDG PET and MRI images. Specifically, the proposed method consists of two main steps. First, based on the segmented brain tissues (i.e., cerebrospinal fluid, gray matter, and white matter) in the MRI image, the authors extract features for each patch in the brain image from both low-dose PET and MRI images to build tissue-specific models that can be used to initially predict standard-dose brain [{sup 18}F]FDG PET images. Second, an iterative refinement strategy, via estimating the predicted image difference, is used to further improve the prediction accuracy. Results: The authors evaluated their algorithm on a brain dataset, consisting of 11 subjects with MRI, low-dose PET, and standard-dose PET images, using leave-one-out cross-validations. The proposed algorithm gives promising results with well-estimated standard-dose brain [{sup 18}F]FDG PET

  8. Using dose-surface maps to predict radiation-induced rectal bleeding: a neural network approach

    NASA Astrophysics Data System (ADS)

    Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Partridge, Mike

    2009-09-01

    The incidence of late-toxicities after radiotherapy can be modelled based on the dose delivered to the organ under consideration. Most predictive models reduce the dose distribution to a set of dose-volume parameters and do not take the spatial distribution of the dose into account. The aim of this study was to develop a classifier predicting radiation-induced rectal bleeding using all available information on the dose to the rectal wall. The dose was projected on a two-dimensional dose-surface map (DSM) by virtual rectum-unfolding. These DSMs were used as inputs for a classification method based on locally connected neural networks. In contrast to fully connected conventional neural nets, locally connected nets take the topology of the input into account. In order to train the nets, data from 329 patients from the RT01 trial (ISRCTN 47772397) were split into ten roughly equal parts. By using nine of these parts as a training set and the remaining part as an independent test set, a ten-fold cross-validation was performed. Ensemble learning was used and 250 nets were built from randomly selected patients from the training set. Out of these 250 nets, an ensemble of expert nets was chosen. The performances of the full ensemble and of the expert ensemble were quantified by using receiver-operator-characteristic (ROC) curves. In order to quantify the predictive power of the shape, ensembles of fully connected conventional neural nets based on dose-surface histograms (DSHs) were generated and their performances were quantified. The expert ensembles performed better than or equally as well as the full ensembles. The area under the ROC curve for the DSM-based expert ensemble was 0.64. The area under the ROC curve for the DSH-based expert ensemble equalled 0.59. This difference in performance indicates that not only volumetric, but also morphological aspects of the dose distribution are correlated to rectal bleeding after radiotherapy. Thus, the shape of the dose

  9. Tumor-Absorbed Dose Predicts Progression-Free Survival Following 131I-Tositumomab Radioimmunotherapy

    PubMed Central

    Dewaraja, Yuni K.; Schipper, Matthew J.; Shen, Jincheng; Smith, Lauren B.; Murgic, Jure; Savas, Hatice; Youssef, Ehab; Regan, Denise; Wilderman, Scott J.; Roberson, Peter L.; Kaminski, Mark S.; Avram, Anca M.

    2014-01-01

    The study aimed at identifying patient-specific dosimetric and nondosimetric factors predicting outcome of non-Hodgkin lymphoma patients after 131I-tositumomab radioimmunotherapy for potential use in treatment planning. Methods Tumor-absorbed dose measures were estimated for 130 tumors in 39 relapsed or refractory non-Hodgkin lymphoma patients by coupling SPECT/CT imaging with the Dose Planning Method (DPM) Monte Carlo code. Equivalent biologic effect was calculated to assess the biologic effects of nonuniform absorbed dose including the effects of the unlabeled antibody. Evaluated nondosimetric covariates included histology, presence of bulky disease, and prior treatment history. Tumor level outcome was based on volume shrinkage assessed on follow-up CT. Patient level outcome measures were overall response (OR), complete response (CR), and progression-free survival (PFS), determined from clinical assessments that included PET/CT. Results The estimated mean tumor-absorbed dose had a median value of 275 cGy (range, 94–711 cGy). A high correlation was observed between tracer-predicted and therapy-delivered mean tumor-absorbed doses (P < 0.001; r = 0.85). In univariate tumor-level analysis, tumor shrinkage correlated significantly with almost all of the evaluated dosimetric factors, including equivalent biologic effect. Regression analysis showed that OR, CR, and PFS were associated with the dosimetric factors and equivalent biologic effect. Both mean tumor-absorbed dose (P = 0.025) and equivalent biologic effect (P = 0.035) were significant predictors of PFS whereas none of the nondosimetric covariates were found to be statistically significant factors affecting PFS. The most important finding of the study was that in Kaplan–Meier curves stratified by mean dose, longer PFS was observed in patients receiving mean tumor-absorbed doses greater than 200 cGy than in those receiving 200 cGy or less (median PFS, 13.6 vs. 1.9 mo for the 2 dose groups; log-rank P < 0

  10. Comparison of Risk Predicted by Multiple Norovirus Dose-Response Models and Implications for Quantitative Microbial Risk Assessment.

    PubMed

    Van Abel, Nicole; Schoen, Mary E; Kissel, John C; Meschke, J Scott

    2016-06-10

    The application of quantitative microbial risk assessments (QMRAs) to understand and mitigate risks associated with norovirus is increasingly common as there is a high frequency of outbreaks worldwide. A key component of QMRA is the dose-response analysis, which is the mathematical characterization of the association between dose and outcome. For Norovirus, multiple dose-response models are available that assume either a disaggregated or an aggregated intake dose. This work reviewed the dose-response models currently used in QMRA, and compared predicted risks from waterborne exposures (recreational and drinking) using all available dose-response models. The results found that the majority of published QMRAs of norovirus use the 1 F1 hypergeometric dose-response model with α = 0.04, β = 0.055. This dose-response model predicted relatively high risk estimates compared to other dose-response models for doses in the range of 1-1,000 genomic equivalent copies. The difference in predicted risk among dose-response models was largest for small doses, which has implications for drinking water QMRAs where the concentration of norovirus is low. Based on the review, a set of best practices was proposed to encourage the careful consideration and reporting of important assumptions in the selection and use of dose-response models in QMRA of norovirus. Finally, in the absence of one best norovirus dose-response model, multiple models should be used to provide a range of predicted outcomes for probability of infection.

  11. Prediction of in-phantom dose distribution using in-air neutron beam characteristics for BNCS

    SciTech Connect

    Verbeke, Jerome M.

    1999-12-14

    A monoenergetic neutron beam simulation study is carried out to determine the optimal neutron energy range for treatment of rheumatoid arthritis using radiation synovectomy. The goal of the treatment is the ablation of diseased synovial membranes in joints, such as knees and fingers. This study focuses on human knee joints. Two figures-of-merit are used to measure the neutron beam quality, the ratio of the synovium absorbed dose to the skin absorbed dose, and the ratio of the synovium absorbed dose to the bone absorbed dose. It was found that (a) thermal neutron beams are optimal for treatment, (b) similar absorbed dose rates and therapeutic ratios are obtained with monodirectional and isotropic neutron beams. Computation of the dose distribution in a human knee requires the simulation of particle transport from the neutron source to the knee phantom through the moderator. A method was developed to predict the dose distribution in a knee phantom from any neutron and photon beam spectra incident on the knee. This method was revealed to be reasonably accurate and enabled one to reduce by a factor of 10 the particle transport simulation time by modeling the moderator only.

  12. Adalimumab Dose Tapering in Psoriasis: Predictive Factors for Maintenance of Complete Clearance.

    PubMed

    Hansel, Katharina; Bianchi, Leonardo; Lanza, Francesco; Bini, Vittorio; Stingeni, Luca

    2017-03-10

    Psoriasis can be managed successfully with long-term biologics. Real-life clinical practice may require dose tapering as a therapeutic option to reduce the risk of drug-exposure and to increase cost-effectiveness. The responsiveness to extended intervals between adalimumab doses and the possible predictive factors of maintenance of complete clearance were studied in a retrospective 7-year single-centre analysis. Thirty patients who achieved complete clearance with adalimumab underwent dose tapering, progressively extending between-dose intervals (to 21-28 days). Sixty percent of subjects (group A) maintained complete clearance, whereas 40.0% (group B) relapsed and were switched back to the standard dosage to re-achieve complete clearance. Body mass index (BMI) and time to achieve Psoriasis Area Severity Index (PASI-100) with adalimumab standard treatment before dose tapering were significantly lower in group A than in group B (multi-variate Cox regression: p < 0.05, Kaplan-Meier analysis: p < 0.001, respectively). This study suggests that patients with lower BMI and shorter time to achieve PASI-100 with adalimumab standard dose were significantly more likely to be candidates for dose tapering.

  13. Per-beam, planar IMRT QA passing rates do not predict clinically relevant patient dose errors

    SciTech Connect

    Nelms, Benjamin E.; Zhen Heming; Tome, Wolfgang A.

    2011-02-15

    Purpose: The purpose of this work is to determine the statistical correlation between per-beam, planar IMRT QA passing rates and several clinically relevant, anatomy-based dose errors for per-patient IMRT QA. The intent is to assess the predictive power of a common conventional IMRT QA performance metric, the Gamma passing rate per beam. Methods: Ninety-six unique data sets were created by inducing four types of dose errors in 24 clinical head and neck IMRT plans, each planned with 6 MV Varian 120-leaf MLC linear accelerators using a commercial treatment planning system and step-and-shoot delivery. The error-free beams/plans were used as ''simulated measurements'' (for generating the IMRT QA dose planes and the anatomy dose metrics) to compare to the corresponding data calculated by the error-induced plans. The degree of the induced errors was tuned to mimic IMRT QA passing rates that are commonly achieved using conventional methods. Results: Analysis of clinical metrics (parotid mean doses, spinal cord max and D1cc, CTV D95, and larynx mean) vs IMRT QA Gamma analysis (3%/3 mm, 2/2, 1/1) showed that in all cases, there were only weak to moderate correlations (range of Pearson's r-values: -0.295 to 0.653). Moreover, the moderate correlations actually had positive Pearson's r-values (i.e., clinically relevant metric differences increased with increasing IMRT QA passing rate), indicating that some of the largest anatomy-based dose differences occurred in the cases of high IMRT QA passing rates, which may be called ''false negatives.'' The results also show numerous instances of false positives or cases where low IMRT QA passing rates do not imply large errors in anatomy dose metrics. In none of the cases was there correlation consistent with high predictive power of planar IMRT passing rates, i.e., in none of the cases did high IMRT QA Gamma passing rates predict low errors in anatomy dose metrics or vice versa. Conclusions: There is a lack of correlation between

  14. Clinical implementation of dose-volume histogram predictions for organs-at-risk in IMRT planning

    NASA Astrophysics Data System (ADS)

    Moore, K. L.; Appenzoller, L. M.; Tan, J.; Michalski, J. M.; Thorstad, W. L.; Mutic, S.

    2014-03-01

    True quality control (QC) of the planning process requires quantitative assessments of treatment plan quality itself, and QC in IMRT has been stymied by intra-patient anatomical variability and inherently complex three-dimensional dose distributions. In this work we describe the development of an automated system to reduce clinical IMRT planning variability and improve plan quality using mathematical models that predict achievable OAR DVHs based on individual patient anatomy. These models rely on the correlation of expected dose to the minimum distance from a voxel to the PTV surface, whereby a three-parameter probability distribution function (PDF) was used to model iso-distance OAR subvolume dose distributions. DVH models were obtained by fitting the evolution of the PDF with distance. Initial validation on clinical cohorts of 40 prostate and 24 head-and-neck plans demonstrated highly accurate model-based predictions for achievable DVHs in rectum, bladder, and parotid glands. By quantifying the integrated difference between candidate DVHs and predicted DVHs, the models correctly identified plans with under-spared OARs, validated by replanning all cases and correlating any realized improvements against the predicted gains. Clinical implementation of these predictive models was demonstrated in the PINNACLE treatment planning system by use of existing margin expansion utilities and the scripting functionality inherent to the system. To maintain independence from specific planning software, a system was developed in MATLAB to directly process DICOM-RT data. Both model training and patient-specific analyses were demonstrated with significant computational accelerations from parallelization.

  15. A portal dosimetry dose prediction method based on collapsed cone algorithm using the clinical beam model.

    PubMed

    Martínez Ortega, J; Gómez González, N; Castro Tejero, P; Pinto Monedero, M; Tolani, N B; Núñez Martín, L; Sánchez Montero, R

    2017-01-01

    Amorphous silicon electronical portal imaging devices (EPIDs) are widely used for dosimetric measurements in Radiation Therapy. The purpose of this work was to determine if a portal dose prediction method can be utilized for dose map calculations based on the linear accelerator model within a commercial treatment planning system (Pinnacle(3) v8.0 m). The method was developed for a 6 MV photon beam on the Varian Clinac 21-EX, at a nominal dose rate of 400 MU/min. The Varian aS1000 EPID was unmounted from the linear accelerator and scanned to acquire CT images of the EPID. The CT images were imported into Pinnacle(3) and were used as a quality assurance phantom to calculate dose on the EPID setup at a source to detector distance of 105 cm. The best match of the dose distributions was obtained considering the image plane located at 106 cm from the source to detector plane. The EPID was calibrated according to the manufacturer procedure and corrections were made for output factors. Arm-backscattering effect, based on profile correction curves, has been introduced. Five low-modulated and three high-modulated clinical planned treatments were predicted and measured with the method presented here and with MatriXX (IBA Dosimetry, Schwarzenbruck, Germany). A portal dose prediction method based on Pinnacle(3) was developed without modifying the commissioned parameters of the model in use in the clinic. CT images of the EPID were acquired and used as a quality assurance phantom. The CT images indicated a mean density of 1.16 g/cm(3) for the sensitive area of the EPID. Output factor measured with the EPID were lower for small fields and larger for larger fields (beyond 10 × 10 cm(2) ). Arm-backscatter correction showed a better agreement at the target side of the EPID. Analysis of Gamma index comparison (3%, 3 mm) indicated a minimum of 97.4% pass rate for low modulated and 98.3% for high modulated treatments. Pass rates were similar for MatriXX measurements. The

  16. A predictive equation to guide vitamin D replacement dose in patients.

    PubMed

    Singh, Gurmukh; Bonham, Aaron J

    2014-01-01

    Vitamin D is essential for bone health and probably the health of most nonskeletal tissues. Vitamin D deficiency is widespread, and recommended doses are usually inadequate to maintain healthy levels. We conducted a retrospective observational study to determine whether the recommended doses of vitamin D are adequate to correct deficiency and maintain normal levels in a population seeking health care. We also sought to develop a predictive equation for replacement doses of vitamin D. We reviewed the response to vitamin D supplementation in 1327 patients and 3885 episodes of vitamin D replacement and attempted to discern factors affecting the response to vitamin D replacement by conducting multiple regression analyses. For the whole population, average daily dose resulting in any increase in serum 25-hydroxyvitamin D level was 4707 IU/day; corresponding values for ambulatory and nursing home patients were 4229 and 6103 IU/day, respectively. Significant factors affecting the change in serum concentrations of 25-hydroxyvitamin D, in addition to the dose administered, are (1) starting serum concentration of 25-hydroxyvitamin D, (2) body mass index (BMI), (3) age, and (f) serum albumin concentration. The following equation predicts the dose of vitamin D needed (in international units per day) to affect a given change in serum concentrations of 25-hydroxyvitamin D: Dose = [(8.52 - Desired change in serum 25-hydroxyvitamin D level) + (0.074 × Age) - (0.20 × BMI) + (1.74 × Albumin concentration) - (0.62 × Starting serum 25-hydroxyvitamin D concentration)]/(-0.002). Analysis of the dose responses among 3 racial groups-white, black, and others-did not reveal clinically meaningful differences between the races. The main limitation of the study is its retrospective observational nature; however, that is also its strength in that we assessed the circumstances seen in usual health care setting. The recommended daily allowance for vitamin D is grossly inadequate for

  17. Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs.

    PubMed

    McGinnity, D F; Collington, J; Austin, R P; Riley, R J

    2007-06-01

    In this article approaches to predict human pharmacokinetics (PK) are discussed and the capability of the exemplified methodologies to estimate individual PK parameters and therapeutic dose for a set of marketed oral drugs has been assessed. For a set of 63 drugs where the minimum efficacious concentration (MEC) and human PK were known, the clinical dose was shown to be well predicted or in some cases over-estimated using a simple one-compartment oral PK model. For a subset of these drugs, in vitro potency against the primary human targets was gathered, and compared to the observed MEC. When corrected for plasma protein binding, the MEC of the majority of compounds was < or=3 fold over the respective in vitro target potency value. A series of in vitro and in vivo experiments were conducted to predict the human PK parameters. Metabolic clearance was generally predicted well from human hepatocytes. Interestingly, for this compound set, allometry or glomerular filtration rate (GFR) ratio methods appeared to be applicable for renal CL even where CL(renal) > GFR. For approximately 90% of compounds studied, the predicted CL using in vitro-in vivo (IVIV) extrapolation together with a CL(renal) estimate, where appropriate, was within 2-fold of that observed clinically. Encouragingly volume of distribution at steady state (V(ss)) estimated in preclinical species (rat and dog) when corrected for plasma protein binding, predicted human V(ss) successfully on the majority of occasions--73% of compounds within 2-fold. In this laboratory, absorption estimated from oral rat PK studies was lower than the observed human absorption for most drugs, even when solubility and permeability appeared not to be limiting. Preliminary data indicate absorption in the dog may be more representative of human for compounds absorbed via the transcellular pathway. Using predicted PK and MEC values estimated from in vitro potency assays there was a good correlation between predicted and observed dose

  18. Effects of dose reduction on bone strength prediction using finite element analysis

    NASA Astrophysics Data System (ADS)

    Anitha, D.; Subburaj, Karupppasamy; Mei, Kai; Kopp, Felix K.; Foehr, Peter; Noel, Peter B.; Kirschke, Jan S.; Baum, Thomas

    2016-12-01

    This study aimed to evaluate the effect of dose reduction, by means of tube exposure reduction, on bone strength prediction from finite-element (FE) analysis. Fresh thoracic mid-vertebrae specimens (n = 11) were imaged, using multi-detector computed tomography (MDCT), at different intensities of X-ray tube exposures (80, 150, 220 and 500 mAs). Bone mineral density (BMD) was estimated from the mid-slice of each specimen from MDCT images. Differences in image quality and geometry of each specimen were measured. FE analysis was performed on all specimens to predict fracture load. Paired t-tests were used to compare the results obtained, using the highest CT dose (500 mAs) as reference. Dose reduction had no significant impact on FE-predicted fracture loads, with significant correlations obtained with reference to 500 mAs, for 80 mAs (R2  = 0.997, p < 0.001), 150 mAs (R2 = 0.998, p < 0.001) and 220 mAs (R2 = 0.987, p < 0.001). There were no significant differences in volume quantification between the different doses examined. CT imaging radiation dose could be reduced substantially to 64% with no impact on strength estimates obtained from FE analysis. Reduced CT dose will enable early diagnosis and advanced monitoring of osteoporosis and associated fracture risk.

  19. Effects of dose reduction on bone strength prediction using finite element analysis

    PubMed Central

    Anitha, D.; Subburaj, Karupppasamy; Mei, Kai; Kopp, Felix K.; Foehr, Peter; Noel, Peter B.; Kirschke, Jan S.; Baum, Thomas

    2016-01-01

    This study aimed to evaluate the effect of dose reduction, by means of tube exposure reduction, on bone strength prediction from finite-element (FE) analysis. Fresh thoracic mid-vertebrae specimens (n = 11) were imaged, using multi-detector computed tomography (MDCT), at different intensities of X-ray tube exposures (80, 150, 220 and 500 mAs). Bone mineral density (BMD) was estimated from the mid-slice of each specimen from MDCT images. Differences in image quality and geometry of each specimen were measured. FE analysis was performed on all specimens to predict fracture load. Paired t-tests were used to compare the results obtained, using the highest CT dose (500 mAs) as reference. Dose reduction had no significant impact on FE-predicted fracture loads, with significant correlations obtained with reference to 500 mAs, for 80 mAs (R2  = 0.997, p < 0.001), 150 mAs (R2 = 0.998, p < 0.001) and 220 mAs (R2 = 0.987, p < 0.001). There were no significant differences in volume quantification between the different doses examined. CT imaging radiation dose could be reduced substantially to 64% with no impact on strength estimates obtained from FE analysis. Reduced CT dose will enable early diagnosis and advanced monitoring of osteoporosis and associated fracture risk. PMID:27934902

  20. Early prediction for the requirement of second or third dose methotrexate in women with ectopic pregnancy, treated with single-dose regimen.

    PubMed

    Yıldırım, Aysegul; Cırık, Derya Akdağ; Altay, Metin; Gelisen, Orhan

    2015-06-01

    To investigate the predictive factors for the requirement of additional doses of methotrexate in women with ectopic pregnancy treated with single-dose methotrexate regimen. This retrospective cohort study was conducted on women treated with single-dose methotrexate regimen for ectopic pregnancy at a tertiary referral center. Control group included the patients who were treated only with a single dose of methotrexate (n = 131) and study group included the patients who need a second dose or third dose methotrexate (n = 76). The sonographic variables such as size of the ectopic mass, the endometrial thickness and biochemical variables were analyzed via Chi square and student t test. Logistic regression analysis used to determine independent predictors of the additional dose requirement. The size of the ectopic mass and the endometrial thickness were similar in both groups. However, all human chorionic gonadotropin values on day 1, 4 and 7 were significantly higher in study group than the control group (p = 0.0001). Logistic regression analysis revealed that the human chorionic gonadotropin changes between day 1 and 4 is a predictive factor for requirement of additional doses of methotrexate (area under curve: 0.763, p < 0.001) and the cutoff value for human chorionic gonadotropin change was calculated as 22%. The probability of the requirement for an additional dose of methotrexate is 6.45 times more in patients who had less than 22% reduction in human chorionic gonadotropin levels from day 1 to 4 compared to those who had >22% reduction from day 1 to 4. Less than 22% reduction in human chorionic gonadotropin levels from day 1 to 4 can be used as a predictive factor for the requirement of an additional dose of methotrexate in single-dose regimen. This cutoff value can be used for patients to inform about the probable longer resolution time and refer to alternative treatment modalities such as two-dose, multiple-dose regimens or surgery.

  1. Prediction analysis of dose equivalent responses of neutron dosemeters used at a MOX fuel facility.

    PubMed

    Tsujimura, N; Yoshida, T; Takada, C

    2011-07-01

    To predict how accurately neutron dosemeters can measure the neutron dose equivalent (rate) in MOX fuel fabrication facility work environments, the dose equivalent responses of neutron dosemeters were calculated by the spectral folding method. The dosemeters selected included two types of personal dosemeter, namely a thermoluminescent albedo neutron dosemeter and an electronic neutron dosemeter, three moderator-based neutron survey meters, and one special instrument called an H(p)(10) monitor. The calculations revealed the energy dependences of the responses expected within the entire range of neutron spectral variations observed in neutron fields at workplaces.

  2. The prediction of transmitted dose distributions using a 3D treatment planning system.

    PubMed

    Reich, P; Bezak, E; Mohammadi, M; Fog, L

    2006-03-01

    Patient dose verification is becoming increasingly important with the advent of new complex radiotherapy techniques such as conformal radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT). An electronic portal imaging device (EPID) has potential application for in vivo dosimetry. In the current work, an EPID has been modelled using a treatment planning system (TPS) to predict transmitted dose maps. A thin slab of RW3 material used to initially represent the EPID. A homogeneous RW3 phantom and the thin RW3 slab placed at a clinical distance away from the phantom were scanned using a CT simulator. The resulting CT images were transferred via DICOM to the TPS and the density of the CT data corresponding to the thin RW3 slab was changed to 1 g/cm3. Transmitted dose maps (TDMs) in the modelled EPID were calculated by the TPS using the collapsed-cone (C-C) convolution superposition (C/S) algorithm. A 6 MV beam was used in the simulation to deliver 300 MU to the homogenous phantom using an isocentric and SSD (source-to-surface) technique. The phantom thickness was varied and the calculated TDMs in the modelled EPID were compared with corresponding measurements obtained from a calibrated scanning liquid-filled ionisation chamber (SLIC) EPID. The two TDMs were compared using the gamma evaluation technique of Low et al. The predicted and measured TDMs agree to within 2 % (averaged over all phantom thicknesses) on the central beam axis. More than 90 % of points in the dose maps (excluding field edges) produce a gamma index less than or equal to 1, for dose difference (averaged over all phantom thicknesses), and distance-to-agreement criteria of 4 %, 3.8 mm, respectively. In addition, the noise level on the central axis in the predicted dose maps is less than 0.1 %. We found that phantom thickness changes of approximately 1 mm, which correspond to dose changes on the central beam axis of less than 0.6 %, can be detected in the predicted transmitted dose distributions.

  3. Evidence for under-diagnosis of childhood acute lymphoblastic leukaemia in poorer communities within Great Britain.

    PubMed

    Kroll, M E; Stiller, C A; Richards, S; Mitchell, C; Carpenter, L M

    2012-04-24

    Recorded incidence of childhood acute lymphoblastic leukaemia tends to be lower in poorer communities. A 'preemptive infection hypothesis' proposes that some children with leukaemia die from infection without diagnosis of leukaemia. Various different blood abnormalities can occur in untreated leukaemia. Logistic regression was used to compare pre-treatment blood counts among children aged 1-13 years at recruitment to national clinical trials for acute lymphoblastic leukaemia during 1980-2002 (N=5601), grouped by address at diagnosis within Great Britain into quintiles of the 1991 Carstairs deprivation index. Children combining severe neutropenia (risk of serious infection) with relatively normal haemoglobin and platelet counts (lack of pallor and bleeding) were postulated to be at risk of dying from infection without leukaemia being suspected. A deficit of these children among diagnosed patients from poorer communities was predicted. As predicted, there was a deficit of children at risk of non-diagnosis (two-sided P(trend)=0.004; N=2009), and an excess of children with pallor (P(trend)=0.045; N=5535) and bleeding (P(trend)=0.036; N=5541), among cases from poorer communities. Under-diagnosis in poorer communities may have contributed to socioeconomic variation in recorded childhood acute lymphoblastic leukaemia incidence within Great Britain, and elsewhere. Implications for clinical practice and epidemiological studies should be considered.

  4. Standard error of inverse prediction for dose-response relationship: approximate and exact statistical inference.

    PubMed

    Demidenko, Eugene; Williams, Benjamin B; Flood, Ann Barry; Swartz, Harold M

    2013-05-30

    This paper develops a new metric, the standard error of inverse prediction (SEIP), for a dose-response relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in the denominator. We develop confidence intervals and hypothesis testing for SEIP on the basis of the normal approximation and using the exact statistical inference based on the noncentral t-distribution. We derive the power functions for both approaches and test them via statistical simulations. The theoretical SEIP, as the ratio of the regression standard error to the slope, is viewed as reciprocal of the signal-to-noise ratio, a popular measure of signal processing. The SEIP, as a figure of merit for inverse prediction, can be used for comparison of calibration curves with different dependent variables and slopes. We illustrate our theory with electron paramagnetic resonance tooth dosimetry for a rapid estimation of the radiation dose received in the event of nuclear terrorism.

  5. Analytic IMRT dose calculations utilizing Monte Carlo to predict MLC fluence modulation

    PubMed Central

    Mihaylov, I. B.; Lerma, F. A.; Wu, Y.; Siebers, J. V.

    2007-01-01

    A hybrid dose-computation method is designed which accurately accounts for multileaf collimator (MLC)-induced intensity modulation in intensity modulated radiation therapy (IMRT) dose calculations. The method employs Monte Carlo (MC) modeling to determine the fluence modulation caused by the delivery of dynamic or multisegmental (step-and-shoot) MLC fields, and a conventional dose-computation algorithm to estimate the delivered dose to a phantom or a patient. Thus, it determines the IMRT fluence prediction accuracy achievable by analytic methods in the limit that the analytic method includes all details of the MLC leaf transport and scatter. The hybrid method is validated and benchmarked by comparison with in-phantom film dose measurements, as well as dose calculations from two in-house, and two commercial treatment planning system analytic fluence estimation methods. All computation methods utilize the same dose algorithm to calculate dose to a phantom, varying only in the estimation of the MLC modulation of the incident photon energy fluence. Gamma analysis, with respect to measured two-dimensional (2D) dose planes, is used to benchmark each algorithm’s performance. The analyzed fields include static and dynamic test patterns, as well as fields from ten DMLC IMRT treatment plans (79 fields) and five SMLC treatment plans (29 fields). The test fields (fully closed MLC, picket fence, sliding windows of different size, and leaf-tip profiles) cover the extremes of MLC usage during IMRT, while the patient fields represent realistic clinical conditions. Of the methods tested, the hybrid method most accurately reproduces measurements. For the hybrid method, 79 of 79 DMLC field calculations have γ ≤1 (3% /3 mm) for more than 95% of the points (per field) while for SMLC fields, 27 of 29 pass the same criteria. The analytic energy fluence estimation methods show inferior pass rates, with 76 of 79 DMLC and 24 of 29 SMLC fields having more than 95% of the test points

  6. Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.

    PubMed

    Duffull, S B; Isbister, G K

    2013-01-01

    There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose. Objective. To determine if reported dose predicts the need for N-acetylcysteine (NAC). Data were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line. There were 1571 admissions in 1303 patients, with a median age of 27 years (12-96 years) and 1140 (73%) were females. The median dose was 10 g (1-100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4-7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6-9 g, a 10% chance of requiring NAC at a dose of 13-16 g, a 50% chance of requiring NAC at a dose of 30-34 g and a 90% chance for needing NAC at 48-50 g. Reported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be

  7. Prediction of the warfarin maintenance dose after completion of the 10 mg initiation nomogram: do we really need genotyping?

    PubMed

    Le Gal, G; Carrier, M; Tierney, S; Majeed, H; Rodger, M; Wells, P S

    2010-01-01

    Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients. Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule. Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg. In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

  8. Radiation dose prediction using data on time to emesis in the case of nuclear terrorism.

    PubMed

    Demidenko, Eugene; Williams, Benjamin B; Swartz, Harold M

    2009-03-01

    A rigorous statistical analysis of the retrospective estimation of radiation dose received using time to emesis and its uncertainty is provided based on 108 observations associated with accidents with significant exposures to ionizing radiation in the period 1956-2001. The standard error, confidence interval, specificity and sensitivity, and Receiver Operating Characteristic (ROC) curve are used to characterize the uncertainty of the dose prediction. The relative error of the dose prediction using time to emesis data is about 200%. Consequently, if D is the dose assessment, the 95% confidence interval is approximately (D/4, 4D). Our assessment of the precision is applied to computation of the probabilities in triage medical management in the case of a nuclear terrorism event. We also note several factors that indicate that there are additional problems in the use of time to emesis for triage, including a lack of consideration of individuals that do not vomit, differences between the conditions under which the data were obtained and the conditions under which they are likely to be used, and the potential for the incidence of vomiting to be altered by factors unrelated to radiation exposure such as psychogenic factors and the use of emetic agents. In summary, while time to emesis is a rapid and inexpensive method for estimating the radiation dose, it should be used with caution because it is imprecise and may lead to a very high false positive rate. More reliable methods for after-the-fact assessment of radiation dose are needed to complement the use of time to emesis.

  9. Radiation Dose Prediction Using Data on Time to Emesis in the Case of Nuclear Terrorism

    PubMed Central

    Demidenko, Eugene; Williams, Benjamin B.; Swartz, Harold M.

    2009-01-01

    A rigorous statistical analysis of the retrospective estimation of radiation dose received using time to emesis and its uncertainty is provided based on 108 observations associated with accidents with significant exposures to ionizing radiation in the period 1956–2001. The standard error, confidence interval, specificity and sensitivity, and Receiver Operating Characteristic (ROC) curve are used to characterize the uncertainty of the dose prediction. The relative error of the dose prediction using time to emesis data is about 200%. Consequently, if D is the dose assessment, the 95% confidence interval is approximately (D/4, 4D). Our assessment of the precision is applied to computation of the probabilities in triage medical management in the case of a nuclear terrorism event. We also note several factors that indicate that there are additional problems in the use of time to emesis for triage, including a lack of consideration of individuals that do not vomit, differences between the conditions under which the data were obtained and the conditions under which they are likely to be used, and the potential for the incidence of vomiting to be altered by factors unrelated to radiation exposure such as psychogenic factors and the use of emetic agents. In summary, while time to emesis is a rapid and inexpensive method for estimating the radiation dose, it should be used with caution because it is imprecise and may lead to a very high false positive rate. More reliable methods for after-the-fact assessment of radiation dose are needed to complement the use of time to emesis. PMID:19267558

  10. Uncertainties on predicted concentrations of radionuclides in terrestrial foods and ingestion doses.

    PubMed

    Smith, K R; Brown, J; Jones, J A; Mansfield, P; Smith, J G; Haywood, S M; Walters, C B

    2002-01-01

    Models are routinely used to calculate doses following routine releases and potential accidental releases of radionuclides. These models contain a number of parameters. Values for many of these are not accurately known. The primary aim of this study was to determine the level of uncertainty on predicted concentrations of radionuclides in foods, and doses to individuals consuming those foods, arising from uncertainties on the model input parameter values. A secondary objective was to identify those input parameters whose uncertainty makes a major contribution to the overall uncertainty on the predicted endpoints. The methodology adopted and results obtained are presented for the following radionuclides: 90Sr, 131I, 137Cs and 239Pu. The estimated uncertainty ratios (the ratio of the 95th to the 5th percentile) are frequently very large, often two to three orders of magnitude. The results of this study may be used to identify areas where further research could improve assessment capabilities.

  11. Optimization of human dose prediction by using quantitative and translational pharmacology in drug discovery.

    PubMed

    Bueters, Tjerk; Gibson, Christopher; Visser, Sandra A G

    2015-01-01

    In this perspective article, we explain how quantitative and translational pharmacology, when well-implemented, is believed to lead to improved clinical candidates and drug targets that are differentiated from current treatment options. Quantitative and translational pharmacology aims to build and continuously improve the quantitative relationship between drug exposure, target engagement, efficacy, safety and its interspecies relationship at every phase of drug discovery. Drug hunters should consider and apply these concepts to develop compounds with a higher probability of interrogating the clinical biological hypothesis. We offer different approaches to set an initial effective concentration or pharmacokinetic-pharmacodynamic target in man and to predict human pharmacokinetics that determine together the predicted human dose and dose schedule. All concepts are illustrated with ample literature examples.

  12. Cellular response of the rat brain to single doses of 137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

    PubMed Central

    Greene-Schloesser, Dana M.; Kooshki, Mitra; Payne, Valerie; D’Agostino, Ralph B.; Wheeler, Kenneth T.; Metheny-Barlow, Linda J.; Robbins, Mike E.

    2014-01-01

    Purpose To determine if the brain’s response to single doses predicts its response to ‘biologically equivalent’ fractionated doses. Methods Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of 137Cs γ rays or their ‘biologically equivalent’ 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 µm sections of the dentate gyrus (DG). Results Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). Conclusions These data demonstrate that the rat brain’s cellular response to single doses often does not predict its cellular response to ‘biologically equivalent’ fWBI doses. PMID:24937374

  13. A two-dimensional matrix correction for off-axis portal dose prediction errors

    SciTech Connect

    Bailey, Daniel W.; Kumaraswamy, Lalith; Bakhtiari, Mohammad; Podgorsak, Matthew B.

    2013-05-15

    Purpose: This study presents a follow-up to a modified calibration procedure for portal dosimetry published by Bailey et al. ['An effective correction algorithm for off-axis portal dosimetry errors,' Med. Phys. 36, 4089-4094 (2009)]. A commercial portal dose prediction system exhibits disagreement of up to 15% (calibrated units) between measured and predicted images as off-axis distance increases. The previous modified calibration procedure accounts for these off-axis effects in most regions of the detecting surface, but is limited by the simplistic assumption of radial symmetry. Methods: We find that a two-dimensional (2D) matrix correction, applied to each calibrated image, accounts for off-axis prediction errors in all regions of the detecting surface, including those still problematic after the radial correction is performed. The correction matrix is calculated by quantitative comparison of predicted and measured images that span the entire detecting surface. The correction matrix was verified for dose-linearity, and its effectiveness was verified on a number of test fields. The 2D correction was employed to retrospectively examine 22 off-axis, asymmetric electronic-compensation breast fields, five intensity-modulated brain fields (moderate-high modulation) manipulated for far off-axis delivery, and 29 intensity-modulated clinical fields of varying complexity in the central portion of the detecting surface. Results: Employing the matrix correction to the off-axis test fields and clinical fields, predicted vs measured portal dose agreement improves by up to 15%, producing up to 10% better agreement than the radial correction in some areas of the detecting surface. Gamma evaluation analyses (3 mm, 3% global, 10% dose threshold) of predicted vs measured portal dose images demonstrate pass rate improvement of up to 75% with the matrix correction, producing pass rates that are up to 30% higher than those resulting from the radial correction technique alone. As in

  14. Effective dose delivery in atmospheric pressure plasma jets for plasma medicine: a model predictive control approach

    NASA Astrophysics Data System (ADS)

    Gidon, Dogan; Graves, David B.; Mesbah, Ali

    2017-08-01

    Atmospheric pressure plasma jets (APPJs) have been identified as a promising tool for plasma medicine. This paper aims to demonstrate the importance of using model-based feedback control strategies for safe, reproducible, and therapeutically effective application of APPJs for dose delivery to a target substrate. Key challenges in model-based control of APPJs arise from: (i) the multivariable, nonlinear nature of system dynamics, (ii) the need for constraining the system operation within an operating region that ensures safe plasma treatment, and (iii) the cumulative, nondecreasing nature of dose metrics. To systematically address these challenges, we propose a model predictive control (MPC) strategy for real-time feedback control of a radio-frequency APPJ in argon. To this end, a lumped-parameter, physics-based model is developed for describing the jet dynamics. Cumulative dose metrics are defined for quantifying the thermal and nonthermal energy effects of the plasma on substrate. The closed-loop performance of the MPC strategy is compared to that of a basic proportional-integral control system. Simulation results indicate that the MPC stategy provides a versatile framework for dose delivery in the presence of disturbances, while the safety and practical constraints of the APPJ operation can be systematically handled. Model-based feedback control strategies can lead to unprecedented opportunities for effective dose delivery in plasma medicine.

  15. Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration.

    PubMed

    Farah, Claude S; King, Gregory G; Brown, Nathan J; Peters, Matthew J; Berend, Norbert; Salome, Cheryl M

    2012-07-01

    Asthma guidelines recommend inhaled corticosteroid (ICS) dose titration for patients on the basis of an assessment of current asthma control. However, the physiological determinants of asthma symptom control are poorly understood and spirometry is a poor predictor of symptomatic response. To determine the role of small airway measurements in predicting the symptom response following ICS dose titration. Adult asthmatic patients had the Asthma Control Questionnaire (ACQ) scores and lung function measured at baseline and after 8 weeks. Tests included spirometry, plethysmography, sputum cell count, exhaled nitric oxide, airway hyperresponsiveness to mannitol, respiratory system mechanics using the forced oscillation technique, and ventilation heterogeneity using the multiple breath nitrogen washout. The parameters ventilation heterogeneity in convection-dependent airways and ventilation heterogeneity in diffusion-dependent airways were derived as measures of ventilation heterogeneity in the small airways. The dose of ICS was doubled if the ACQ score was greater than or equal to 1.5 (uptitration) and quartered if the ACQ score was less than 1.5 (downtitration). The relationships between baseline physiological parameters and the change in the symptom-only 5-item ACQ (deltaACQ-5) were examined by using Spearman correlations, forward stepwise linear regressions, and receiver operator curve analyses. ICS dose uptitration (n= 20) improved ACQ-5 scores (1.76 to 1.16; P= .04). Baseline fraction of exhaled nitric oxide (r= -0.55; P= .01) and ventilation heterogeneity in convection-dependent airways (r= -0.64; P= .002) correlated with deltaACQ-5, but ventilation heterogeneity in convection-dependent airways was the only independent predictor (r(2) = 0.34; P = 0.007). ICS dose downtitration (n= 41) worsened ACQ-5 scores (0.46 to 0.80; P< .001), with 29% of the patients having a deltaACQ-5 of greater than 0.5. Only baseline ventilation heterogeneity in diffusion-dependent airways

  16. Improving the time efficiency of identifying dairy herds with poorer welfare in a population.

    PubMed

    de Vries, M; Bokkers, E A M; van Schaik, G; Engel, B; Dijkstra, T; de Boer, I J M

    2016-10-01

    Animal-based welfare assessment is time consuming and expensive. A promising strategy for improving the efficiency of identifying dairy herds with poorer welfare is to first estimate levels of welfare in herds based on data that are more easily obtained. Our aims were to evaluate the potential of herd housing and management data for estimating the level of welfare in dairy herds, and to estimate the associated reduction in the number of farm visits required for identification of herds with poorer welfare in a population. Seven trained observers collected data on 6 animal-based welfare indicators in a selected sample of 181 loose-housed Dutch dairy herds (herd size: 22 to 211 cows). Severely lame cows, cows with lesions or swellings, cows with a dirty hindquarter, and very lean cows were counted, and avoidance distance was assessed for a sample of cows. Occurrence of displacements (social behavior) was recorded in the whole barn during 120 min of observation. For the same herds, data regarding cattle housing and management were collected on farms, and data relating to demography, management, milk production and composition, and fertility were extracted from national databases. A herd was classified as having poorer welfare when it belonged to the 25% worst-scoring herds. We used variables of herd housing and management data as potential predictors for individual animal-based welfare indicators in logistic regressions at the herd level. Prediction was less accurate for the avoidance distance index [area under the curve (AUC)=0.69], and moderately accurate for prevalence of severely lame cows (AUC=0.83), prevalence of cows with lesions or swellings (AUC=0.81), prevalence of cows with a dirty hindquarter (AUC=0.74), prevalence of very lean cows (AUC=0.83), and frequency of displacements (AUC=0.72). We compared the number of farm visits required for identifying herds with poorer welfare in a population for a risk-based screening with predictions based on herd housing

  17. A model predicting fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone.

    PubMed

    Moreau, Caroline; Pautas, Eric; Duverlie, Charlotte; Berndt, Celia; Andro, Marion; Mahé, Isabelle; Emmerich, Joseph; Lacut, Karine; Le Gal, Grégoire; Peyron, Isabelle; Gouin-Thibault, Isabelle; Golmard, Jean-Louis; Loriot, Marie-Anne; Siguret, Virginie

    2014-04-01

    Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0-3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

  18. In silico models for the prediction of dose-dependent human hepatotoxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  19. Prediction of error rates in dose-imprinted memories on board CRRES by two different methods

    NASA Astrophysics Data System (ADS)

    Brucker, G. J.; Stassinopoulos, E. G.

    1991-06-01

    An analysis of the expected space radiation effects on the single event upset (SEU) properties of CMOS/bulk memories onboard the Combined Release and Radiation Effects Satellite (CRRES) is presented. Dose-imprint data from ground test irradiations of identical devices are applied to the predictions of cosmic-ray-induced space upset rates in the memories onboard the spacecraft. The calculations take into account the effect of total dose on the SEU sensitivity of the devices as the dose accumulates in orbit. Estimates of error rates, which involved an arbitrary selection of a single pair of threshold linear energy transfer (LET) and asymptotic cross-section values, were compared to the results of an integration over the cross-section curves versus LET. The integration gave lower upset rates than the use of the selected values of the SEU parameters. Since the integration approach is more accurate and eliminates the need for an arbitrary definition of threshold LET and asymptotic cross section, it is recommended for all error rate predictions where experimental sigma-versus-LET curves are available.

  20. Factors for predicting rectal dose of high-dose-rate intracavitary brachytherapy after pelvic irradiation in patients with cervical cancer: a retrospective study with radiography-based dosimetry.

    PubMed

    Huang, Eng-Yen; Wang, Chong-Jong; Lan, Jen-Hong; Chen, Hui-Chun; Fang, Fu-Min; Hsu, Hsuan-Chih; Huang, Yu-Jie; Wang, Chang-Yu; Wang, Yu-Ming

    2010-02-01

    To evaluate the predictive factors for rectal dose of the first fraction of high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. From March 1993 through February 2008, 946 patients undergoing pelvic irradiation and HDR-ICBT were analyzed. Examination under anesthesia (EUA) at the first implantation of the applicator was usually performed in the early period. Rectal point was determined radiographically according to the 38th Report of the International Commission of Radiation Units and Measurements (ICRU). The ICRU rectal dose (PRD) as a percentage of point A dose was calculated; multiple linear regression models were used to predict PRD. Factors influencing successful rectal dose calculation were EUA (p < 0.001) and absence of diabetes (p = 0.047). Age (p < 0.001), body weight (p = 0.002), diabetes (p = 0.020), and EUA (p < 0.001) were independent factors for the PRD. The predictive equation derived from the regression model was PRD (%) = 57.002 + 0.443 x age (years) - 0.257 x body weight (kg) + 6.028 x diabetes (no: 0; yes: 1) - 8.325 x EUA (no: 0; yes: 1) Rectal dose at the first fraction of HDR-ICBT is positively influenced by age and diabetes, and negatively correlated with EUA and body weight. A small fraction size at point A may be considered in patients with a potentially high rectal dose to reduce the biologically effective dose if the ICRU rectal dose has not been immediately obtained in the first fraction of HDR-ICBT. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Factors for Predicting Rectal Dose of High-Dose-Rate Intracavitary Brachytherapy After Pelvic Irradiation in Patients With Cervical Cancer: A Retrospective Study With Radiography-Based Dosimetry

    SciTech Connect

    Huang Engyen; Wang Chongjong; Lan Jenhong; Chen Huichun; Fang Fumin; Hsu, H.-C.; Huang Yujie; Wang Changyu; Wang Yuming

    2010-02-01

    Purpose: To evaluate the predictive factors for rectal dose of the first fraction of high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. Methods and Materials: From March 1993 through February 2008, 946 patients undergoing pelvic irradiation and HDR-ICBT were analyzed. Examination under anesthesia (EUA) at the first implantation of the applicator was usually performed in the early period. Rectal point was determined radiographically according to the 38th Report of the International Commission of Radiation Units and Measurements (ICRU). The ICRU rectal dose (PRD) as a percentage of point A dose was calculated; multiple linear regression models were used to predict PRD. Results: Factors influencing successful rectal dose calculation were EUA (p < 0.001) and absence of diabetes (p = 0.047). Age (p < 0.001), body weight (p = 0.002), diabetes (p = 0.020), and EUA (p < 0.001) were independent factors for the PRD. The predictive equation derived from the regression model was PRD (%) = 57.002 + 0.443 x age (years) - 0.257 x body weight (kg) + 6.028 x diabetes (no: 0; yes: 1) - 8.325 x EUA (no: 0; yes: 1) Conclusion: Rectal dose at the first fraction of HDR-ICBT is positively influenced by age and diabetes, and negatively correlated with EUA and body weight. A small fraction size at point A may be considered in patients with a potentially high rectal dose to reduce the biologically effective dose if the ICRU rectal dose has not been immediately obtained in the first fraction of HDR-ICBT.

  2. Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.

    PubMed

    Damon, C; Luck, M; Toullec, L; Etienne, I; Buchler, M; Hurault de Ligny, B; Choukroun, G; Thierry, A; Vigneau, C; Moulin, B; Heng, A-E; Subra, J-F; Legendre, C; Monnot, A; Yartseva, A; Bateson, M; Laurent-Puig, P; Anglicheau, D; Beaune, P; Loriot, M A; Thervet, E; Pallet, N

    2017-04-01

    Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  3. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

    NASA Astrophysics Data System (ADS)

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-02-01

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

  4. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

    PubMed Central

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-01-01

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67–0.76)] and validation cohorts [0.73 (0.63–0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future. PMID:28176850

  5. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

    PubMed

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-02-08

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

  6. Absorbed Dose Determination Using Experimental and Analytical Predictions of X-Ray Spectra

    NASA Technical Reports Server (NTRS)

    Edwards, D. L.; Carruth, Ralph (Technical Monitor)

    2001-01-01

    Electron beam welding in a vacuum is a technology that NASA is investigating as a joining technique for manufacture of space structures. This investigation characterizes the x-ray environment due to operation of an in-vacuum electron beam welding tool and provides recommendations for adequate shielding for astronauts performing the in-vacuum electron beam welding. NASA, in a joint venture with the Russian Space Agency, was scheduled to perform a series of welding in space experiments on board the U.S. Space Shuttle. This series of experiments was named the international space welding experiment (ISWE). The hardware associated with the ISWE was leased to NASA by the Paton Welding Institute (PWI) in Ukraine for ground-based welding experiments in preparation for flight. Two ground tests were scheduled, using the ISWE electron beam welding tool, to characterize the radiation exposure to an astronaut during the operation of the ISWE. These radiation exposure tests used thermoluminescence dosimeters (TLD's) shielded with material currently used by astronauts during extravehicular activities to measure the radiation dose. The TLD's were exposed to x-ray radiation generated by operation of the ISWE in-vacuum electron beam welding tool. This investigation was the first known application of TLD's to measure absorbed dose from x rays of energy less than 10 keV. The ISWE hardware was returned to Ukraine before the issue of adequate shielding for the astronauts was completely verified. Therefore, alternate experimental and analytical methods were developed to measure and predict the x-ray spectral and intensity distribution generated by ISWE electron beam impact with metal. These x-ray spectra were normalized to an equivalent ISWE exposure, then used to calculate the absorbed radiation dose to astronauts. These absorbed dose values were compared to TLD measurements obtained during actual operation of the ISWE in-vacuum electron beam welding tool. The calculated absorbed dose

  7. Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

    PubMed

    Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

    2015-01-01

    Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

  8. Predictive factors for anti-HBs status after 1 booster dose of hepatitis B vaccine.

    PubMed

    Lu, I-Cheng; Jean, Mei-Chu Yen; Lin, Chi-Wei; Chen, Wei-Hung; Perng, Daw-Shyong; Lin, Chih-Wen; Chuang, Hung-Yi

    2016-09-01

    In Taiwan, infants need to receive 3 doses of hepatitis B virus (HBV) vaccine under the public health policy from the government. However, there are many young adults who even though received complete HBV vaccination in their childhood would lose the positive response of anti-hepatitis B surface antibody (HBs) and need the booster dose of HBV vaccine. The aim of our study is to determine the powerful predictive factor for screening the candidates who need only 1 booster dose of HB vaccine then they can regain positive postbooster anti-HBs status (≧10 mIU/mL) or protective postbooster anti-HBs status (≧100 mIU/mL).We recruited 103 university freshmen who were born after July 1986 with complete HBV vaccination in childhood, but displayed negative results for hepatitis B surface antigen and anti-HBs levels at their health examinations upon university entry. They received 1 booster dose of HB vaccine, and their anti-HBs titers were rechecked 4 weeks after the booster administration. Multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL, model 1) and protective postbooster anti-HBs status (≧100 mIU/mL, model 2) was done with predictive factors of prebooster anti-HBs level, body mass index, serum glutamate pyruvate transaminase level, and sex.Twenty-four students got positive postbooster anti-HBs status (10-100 mIU/mL) and 50 students got protective postbooster anti-HBs status (≧100 mIU/mL). In the model of multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL), prebooster anti-HBs level was the strongest predictive factor. The odds ratio was 218.645 and the P value was 0.001. Even in the model of multivariate analysis logistic regression for protective postbooster anti-HBs status (≧100 mIU/mL), prebooster anti-HBs level was still the strongest predictive factor, but the odds ratio of a protective booster effect was 2.143, with 95% confidence interval between 1

  9. Predictive factors for anti-HBs status after 1 booster dose of hepatitis B vaccine

    PubMed Central

    Lu, I-Cheng; Jean, Mei-Chu Yen; Lin, Chi-Wei; Chen, Wei-Hung; Perng, Daw-Shyong; Lin, Chih-Wen; Chuang, Hung-Yi

    2016-01-01

    Abstract In Taiwan, infants need to receive 3 doses of hepatitis B virus (HBV) vaccine under the public health policy from the government. However, there are many young adults who even though received complete HBV vaccination in their childhood would lose the positive response of anti-hepatitis B surface antibody (HBs) and need the booster dose of HBV vaccine. The aim of our study is to determine the powerful predictive factor for screening the candidates who need only 1 booster dose of HB vaccine then they can regain positive postbooster anti-HBs status (≧10 mIU/mL) or protective postbooster anti-HBs status (≧100 mIU/mL). We recruited 103 university freshmen who were born after July 1986 with complete HBV vaccination in childhood, but displayed negative results for hepatitis B surface antigen and anti-HBs levels at their health examinations upon university entry. They received 1 booster dose of HB vaccine, and their anti-HBs titers were rechecked 4 weeks after the booster administration. Multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL, model 1) and protective postbooster anti-HBs status (≧100 mIU/mL, model 2) was done with predictive factors of prebooster anti-HBs level, body mass index, serum glutamate pyruvate transaminase level, and sex. Twenty-four students got positive postbooster anti-HBs status (10–100 mIU/mL) and 50 students got protective postbooster anti-HBs status (≧100 mIU/mL). In the model of multivariate analysis logistic regression for positive postbooster anti-HBs status (≧10 mIU/mL), prebooster anti-HBs level was the strongest predictive factor. The odds ratio was 218.645 and the P value was 0.001. Even in the model of multivariate analysis logistic regression for protective postbooster anti-HBs status (≧100 mIU/mL), prebooster anti-HBs level was still the strongest predictive factor, but the odds ratio of a protective booster effect was 2.143, with 95% confidence

  10. Slow sluggish cognitive tempo symptoms are associated with poorer academic performance in children with ADHD.

    PubMed

    Tamm, Leanne; Garner, Annie A; Loren, Richard E A; Epstein, Jeffery N; Vaughn, Aaron J; Ciesielski, Heather A; Becker, Stephen P

    2016-08-30

    Sluggish cognitive tempo (SCT) symptoms may confer risk for academic impairment in attention-deficit/hyperactivity disorder (ADHD). We investigated SCT in relation to academic performance and impairment in 252 children (ages 6-12, 67% boys) with ADHD. Parents and teachers completed SCT and academic impairment ratings, and achievement in reading, math, and spelling was assessed. Simultaneous regressions controlling for IQ, ADHD, and comorbidities were conducted. Total SCT predicted parent-rated impairments in writing, mathematics, and overall school but not reading. Parent-rated SCT Slow predicted poorer reading and spelling, but not math achievement. Teacher-rated SCT Slow predicted poorer spelling and math, but not reading achievement. Parent-rated SCT Slow predicted greater academic impairment ratings across all domains, whereas teacher-rated SCT Slow predicted greater impairment in writing only. Age and gender did not moderate these relationships with the exception of math impairment; SCT slow predicted math impairment for younger but not older children. Parent and teacher SCT Sleepy and Daydreamy ratings were not significant predictors. SCT Slow appears to be uniquely related to academic problems in ADHD, and may be important to assess and potentially target in intervention. More work is needed to better understand the nature of SCT Slow symptoms in relation to inattention and amotivation.

  11. An efficient numerical tool for dose deposition prediction applied to synchrotron medical imaging and radiation therapy.

    PubMed

    Mittone, Alberto; Baldacci, Fabien; Bravin, Alberto; Brun, Emmanuel; Delaire, François; Ferrero, Claudio; Gasilov, Sergei; Freud, Nicolas; Létang, Jean Michel; Sarrut, David; Smekens, François; Coan, Paola

    2013-09-01

    Medical imaging and radiation therapy are widely used synchrotron-based techniques which have one thing in common: a significant dose delivery to typically biological samples. Among the ways to provide the experimenters with image guidance techniques indicating optimization strategies, Monte Carlo simulation has become the gold standard for accurately predicting radiation dose levels under specific irradiation conditions. A highly important hampering factor of this method is, however, its slow statistical convergence. A track length estimator (TLE) module has been coded and implemented for the first time in the open-source Monte Carlo code GATE/Geant4. Results obtained with the module and the procedures used to validate them are presented. A database of energy-absorption coefficients was also generated, which is used by the TLE calculations and is now also included in GATE/Geant4. The validation was carried out by comparing the TLE-simulated doses with experimental data in a synchrotron radiation computed tomography experiment. The TLE technique shows good agreement versus both experimental measurements and the results of a classical Monte Carlo simulation. Compared with the latter, it is possible to reach a pre-defined statistical uncertainty in about two to three orders of magnitude less time for complex geometries without loss of accuracy.

  12. BIODOSE: a code for predicting the dose to man from radionuclides released from underground nuclear waste repositories

    SciTech Connect

    Bonner, N.A.; Ng, Y.C.

    1980-03-01

    The BIODOSE computer program simulates the environmental transport of radionuclides released to surface water and predicts the resulting dosage to humans. This report describes the program and discusses its use in the evaluation of nuclear waste repositories. The methods used to estimate dose are examined critically, and the most important parameters in each stage of the calculations are identified as an aid in planning for measurements in the field. Dose predictions from releases of nuclear waste to a large northwestern river (the baseline river) are presented to point out the nuclides, compartments and pathways that contribute most to the hazard as a function of waste storage time. Predictions for five other water systems are presented to identify the most important system parameters that determine the concentrations of individual nuclides in compartments and the resultant dose. The uncertainties in the biological parameters for dose prediction are identified, and changes in current values are suggested. Various ways of reporting dose estimates for radiological safety assessments are discussed. Additional work needed to improve the dose predictions from BIODOSE and specific areas and steps to improve our capabilities to assess the environmental transport of nuclides released from nuclear waste repositories and the resultant dose to man are suggested.

  13. Comparison of enhanced device response and predicted x-ray dose enhancement effects on MOS oxides

    SciTech Connect

    Fleetwood, D.M.; Beutler, D.E.; Lorence, L.J. Jr.; Draper, B.L.; Brown, D.B.; Riewe, L.C.; Rosenstock, H.B.; Knott, D.P.

    1988-12-01

    The response of MOS capacitors to low- and medium-energy x-ray irradiation is investigated as a function of gate material (TaSi or Al), oxide thickness, and electric field. Measured device response is compared with predictions based on discrete ordinates and Monte Carlo code simulations of dose enhancement effects, coupled with recent estimates of electron-hole recombination in MOS oxides. In comparisons of 10-keV x-ray and Co-60 irradiations of Al-gate MOS capacitors at an oxide electric field of 1 MV/cm, it is found that predictions and experiments agree to within better than 20 percent for oxide thicknesses ranging from 35 to 1060 nm. For capacitors having TaSi/Al gates, predictions and experiments agree to within better than 30 percent at 1 MV/cm, with the largest differences occurring for 35-nm gate oxides. At other electric fields, the disagreement between experiment and prediction increases significantly for both Al- and TaSi/Al-gate capacitors, and can be greater than a factor of 2 at applied electric fields below 0.1 MV/cm. For medium energy (-- 100 keV average photon energy) x-ray irradiations, the enhanced device response exhibits a much stronger dependence on endpoint bremsstrahlung energy than expected from TIGERP or CEPXS/ONETRAN simulations. Implications for hardness assurance testing are discussed.

  14. Effects of positioning uncertainty and breathing on dose delivery and radiation pneumonitis prediction in breast cancer.

    PubMed

    Mavroidis, Panayiotis; Axelsson, Sofie; Hyödynmaa, Simo; Rajala, Juha; Pitkänen, Maunu A; Lind, Bengt K; Brahme, Anders

    2002-01-01

    complication probabilities than the original plans. This means that the true expected complications are often underestimated in clinical practice. The lung density variation during breathing is calculated from the maximal change in average density during tidal breathing. The change in density in the lung due to breathing is shown to have almost no influence on the dose distribution in the lung. The proposed treatment-plan adjustments taking positioning uncertainty and breathing effects into account indicate significant deviations in the dose delivery and the predicted lung complications.

  15. Evaluation of ability of biochemical markers of bone turnover to predict a response to increased doses of HRT.

    PubMed

    Rosen, H N; Parker, R A; Greenspan, S L; Iloputaife, I D; Bookman, L; Chapin, D; Perlmutter, I; Kessel, B; Qvist, P; Rosenblatt, M

    2004-05-01

    Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (-4.1% to -19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX ( N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% +/- 3.9% versus 1.2% +/- 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individual's changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.

  16. Ultrasound measured renal length versus low dose CT volume in predicting single kidney glomerular filtration rate.

    PubMed

    Widjaja, E; Oxtoby, J W; Hale, T L; Jones, P W; Harden, P N; McCall, I W

    2004-09-01

    Ultrasound measured renal length and CT measured renal volume are potential surrogate markers for single kidney glomerular filtration rate (SKGFR). The aims of this study are to determine: (1) the repeatability of ultrasound measured length and low radiation dose spiral CT measured volume; (2) the relationship between renal length and volume; and (3) whether length and/or volume is a predictor of SKGFR. 69 patients with suspected renal artery stenosis underwent ultrasound renal length measurement, CT evaluation of renal volume and assessment of SKGFR. 40 patients had ultrasound measurement of length and CT evaluation of volume performed twice on two separate visits. 25 patients also had ultrasound measured renal parenchymal thickness and area. The region of interest was drawn around the kidneys and a threshold set to subtract renal peripelvic fat and renal pelvis. The volume from each slice was summed to obtain the total volume for each kidney. The limits of agreement for ultrasound measured renal length were -1.6 cm to 1.52 cm and that for CT renal volume were -33 ml to 32 ml. There was significant correlation between ultrasound measured length and CT volume (r=0.74, p<0.01). Volume was a better predictor of SKGFR (r(2)=0.57) than length (r(2)=0.48). The combined parameters of ultrasound measured length, area and parenchymal thickness were a better predictor of volume (r(2)=0.81) and SKGFR (r(2)=0.58) than ultrasound measured length on its own. The low dose CT technique was reasonably reproducible and renal volume measurements correlate better with SKGFR than length. Ultrasound predictions of renal volume and SKGFR can be improved by incorporating cross-sectional area and parenchymal thickness. Further investigation is required to refine our low dose CT technique.

  17. Animal studies on medicinal herbs: predictability, dose conversion and potential value.

    PubMed

    Wojcikowski, Ken; Gobe, Glenda

    2014-01-01

    Animal studies testing medicinal herbs are often misinterpreted by both translational researchers and clinicians due to a lack of information regarding their predictability, human dose equivalent and potential value. The most common mistake is to design or translate an animal study on a milligram per kilogram basis. This can lead to underestimation of the toxicity and/or overestimation of the amount needed for human therapy. Instead, allometric scaling, which involves body surface area, should be used. While the differences in the pharmacokinetic and pharmacodynamic phases between species will inevitably lead to some degree of error in extrapolation of results regardless of the conversion method used, correct design and interpretation of animal studies can provide information that is not able to be provided by in vitro studies, computer modeling or even traditional use.

  18. Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia.

    PubMed

    Noble, Sarah L; Sherer, Eric; Hannemann, Robert E; Ramkrishna, Doraiswami; Vik, Terry; Rundell, Ann E

    2010-06-07

    Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  19. Prediction of drug responses in schizophrenia: a method using a test dose of chlorpromazine.

    PubMed

    Minami, H; Nakahara, T; Miyahara, A; Nakane, Y

    1997-08-01

    Thirty-seven newly admitted schizophrenic patients were treated with an open and flexible dosage of chlorpromazine for 3 months after receiving a test dose. Levels of chlorpromazine, demethylated chlorpromazine and chlorpromazine sulfoxide 3 h after the test dose were measured. Twenty-three patients responded to long-term chlorpromazine treatment but 14 did not, a rate of 62.2%. A discriminant function analysis was performed using variables relating to the patients, backgrounds added to the ratios of plasma drug levels separately by sex to increase predictability over the level of previous studies. The obtained equations were applied to 23 newly admitted schizophrenic patients, with the prescription of chlorpromazine for designated responders and haloperidol for designated non-responders for 4 weeks. The patients in the latter study responded better than those of the former with chlorpromazine alone; 71.4 and 88.9% of chlorpromazine- and haloperidol-treated groups improved, respectively, for an overall rate of 78.3%. However, the chlorpromazine-treated group had a lower level of positive symptoms than the haloperidol-treated group before treatment and this and other differences between the groups should be further examined.

  20. EPR oxygen images predict tumor control by a 50 percent tumor control radiation dose

    PubMed Central

    Elas, Martyna; Magwood, Jessica M.; Butler, Brandi; Li, Chanel; Wardak, Rona; Barth, Eugene D.; Epel, Boris; Rubinstein, Samuel; Pelizzari, Charles A.; Weichselbaum, Ralph R.; Halpern, Howard J.

    2013-01-01

    Clinical trials to ameliorate hypoxia as a strategy to relieve the radiation resistance it causes have prompted a need to assay the precise extent and location of hypoxia in tumors. Electron Paramagnetic Resonance oxygen imaging (EPR O2 imaging) provides a non-invasive means to address this need. To obtain a preclinical proof of principle that EPR O2 images could predict radiation control, we treated mouse tumors at or near doses required to achieve 50 percent control (TCD50). Mice with FSa fibrosarcoma or MCa4 carcinoma were subjected to EPR O2 imaging and immediately radiated to a TCD50 or TCD50 ±10 Gy.. Statistical analysis was permitted by collection of ~ 1300 tumor pO2 image voxels, including the fraction of tumor voxels with pO2 less than 10 mm Hg (HF10). Tumors were followed for 90 days (FSa) or 120 days (MCa4) to determine local control or failure. HF10 obtained from EPR images showed statistically significant differences between tumors that were controlled by the TCD50 and those that were not controlled for both FSa and MCa4. Kaplan-Meier analysis of both types of tumors showed ~90% of mildly hypoxic tumors were controlled (HF10<10%), and only 37% (FSA) and 23% (MCa4) tumors controlled if hypoxic. EPR pO2 image voxel distributions in these ~0.5 ml tumors provide a prediction of radiation curability independent of radiation dose. These data confirm the significance of EPR pO2 hypoxic fractions. The ~90% control of low HF10 tumors argue that ½ ml subvolumes of tumors may be more sensitive to radiation and may need less radiation for high tumor control rates. PMID:23861469

  1. Predicting physical stability in pressurized metered dose inhalers via dwell and instantaneous force colloidal probe microscopy.

    PubMed

    D'Sa, Dexter; Chan, Hak-Kim; Chrzanowski, Wojciech

    2014-09-01

    Colloidal probe microscopy (CPM) is a quantitative predictive tool, which can offer insight into particle behavior in suspension pressurized metered dose inhalers (pMDIs). Although CPM instantaneous force measurements, which involve immediate retraction of the probe upon sample contact, can provide information on inter-particle attractive forces, they lack the ability to appropriately imitate all critical particle pMDI interactions (e.g., particle re-dispersion after prolonged pMDI storage). In this paper, two novel dwell force techniques - indentation and deflection dwell - were employed to mimic long-term particle interactions present in pMDIs, using particles of various internal structures and a model liquid propellant (2H,3H perfluoropentane) as a model system. Dwell measurements involve particle contact for an extended period of time. In deflection dwell mode the probe is held at a specific position, while in indentation dwell mode the probe is forced into the sample with a constant force for the entirety of the contact time. To evaluate the applicability of CPM to predict actual pMDI physical stability, inter-particle force measurements were compared with qualitative and quantitative bulk pMDI measurement techniques (visual quality and light scattering). Measured instantaneous attractive (snap-in) and adhesive (max-pull) forces decreased as a function of increasing surface area, while adhesive forces measured by indentation dwell decreased as a function of dwell contact time for particles containing voids. Instantaneous force measurements provided information on the likelihood of floccule formation, which was predictive of partitioning rates, while indentation dwell force measurements were predictive of formulation re-dispersibility after prolonged storage. Dwell force measurements provide additional information on particle behavior within a pMDI not obtainable via instantaneous measurements. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Individual external dose monitoring of all citizens of Date City by passive dosimeter 5 to 51 months after the Fukushima NPP accident (series): II. Prediction of lifetime additional effective dose and evaluating the effect of decontamination on individual dose.

    PubMed

    Miyazaki, Makoto; Hayano, Ryugo

    2017-09-25

    In the first paper of this series, we showed that the ratio c of individual dose to ambient dose did not change with time in Date City, Fukushima Prefecture, after the Fukushima Daiichi Nuclear Power Plant accident. The purpose of the present paper, the second in a series, is to estimate the lifetime doses of the Date City residents, based on continuous glass badge monitoring data, extrapolated by means of the ambient-dose-rate reduction function obtained from the airborne monitoring data. As a result, we found that the external exposure contribution to the mean additional lifetime dose of residents living in Date City is not expected to exceed 18 mSv. In addition, effects of decontamination on the reduction of individual doses were not evident. This method of combining individual doses and the ambient doses, as developed in this study, has made it possible to predict with reasonable certainty the lifetime doses of residents who continue to live in this radiologically contaminated area.

  3. Determining Cutoff Point of Ensemble Trees Based on Sample Size in Predicting Clinical Dose with DNA Microarray Data

    PubMed Central

    Karabulut, Erdem; Alpar, Celal Reha

    2016-01-01

    Background/Aim. Evaluating the success of dose prediction based on genetic or clinical data has substantially advanced recently. The aim of this study is to predict various clinical dose values from DNA gene expression datasets using data mining techniques. Materials and Methods. Eleven real gene expression datasets containing dose values were included. First, important genes for dose prediction were selected using iterative sure independence screening. Then, the performances of regression trees (RTs), support vector regression (SVR), RT bagging, SVR bagging, and RT boosting were examined. Results. The results demonstrated that a regression-based feature selection method substantially reduced the number of irrelevant genes from raw datasets. Overall, the best prediction performance in nine of 11 datasets was achieved using SVR; the second most accurate performance was provided using a gradient-boosting machine (GBM). Conclusion. Analysis of various dose values based on microarray gene expression data identified common genes found in our study and the referenced studies. According to our findings, SVR and GBM can be good predictors of dose-gene datasets. Another result of the study was to identify the sample size of n = 25 as a cutoff point for RT bagging to outperform a single RT. PMID:28096893

  4. Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

    PubMed

    Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

    2017-01-01

    We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

  5. SU-E-T-430: Feasibility Study On Using Overlap Volume Histogram to Predict the Dose Difference by Respiratory Motion

    SciTech Connect

    Shin, D; Kang, S; Kim, D; Kim, T; Kim, K; Cho, M; Suh, T

    2015-06-15

    Purpose: The dose difference between three-dimensional dose (3D dose) and 4D dose which considers motion due to respiratory can be varied according to geometrical relationship between planning target volume (PTV) and organ at risk (OAR). The purpose of the study is to investigate the dose difference between 3D and 4D dose using overlap volume histogram (OVH) which is an indicator that quantify geometrical relationship between a PTV and an OAR. Methods: Five liver cancer patients who previously treated stereotactic body radiotherapy (SBRT) were investigated. Four-dimensional computed tomography (4DCT) images were acquired for all patients. ITV-based treatment planning was performed. 3D dose was calculated on the end-exhale phase image as a reference phase image. 4D dose accumulation was implemented from all phase images using dose warping technique used deformable image registration (DIR) algorithm (Horn and Schunck optical flow) in DIRART. In this study OVH was used to quantify geometrical relationship between a PTV and an OAR. OVH between a PTV and a selected OAR was generated for each patient case and compared for all cases. The dose difference between 3D and 4D dose for normal organ was calculated and compared for all cases according to OVH. Results: The 3D and 4D dose difference for OAR was analyzed using dose-volume histogram (DVH). On the basis of a specific point which corresponds to 10% of OAR volume overlapped with expanded PTV, mean dose difference was 34.56% in minimum OVH distance case and 13.36% in maximum OVH distance case. As the OVH distance increased, mean dose difference between 4D and 3D dose was decreased. Conclusion: The tendency of dose difference variation was verified according to OVH. OVH is seems to be indicator that has a potential to predict the dose difference between 4D and 3D dose. This work was supported by the Radiation Technology R&D program (No. 2013M2A2A7043498) and the Mid-career Researcher Program (2014R1A2A1A10050270) through

  6. PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

    EPA Science Inventory

    Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

  7. PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

    EPA Science Inventory

    Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

  8. Postoperative Pain Management in Latino Families: Parent Beliefs about Analgesics Predict Analgesic Doses Provided to Children

    PubMed Central

    Rosales, Alvina; Fortier, Michelle A.; Campos, Belinda; Kain, Zeev N.

    2015-01-01

    Background/Objectives The present study examined whether parental perceptions of children’s pain impacted home-based pain management following outpatient surgery in a sample of Latino families from low socioeconomic backgrounds. Methods Latino parents of children (n = 161) who underwent outpatient surgery were recruited for this study and completed measures assessing attitudes on pain and analgesic use (Parental Pain Expression Perceptions and Medication Attitudes Questionnaire) before their child’s surgery. Parents also rated their child’s pain after their child’s surgery using the Parent Postoperative Pain Measure and collected data on the amount of analgesics they gave to their child on the first postoperative day. Hierarchical regression analyses examined whether parental attitudes predicted pain assessment and management at home. Results A majority of parents reported multiple misconceptions regarding children’s pain and fears of side effects as well as avoidance of analgesic use. For example, over 80% reported believing that a child always tells their parents when they are in pain. Hierarchical regression analyses found that more fear and avoidance regarding analgesic use for children’s pain predicted parents’ providing fewer doses of analgesic to their children on the first postoperative day (β = −0.21, p = 0.028). Conclusions Preoperative parents’ beliefs regarding analgesics for treatment of children’s pain may adversely impact parent postoperative analgesic administration at home in Latino families. PMID:26792407

  9. Poorer Survival in Stage IB Lung Cancer Patients After Pneumonectomy.

    PubMed

    Rodríguez, María; Gómez Hernández, María Teresa; Novoa, Nuria M; Aranda, José Luis; Jiménez, Marcelo F; Varela, Gonzalo

    2015-05-01

    Pneumonectomy may be needed in exceptional cases in patients with early stage NSCLC, especially in stage IB. The aim of this study was to evaluate whether overall survival in stage IB (T2aN0M0) NSCLC patients is worse after pneumonectomy. Retrospective study of a series of pathological IB (pIB) patients who underwent either lobectomy or pneumonectomy between 2000 and 2011. The dependent variable was all-cause death. Operative mortality was excluded. The relationship between the age, FEV1%, Charlson index and performance of pneumonectomy variables and the dependent variable were analyzed using a Cox regression. Overall survival for both groups of patients was then plotted in Kaplan-Meier graphs and compared using the log-rank test. A total of 407 cases were analyzed (373 lobectomies and 34 pneumonectomies). According to Cox regression, age, FEV1% and pneumonectomy were associated with poorer survival (P<.05). Age-adjusted survival and FEV1% showed diminished survival in patients who underwent pneumonectomy (log-rank, P=.0357). In stage pIB NSCLC patients, pneumonectomy is associated with poorer survival compared to lobectomy. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  10. Late Fecal Incontinence After High-Dose Radiotherapy for Prostate Cancer: Better Prediction Using Longitudinal Definitions

    SciTech Connect

    Fiorino, Claudio; Rancati, Tiziana; Fellin, Gianni; Vavassori, Vittorio; Cagna, Emanuela; Casanova Borca, Valeria; Girelli, Giuseppe; Menegotti, Loris; Monti, Angelo Filippo; Tortoreto, Francesca; Delle Canne, Stefania; Valdagni, Riccardo

    2012-05-01

    Purpose: To model late fecal incontinence after high-dose prostate cancer radiotherapy (RT) in patients accrued in the AIROPROS (prostate working group of the Italian Association of Radiation Oncology) 0102 trial using different endpoint definitions. Methods and Materials: The self-reported questionnaires (before RT, 1 month after RT, and every 6 months for {<=}3 years after RT) of 586 patients were available. The peak incontinence (P{sub I}NC) and two longitudinal definitions (chronic incontinence [C{sub I}NC], defined as the persistence of Grade 1 or greater incontinence after any Grade 2-3 event; and mean incontinence score [M{sub I}NC], defined as the average score during the 3-year period after RT) were considered. The correlation between the clinical/dosimetric parameters (including rectal dose-volume histograms) and P{sub I}NC (Grade 2 or greater), C{sub I}NC, and M{sub I}NC of {>=}1 were investigated using multivariate logistic analyses. Receiver operating characteristic curves and the area under the curve were used to assess the predictive value of the different multivariate models. Results: Of the 586 patients, 36 with a Grade 1 or greater incontinence score before RT were not included in the present analysis. Of the 550 included patients, 197 (35.8%) had at least one control with a Grade 1 or greater incontinence score (M{sub I}NC >0). Of these 197 patients, 37 (6.7%), 22 (4.0%), and 17 (3.1%) were scored as having P{sub I}NC, M{sub I}NC {>=}1, and C{sub I}NC, respectively. On multivariate analysis, Grade 2 or greater acute incontinence was the only predictor of P{sub I}NC (odds ratio [OR], 5.9; p = .0009). Grade 3 acute incontinence was predictive of C{sub I}NC (OR, 9.4; p = .02), and percentage of the rectal volume receiving >40 Gy of {>=}80% was predictive of a M{sub I}NC of {>=}1 (OR, 3.8; p = .008) and of C{sub I}NC (OR, 3.6; p = .03). Previous bowel disease, previous abdominal/pelvic surgery, and the use of antihypertensive (protective factor

  11. Developing equations to predict surface dose and therapeutic interval in bolused electron fields: A Monte Carlo Study

    NASA Astrophysics Data System (ADS)

    Jabbari, Nasrollah; Khalkhali, Hamid Reza

    2017-07-01

    In this research, we aim to investigate the influence of different materials, as a bolus, on the low-energy electron beam dose distributions and to develop equations for predicting surface dose based on bolus thickness, as well as the therapeutic interval based on surface dose. All the Monte Carlo (MC) calculations and measurements were conducted on a Siemens PRIMUS linac. Based on EGSnrc MC code, BEAMnrc system was used to model a Siemens linac and generate phase-space files for three electron beams (6, 8, and 10 MeV). The particles were transported from the phase-space files to the bolus materials and the simulated water phantom using DOSXYZnrc. Various materials with different thicknesses were examined as a bolus, and appropriate equations were determined for each material and electron beam. The comparison of percent depth dose (PDD) curves and beam profiles, using MC, with the measured data demonstrated that the calculated values properly matched with the measurements. The results indicated that the use of bolus materials with the density of higher than soft tissue can increase both surface dose and therapeutic interval simultaneously. This finding arises from the fact that the required bolus thickness for achieving the therapeutic surface dose decreases in the case of high-density materials. Two series of prediction equations were proposed for predicting the surface dose based on bolus thickness and the therapeutic interval based on surface dose. These equations are able to calculate properly the bolus thickness required for producing a therapeutic surface dose (above 90%) for any therapeutic interval.

  12. Locally Weighted Learning Methods for Predicting Dose-Dependent Toxicity with Application to the Human Maximum Recommended Daily Dose

    DTIC Science & Technology

    2012-09-10

    Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, United States ABSTRACT: Toxicological ...species. Thus, it is more advantageous to predict the toxicological effects of a compound on humans directly from the human toxicological data of related...compounds. However, many popular quantitative structure−activity relationship ( QSAR ) methods that build a single global model by fitting all training

  13. LINKING DERMAL MODELING AND LOADING DATA TO PREDICT LONG-TERM DOSES FROM INTERMITTENT DERMAL CONTACT

    EPA Science Inventory

    In this paper we assess dermal exposure and dose resulting from intermittent contact with residue-contaminated surfaces. These estimates require an understanding of (1) the quantitative relationship between exposure and absorbed dose; (2) the impact of intermittent exposure on ...

  14. LINKING DERMAL MODELING AND LOADING DATA TO PREDICT LONG-TERM DOSES FROM INTERMITTENT DERMAL CONTACT

    EPA Science Inventory

    In this paper we assess dermal exposure and dose resulting from intermittent contact with residue-contaminated surfaces. These estimates require an understanding of (1) the quantitative relationship between exposure and absorbed dose; (2) the impact of intermittent exposure on ...

  15. Negative communication in psychosis: understanding pathways to poorer patient outcomes.

    PubMed

    Finnegan, Deirdre; Onwumere, Juliana; Green, Catherine; Freeman, Daniel; Garety, Philippa; Kuipers, Elizabeth

    2014-11-01

    High expressed emotion (EE) is a robust predictor of elevated rates of relapse and readmission in schizophrenia. However, far less is known about how high EE leads to poorer patient outcomes. This study was designed to examine links between high EE (criticism), affect, and multidimensional aspects of positive symptoms in patients with psychosis. Thirty-eight individuals with nonaffective psychosis were randomly exposed to proxy high-EE or neutral speech samples and completed self-report measures of affect and psychosis symptoms. Patients reported significant increases in anxiety, anger, and distress after exposure to the proxy high-EE speech sample as well as increases in their appraisals of psychosis symptoms: voice controllability, delusional preoccupation, and conviction. These findings offer further evidence of the potential deleterious impact of a negative interpersonal environment on patient symptoms in psychosis.

  16. Prediction of Warfarin Dose Reductions in Puerto Rican Patients, Based on Combinatorial CYP2C9 and VKORC1 Genotypes

    PubMed Central

    Valentin, Isa Ivette; Vazquez, Joan; Rivera-Miranda, Giselle; Seip, Richard L; Velez, Meredith; Kocherla, Mohan; Bogaard, Kali; Cruz-Gonzalez, Iadelisse; Cadilla, Carmen L; Renta, Jessica Y; Felliu, Juan F; Ramos, Alga S; Alejandro-Cowan, Yirelia; Gorowski, Krystyna; Ruaño, Gualberto; Duconge, Jorge

    2012-01-01

    BACKGROUND The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. OBJECTIVE To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm. METHODS A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested. RESULTS Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients. CONCLUSIONS This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA

  17. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    PubMed

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-09-29

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.

  18. Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

    PubMed

    Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

    2016-05-01

    The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Low dose dobutamine echocardiography for predicting functional recovery after coronary revascularisation

    PubMed Central

    Piscione, F; Perrone-Filardi, P; De Luca, G; Prastaro, M; Indolfi, C; Golino, P; Dellegrottaglie, S; Chiariello, M

    2001-01-01

    OBJECTIVE—To evaluate the effects of chronic coronary occlusion on the accuracy of low dose dobutamine echocardiography in predicting recovery of dysfunctional myocardium after revascularisation.
DESIGN—Retrospective study.
SETTING—Tertiary referral centre.
PATIENTS—53 consecutive patients with ⩾ 70% stenosis of the left anterior descending coronary artery (LAD) and regional ventricular dysfunction (group 1, non-occluded LAD; group 2, occluded LAD) who underwent dobutamine echocardiography.
INTERVENTIONS—26 patients underwent coronary artery bypass grafting and 27 had percutaneous transluminal coronary angioplasty.
MAIN OUTCOME MEASURES—Baseline studies before revascularisation included cross sectional echocardiography at rest and during dobutamine infusion (5-10 µg/kg/min), and coronary angiography. The dobutamine study was performed mean (SD) 35 (28) days before revascularisation. Echocardiography at rest was repeated 90 (48) days after revascularisation.
RESULTS—Of 296 dysfunctional segments, 63 in group 1 (43%; 63/146) and 69 in group 2 (46%; 69/150) (NS) improved at follow up. Mean (SD) regional wall motion score index decreased from 1.97 (0.48) (95% confidence interval (CI) 1.01 to 2.93) before revascularisation to 1.74 (0.52) (95% CI 0.70 to 2.78) at follow up in group 1 (p = 0.001), and from 2.12 (0.41) (95% CI 1.30 to 2.98) to 1.88 (0.36) (95% CI 1.16 to 2.60) in group 2 (p = 0.0006). In group 1, sensitivity (87% v 52%; p < 0.0001), negative predictive value (88% v 65%; p = 0.001), and accuracy (77% v 64%; p = 0.01) were all significantly higher than in group 2, despite the angiographic evidence of collaterals in patients with occluded vessels.
CONCLUSIONS—Dobutamine echocardiography shows reduced sensitivity in predicting recovery of dysfunctional myocardium supplied by totally occluded vessels. Thus caution should be used in selecting such patients for revascularisation on the basis of a

  20. Optimal dose reduction in computed tomography methodologies predicted from real-time dosimetry

    NASA Astrophysics Data System (ADS)

    Tien, Christopher Jason

    Over the past two decades, computed tomography (CT) has become an increasingly common and useful medical imaging technique. CT is a noninvasive imaging modality with three-dimensional volumetric viewing abilities, all in sub-millimeter resolution. Recent national scrutiny on radiation dose from medical exams has spearheaded an initiative to reduce dose in CT. This work concentrates on dose reduction of individual exams through two recently-innovated dose reduction techniques: organ dose modulation (ODM) and tube current modulation (TCM). ODM and TCM tailor the phase and amplitude of x-ray current, respectively, used by the CT scanner during the scan. These techniques are unique because they can be used to achieve patient dose reduction without any appreciable loss in image quality. This work details the development of the tools and methods featuring real-time dosimetry which were used to provide pioneering measurements of ODM or TCM in dose reduction for CT.

  1. Does heightened fear of crime lead to poorer mental health in new suburbs, or vice versa?

    PubMed

    Foster, Sarah; Hooper, Paula; Knuiman, Matthew; Giles-Corti, Billie

    2016-11-01

    Fear of crime is implicated as a risk factor for poorer mental health, yet few studies have explored whether there is a causal relationship between fear of crime and health, or tested the direction of the relationship. Does, for example, heightened fear of crime lead to poorer mental health, or could poorer mental health exacerbate fear of crime? RESIDE participants in Perth, Australia, completed a questionnaire three years after moving to their neighbourhood (2007-2008, n = 1230), and again four years later (2011-2012, n = 531). The impact of fear of crime on psychological distress (Kessler-6) was examined in SAS using the Proc Mixed procedure (marginal repeated measures model with unrestricted variance pattern). Models controlled for demographics and time, and progressively adjusted for avoidance behaviours (i.e., walking, community participation, social cohesion). This approach was repeated with psychological distress as the independent variable and fear of crime as the outcome. For each increase in one standard deviation (SD) in fear of crime, psychological distress increased by 0.680 (p = 0.0001), however in the reversed models, for each one SD increase in psychological distress, fear of crime increased by 0.152 (p = 0.0001). To help explain these results, temporal order models examined whether baseline values predicted follow-up values. There was a significant association between psychological distress (at baseline) and fear of crime (at follow-up), but no association between fear of crime (at baseline) and psychological distress (at follow-up). The findings suggest a bi-directional relationship exists between fear of crime and mental health, however it appears that higher psychological distress over time leads to higher fear of crime, rather than the reverse. Furthermore, the pathway connecting fear of crime and mental health appears to be direct, rather than via constrained social and physical activities. Copyright © 2016 Elsevier Ltd. All rights

  2. Development and implementation of a non Gaussian model for the lateral dose prediction in a proton therapy treatment planning system

    NASA Astrophysics Data System (ADS)

    Bellinzona, V. E.

    2017-05-01

    Challenging issues in treatment planning system for hadrontherapy are the accurate and fast calculation of dose distribution, the reduction in memory space required to store the dose kernel of individual pencil beams and the shortening of computation time for dose optimization and calculation. In this framework, the prediction of lateral dose distributions is a topic of great interest because currently the double gaussian parametrization is typically used as approximation although other parameterizations are also available. The best accuracy for this kind of calculations can be obtained by Monte Carlo methods, at the expense of a long computing time. This work aims to present a flexible computational model for the calculation of the lateral profile of a pencil proton beam and the results of its implementation in a treatment planning system. The model calculation are compared with the currently used double gaussian approximation and the Monte Carlo calculations, and the tests are performed in water and in presence of inhomogeneities.

  3. Development of Dose-Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption.

    PubMed

    Guo, Miao; Mishra, Abhinav; Buchanan, Robert L; Dubey, Jitender P; Hill, Dolores E; Gamble, H Ray; Jones, Jeffrey L; Du, Xianzhi; Pradhan, Abani K

    2016-05-01

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose-response relationship for human exposures to T. gondii-infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose-response models based on animal studies, and to compute scaling factors so that animal-derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal-shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose-response relationship. Exponential and beta-Poisson models, which predicted similar responses, were selected as reasonable dose-response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse-derived models were validated against data for the dose-infection relationship in rats. A human dose-response model was developed as P (d) = 1-exp (-0.0015 × 0.005 × d) or P (d) = 1-(1 + d × 0.003 / 582.414)(-1.479) . Both models predict the human response after consuming T. gondii-infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen.

  4. Prediction of In-Phantom Dose Distribution Using In-Air Neutron Beam Characteristics for Boron Neutron Capture Synovectomy

    SciTech Connect

    Verbeke, Jerome M.; Chen, Allen S.; Vujic, Jasmina L.; Leung, Ka-Ngo

    2000-08-15

    A monoenergetic neutron beam simulation study was carried out to determine the optimal neutron energy range for treatment of rheumatoid arthritis using radiation synovectomy. The goal of the treatment is the ablation of diseased synovial membranes in joints such as knees and fingers. This study focuses on human knee joints. Two figures of merit are used to measure the neutron beam quality, the ratio of the synovium-absorbed dose to the skin-absorbed dose, and the ratio of the synovium-absorbed dose to the bone-absorbed dose. It was found that (a) thermal neutron beams are optimal for treatment and that (b) similar absorbed dose rates and therapeutic ratios are obtained with monodirectional and isotropic neutron beams. Computation of the dose distribution in a human knee requires the simulation of particle transport from the neutron source to the knee phantom through the moderator. A method was developed to predict the dose distribution in a knee phantom from any neutron and photon beam spectra incident on the knee. This method was revealed to be reasonably accurate and enabled one to reduce the particle transport simulation time by a factor of 10 by modeling the moderator only.

  5. Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiotherapy

    PubMed Central

    THOR, MARIA; APTE, ADITYA; DEASY, JOSEPH O.; MUREN, LUDVIG PAUL

    2016-01-01

    Background and purpose Internal organ motion over a course of radiotherapy (RT) leads to uncertainties in the actual delivered dose distributions. In studies predicting RT morbidity, the single estimate of the delivered dose provided by the treatment planning computed tomography (pCT) is typically assumed to be representative of the dose distribution throughout the course of RT. In this paper, a simple model for describing organ motion is introduced, and is associated to late rectal morbidity data, with the aim of improving morbidity prediction. Material and methods Organ motion was described by normally distributed translational motion, with its magnitude characterised by the standard deviation (SD) of this distribution. Simulations of both isotropic and anisotropic (anterior-posterior only) motion patterns were performed, as were random, systematic or combined random and systematic motion. The associations between late rectal morbidity and motion-inclusive delivered dose-volume histograms (dDVHs) were quantified using Spearman's rank correlation coefficient (Rs) in a series of 232 prostate cancer patients, and were compared to the associations obtained with the static/planned DVH (pDVH). Results For both isotropic and anisotropic motion, different associations with rectal morbidity were seen with the dDVHs relative to the pDVHs. The differences were most pronounced in the mid-dose region (40–60 Gy). The associations were dependent on the applied motion patterns, with the strongest association with morbidity obtained by applying random motion with an SD in the range 0.2–0.8 cm. Conclusion In this study we have introduced a simple model for describing organ motion occurring during RT. Differing and, for some cases, stronger dose-volume dependencies were found between the motion-inclusive dose distributions and rectal morbidity as compared to the associations with the planned dose distributions. This indicates that rectal organ motion during RT influences the

  6. Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiotherapy.

    PubMed

    Thor, Maria; Apte, Aditya; Deasy, Joseph O; Muren, Ludvig Paul

    2013-04-01

    Internal organ motion over a course of radiotherapy (RT) leads to uncertainties in the actual delivered dose distributions. In studies predicting RT morbidity, the single estimate of the delivered dose provided by the treatment planning computed tomography (pCT) is typically assumed to be representative of the dose distribution throughout the course of RT. In this paper, a simple model for describing organ motion is introduced, and is associated to late rectal morbidity data, with the aim of improving morbidity prediction. Organ motion was described by normally distributed translational motion, with its magnitude characterised by the standard deviation (SD) of this distribution. Simulations of both isotropic and anisotropic (anterior-posterior only) motion patterns were performed, as were random, systematic or combined random and systematic motion. The associations between late rectal morbidity and motion-inclusive delivered dose-volume histograms (dDVHs) were quantified using Spearman's rank correlation coefficient (Rs) in a series of 232 prostate cancer patients, and were compared to the associations obtained with the static/planned DVH (pDVH). For both isotropic and anisotropic motion, different associations with rectal morbidity were seen with the dDVHs relative to the pDVHs. The differences were most pronounced in the mid-dose region (40-60 Gy). The associations were dependent on the applied motion patterns, with the strongest association with morbidity obtained by applying random motion with an SD in the range 0.2-0.8 cm. In this study we have introduced a simple model for describing organ motion occurring during RT. Differing and, for some cases, stronger dose-volume dependencies were found between the motion-inclusive dose distributions and rectal morbidity as compared to the associations with the planned dose distributions. This indicates that rectal organ motion during RT influences the efforts to model the risk of morbidity using planning distributions

  7. A Novel Method to Incorporate the Spatial Location of the Lung Dose Distribution into Predictive Radiation Pneumonitis Modeling

    SciTech Connect

    Vinogradskiy, Yevgeniy; Tucker, Susan L.; Liao, Zhongxing; Martel, Mary K.

    2012-03-15

    Purpose: Studies have proposed that patients who receive radiation therapy to the base of the lung are more susceptible to radiation pneumonitis than patients who receive therapy to the apex of the lung. The primary purpose of the present study was to develop a novel method to incorporate the lung dose spatial information into a predictive radiation pneumonitis model. A secondary goal was to apply the method to a 547 lung cancer patient database to determine whether including the spatial information could improve the fit of our model. Methods and Materials: The three-dimensional dose distribution of each patient was mapped onto one common coordinate system. The boundaries of the coordinate system were defined by the extreme points of each individual patient lung. Once all dose distributions were mapped onto the common coordinate system, the spatial information was incorporated into a Lyman-Kutcher-Burman predictive radiation pneumonitis model. Specifically, the lung dose voxels were weighted using a user-defined spatial weighting matrix. We investigated spatial weighting matrices that linearly scaled each dose voxel according to the following orientations: superior-inferior, anterior-posterior, medial-lateral, left-right, and radial. The model parameters were fit to our patient cohort with the endpoint of severe radiation pneumonitis. The spatial dose model was compared against a conventional dose-volume model to determine whether adding a spatial component improved the fit of the model. Results: Of the 547 patients analyzed, 111 (20.3%) experienced severe radiation pneumonitis. Adding in a spatial parameter did not significantly increase the accuracy of the model for any of the weighting schemes. Conclusions: A novel method was developed to investigate the relationship between the location of the deposited lung dose and pneumonitis rate. The method was applied to a patient database, and we found that for our patient cohort, the spatial location does not influence

  8. SU-D-BRB-02: Combining a Commercial Autoplanning Engine with Database Dose Predictions to Further Improve Plan Quality

    SciTech Connect

    Robertson, SP; Moore, JA; Hui, X; Cheng, Z; McNutt, TR; DeWeese, TL; Tran, P; Quon, H; Bzdusek, K; Kumar, P

    2016-06-15

    Purpose: Database dose predictions and a commercial autoplanning engine both improve treatment plan quality in different but complimentary ways. The combination of these planning techniques is hypothesized to further improve plan quality. Methods: Four treatment plans were generated for each of 10 head and neck (HN) and 10 prostate cancer patients, including Plan-A: traditional IMRT optimization using clinically relevant default objectives; Plan-B: traditional IMRT optimization using database dose predictions; Plan-C: autoplanning using default objectives; and Plan-D: autoplanning using database dose predictions. One optimization was used for each planning method. Dose distributions were normalized to 95% of the planning target volume (prostate: 8000 cGy; HN: 7000 cGy). Objectives used in plan optimization and analysis were the larynx (25%, 50%, 90%), left and right parotid glands (50%, 85%), spinal cord (0%, 50%), rectum and bladder (0%, 20%, 50%, 80%), and left and right femoral heads (0%, 70%). Results: All objectives except larynx 25% and 50% resulted in statistically significant differences between plans (Friedman’s χ{sup 2} ≥ 11.2; p ≤ 0.011). Maximum dose to the rectum (Plans A-D: 8328, 8395, 8489, 8537 cGy) and bladder (Plans A-D: 8403, 8448, 8527, 8569 cGy) were significantly increased. All other significant differences reflected a decrease in dose. Plans B-D were significantly different from Plan-A for 3, 17, and 19 objectives, respectively. Plans C-D were also significantly different from Plan-B for 8 and 13 objectives, respectively. In one case (cord 50%), Plan-D provided significantly lower dose than plan C (p = 0.003). Conclusion: Combining database dose predictions with a commercial autoplanning engine resulted in significant plan quality differences for the greatest number of objectives. This translated to plan quality improvements in most cases, although special care may be needed for maximum dose constraints. Further evaluation is warranted

  9. A NEW SEMI-EMPIRICAL AMBIENT TO EFFECTIVE DOSE CONVERSION MODEL FOR THE PREDICTIVE CODE FOR AIRCREW RADIATION EXPOSURE (PCAIRE).

    PubMed

    Dumouchel, T; McCall, M; Lemay, F; Bennett, L; Lewis, B; Bean, M

    2016-12-01

    The Predictive Code for Aircrew Radiation Exposure (PCAIRE) is a semi-empirical code that estimates both ambient dose equivalent, based on years of on-board measurements, and effective dose to aircrew. Currently, PCAIRE estimates effective dose by converting the ambient dose equivalent to effective dose (E/H) using a model that is based on radiation transport calculations and on the radiation weighting factors recommended in International Commission on Radiological Protection (ICRP) 60. In this study, a new semi-empirical E/H model is proposed to replace the existing transport calculation models. The new model is based on flight data measured using a tissue-equivalent proportional counter (TEPC). The measured flight TEPC data are separated into a low- and a high-lineal-energy spectrum using an amplitude-weighted (137)Cs TEPC spectrum. The high-lineal-energy spectrum is determined by subtracting the low-lineal-energy spectrum from the measured flight TEPC spectrum. With knowledge of E/H for the low- and high-lineal-energy spectra, the total E/H is estimated for a given flight altitude and geographic location. The semi-empirical E/H model also uses new radiation weighting factors to align the model with the most recent ICRP 103 recommendations. The ICRP 103-based semi-empirical effective dose model predicts that there is a ∼30 % reduction in dose in comparison with the ICRP 60-based model. Furthermore, the ambient dose equivalent is now a more conservative dose estimate for jet aircraft altitudes in the range of 7-13 km (FL230-430). This new semi-empirical E/H model is validated against E/H predicted from a Monte Carlo N-Particle transport code simulation of cosmic ray propagation through the Earth's atmosphere. Its implementation allows PCAIRE to provide an accurate semi-empirical estimate of the effective dose. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Polonium in size fractionated mainstream cigarette smoke, predicted deposition and associated internal radiation dose.

    PubMed

    Tiwari, M; Sahu, S K; Bhangare, R C; Pandit, G G

    2016-10-01

    In this study, size fractionated mass and (210)Po activity concentrations in mainstream cigarette smoke (MCS) were monitored for three popular cigarette brands. Size segregated collection of MCS was carried out using a cascade type impactor, while mass and (210)Po activity concentration were analyzed gravimetrically and alpha spectrometry (following the radiochemical separation) respectively. Multiple-Path Particle Dosimetry (MPPD V2.11) model is used for prediction of deposition fraction calculations for the MCS deposition in different compartment of human respiratory tract. The activity concentration of (210)Po is founds 10.56 ± 2.46 mBq per cigarette for the tested cigarette brands. (210)Po size distribution indicates most of this associates with fine fraction (Dp < 2.23 μm) of cigarette smoke. The committed annual effective dose to smokers (smoking on an average 20 cigarette a day), considering the (210)Po and (210)Pb concentrations (assuming it is in secular equilibrium with (210)Po) in MCS, was estimated between 0.22 and 0.40 mSv, with mean value of 0.30 mSv for tested cigarette brands. Considering the risk factor of fatal cancer due to radiation exposure of lung (exposure time of 30 years); the average collective estimated fatal cancer risk is estimated as 1.5 × 10(-4) due to (210)Po and (210)Pb exposure to smokers. Copyright © 2016. Published by Elsevier Ltd.

  11. Predicted and observed therapeutic dose exceedances of ionizable pharmaceuticals in fish plasma from urban coastal systems.

    PubMed

    Scott, W Casan; Du, Bowen; Haddad, Samuel P; Breed, Christopher S; Saari, Gavin N; Kelly, Martin; Broach, Linda; Chambliss, C Kevin; Brooks, Bryan W

    2016-04-01

    Instream flows of the rapidly urbanizing watersheds and estuaries of the Gulf of Mexico in Texas (USA) are increasingly dominated by reclaimed waters. Though ionizable pharmaceuticals have received increasing attention in freshwaters, many research questions remain unanswered, particularly in tidally influenced urban coastal systems, which experience significant spatiotemporal variability in pH that influences bioavailability and bioaccumulation. The authors coupled fish plasma modeling of therapeutic hazard values with field monitoring of water chemistry variability and pharmaceutical occurrence to examine whether therapeutic hazards to fish existed within these urban coastal ecosystems and whether therapeutic hazards differed within and among coastal locations and seasons. Spatial and temporal fluctuations in pH within study sites altered the probability of encountering pharmaceutical hazards to fish. Significant water quality differences were consistently observed among traditional parameters and pharmaceuticals collected from surface and bottom waters, which are rarely sampled during routine surface water quality assessments. The authors then compared modeling predictions of fish plasma concentrations of pharmaceuticals to measured plasma levels from various field-collected fish species. Diphenhydramine and diltiazem were observed in plasma of multiple species, and diltiazem exceeded human therapeutic doses in largemouth bass, catfish, and mullet inhabiting these urban estuaries. Though the present study only examined a small number of target analytes, which represent a microcosm of the exposome of these fish, coastal systems are anticipated to be more strongly influenced by continued urbanization, altered instream flows, and population growth in the future. Unfortunately, aquatic toxicology information for diltiazem and many other pharmaceuticals is not available for marine and estuarine organisms, but such field observations suggest that potential adverse

  12. [Perspective of predictive toxicity assessment of in vivo repeated dose toxicity using structural activity relationship].

    PubMed

    Ono, Atsushi

    2010-01-01

    Tens of thousands of existing chemicals have been widely used for manufacture, agriculture, household and other purposes in worldwide. Only approximately 10% of chemicals have been assessed for human health hazard. The health hazard assessment of residual large number of chemicals for which little or no information of their toxicity is available is urgently needed for public health. However, the conduct of traditional toxicity tests which involves using animals for all of these chemicals would be economically impractical and ethically unacceptable. (Quantitative) Structure-Activity Relationships [(Q)SARs] are expected as method to have the potential to estimate hazards of chemicals from their structure, while reducing time, cost and animal testing currently needed. Therefore, our studies have been focused on evaluation of available (Q)SAR systems for estimating in vivo repeated toxicity on the liver. The results from our preliminary analysis showed the distribution for LogP of the chemicals which have potential to induce liver toxicity was bell-shape and indicating the possibility to estimate liver toxicity of chemicals from their physicochemical property. We have developed (Q)SAR models to in vivo liver toxicity using three commercially available systems (DEREK, ADMEWorks and MultiCASE) as well as combinatorial use of publically available chemoinformatic tools (CDK, MOSS and WEKA). Distinct data-sets of the 28-day repeated dose toxicity test of new and existing chemicals evaluated in Japan were used for model development and performance test. The results that concordances of commercial systems and public tools were almost same which below 70% may suggest currently attainable knowledge of in silico estimation of complex biological process, though it possible to obtain complementary and enhanced performance by combining predictions from different programs. In future, the combinatorial application of in silico and in vitro tests might provide more accurate

  13. Plasma Coenzyme Q10 Predicts Lipid-lowering Response to High-Dose Atorvastatin

    PubMed Central

    Pacanowski, Michael A.; Frye, Reginald F.; Enogieru, Osatohanmen; Schofield, Richard S.; Zineh, Issam

    2008-01-01

    Background Coenzyme Q10 (CoQ10) is a provitamin synthesized via the HMG-CoA reductase pathway, and thus may serve as a potential marker of intrinsic HMG-CoA reductase activity. HMG-CoA reductase inhibitors (statins) decrease CoQ10, although it is unclear whether this is due to reductions in lipoproteins, which transport CoQ10. Objectives We evaluated whether baseline plasma CoQ10 concentrations predict the lipid-lowering response to high-dose atorvastatin, and to what extent CoQ10 changes following atorvastatin therapy depend on lipoprotein changes. Methods Individuals without dyslipidemia or known cardiovascular disease (n=84) received atorvastatin 80 mg daily for 16 weeks. Blood samples collected at baseline and after 4, 8, and 16 weeks of treatment were assayed for CoQ10. Results Individuals with higher baseline CoQ10:LDL-C ratios displayed diminished absolute and percent LDL-C reductions at 8 and 16 weeks of atorvastatin treatment (P<0.001 to 0.01). After 16 weeks of atorvastatin, plasma CoQ10 decreased 45% from 762±301 ng/ml to 374±150 ng/ml (P<0.001). CoQ10 changes were correlated with LDL-C and apolipoprotein B changes (r=0.27-0.38, P=0.001-0.02), but remained significant when normalized to all lipoproteins. CoQ10 changes were not associated with adverse drug reactions. Conclusion Baseline CoQ10:LDL-C ratio was associated with the degree of LDL-C response to atorvastatin. Atorvastatin decreased CoQ10 concentrations in a manner that was not completely dependent on lipoprotein changes. The utility of CoQ10 as a predictor of atorvastatin response should be further explored in patients with dyslipidemia. PMID:19649137

  14. Are dual eligibles admitted to poorer quality skilled nursing facilities?

    PubMed

    Rahman, Momotazur; Grabowski, David C; Gozalo, Pedro L; Thomas, Kali S; Mor, Vincent

    2014-06-01

    Dual eligibles, persons who qualify for both Medicare and Medicaid coverage, often receive poorer quality care relative to other Medicare beneficiaries. To determine whether dual eligibles are discharged to lower quality post-acute skilled nursing facilities (SNFs) compared with Medicare-only beneficiaries. Following the random utility maximization model, we specified a discharge function using a conditional logit model and tested how this discharge rule varied by dual-eligibility status. A total of 692,875 Medicare fee-for-service patients (22% duals) who were discharged for Medicare paid SNF care between July 2004 and June 2005. Medicare enrollment and the Medicaid Analytic Extract files were used to determine dual eligibility. The proportion of Medicaid patients and nursing staff characteristics provided measures of SNF quality. Duals are more likely to be discharged to SNFs with a higher share of Medicaid patients and fewer nurses. These results are robust to estimation with an alternative subsample of patients based on primary diagnoses, propensity of being dual eligible, and likelihood of remaining in the nursing home. Disparities exist in access to quality SNF care for duals. Strategies to improve discharge planning processes are required to redirect patients to higher quality providers, regardless of Medicaid eligibility. © Health Research and Educational Trust.

  15. Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

    SciTech Connect

    Yuan, Lulin Wu, Q. Jackie; Yin, Fang-Fang; Yoo, David; Jiang, Yuliang; Ge, Yaorong

    2014-02-15

    Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trained with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined

  16. Dose prediction accuracy of anisotropic analytical algorithm and pencil beam convolution algorithm beyond high density heterogeneity interface

    PubMed Central

    Rana, Suresh B.

    2013-01-01

    Purpose: It is well known that photon beam radiation therapy requires dose calculation algorithms. The objective of this study was to measure and assess the ability of pencil beam convolution (PBC) and anisotropic analytical algorithm (AAA) to predict doses beyond high density heterogeneity. Materials and Methods: An inhomogeneous phantom of five layers was created in Eclipse planning system (version 8.6.15). Each layer of phantom was assigned in terms of water (first or top), air (second), water (third), bone (fourth), and water (fifth or bottom) medium. Depth doses in water (bottom medium) were calculated for 100 monitor units (MUs) with 6 Megavoltage (MV) photon beam for different field sizes using AAA and PBC with heterogeneity correction. Combinations of solid water, Poly Vinyl Chloride (PVC), and Styrofoam were then manufactured to mimic phantoms and doses for 100 MUs were acquired with cylindrical ionization chamber at selected depths beyond high density heterogeneity interface. The measured and calculated depth doses were then compared. Results: AAA's values had better agreement with measurements at all measured depths. Dose overestimation by AAA (up to 5.3%) and by PBC (up to 6.7%) was found to be higher in proximity to the high-density heterogeneity interface, and the dose discrepancies were more pronounced for larger field sizes. The errors in dose estimation by AAA and PBC may be due to improper beam modeling of primary beam attenuation or lateral scatter contributions or combination of both in heterogeneous media that include low and high density materials. Conclusions: AAA is more accurate than PBC for dose calculations in treating deep-seated tumor beyond high-density heterogeneity interface. PMID:24455541

  17. Dose prediction accuracy of anisotropic analytical algorithm and pencil beam convolution algorithm beyond high density heterogeneity interface.

    PubMed

    Rana, Suresh B

    2013-01-01

    It is well known that photon beam radiation therapy requires dose calculation algorithms. The objective of this study was to measure and assess the ability of pencil beam convolution (PBC) and anisotropic analytical algorithm (AAA) to predict doses beyond high density heterogeneity. An inhomogeneous phantom of five layers was created in Eclipse planning system (version 8.6.15). Each layer of phantom was assigned in terms of water (first or top), air (second), water (third), bone (fourth), and water (fifth or bottom) medium. Depth doses in water (bottom medium) were calculated for 100 monitor units (MUs) with 6 Megavoltage (MV) photon beam for different field sizes using AAA and PBC with heterogeneity correction. Combinations of solid water, Poly Vinyl Chloride (PVC), and Styrofoam were then manufactured to mimic phantoms and doses for 100 MUs were acquired with cylindrical ionization chamber at selected depths beyond high density heterogeneity interface. The measured and calculated depth doses were then compared. AAA's values had better agreement with measurements at all measured depths. Dose overestimation by AAA (up to 5.3%) and by PBC (up to 6.7%) was found to be higher in proximity to the high-density heterogeneity interface, and the dose discrepancies were more pronounced for larger field sizes. The errors in dose estimation by AAA and PBC may be due to improper beam modeling of primary beam attenuation or lateral scatter contributions or combination of both in heterogeneous media that include low and high density materials. AAA is more accurate than PBC for dose calculations in treating deep-seated tumor beyond high-density heterogeneity interface.

  18. Prediction of terrestrial gamma dose rate based on geological formations and soil types in the Johor State, Malaysia.

    PubMed

    Saleh, Muneer Aziz; Ramli, Ahmad Termizi; bin Hamzah, Khaidzir; Alajerami, Yasser; Moharib, Mohammed; Saeed, Ismael

    2015-10-01

    This study aims to predict and estimate unmeasured terrestrial gamma dose rate (TGDR) using statistical analysis methods to derive a model from the actual measurement based on geological formation and soil type. The measurements of TGDR were conducted in the state of Johor with a total of 3873 measured points which covered all geological formations, soil types and districts. The measurements were taken 1 m above the soil surface using NaI [Ti] detector. The measured gamma dose rates ranged from 9 nGy h(-1) to 1237 nGy h(-1) with a mean value of 151 nGy h(-1). The data have been normalized to fit a normal distribution. Tests of significance were conducted among all geological formations and soil types, using the unbalanced one way ANOVA. The results indicated strong significant differences due to the different geological formations and soil types present in Johor State. Pearson Correlation was used to measure the relations between gamma dose rate based on geological formation and soil type (D(G,S)) with the gamma dose rate based on geological formation (D(G)) or soil type (D(s)). A very good correlation was found between D(G,S) and D(G) or D(G,S) and D(s). A total of 118 pairs of geological formations and soil types were used to derive the statistical contribution of geological formations and soil types to gamma dose rates. The contribution of the gamma dose rate from geological formation and soil type were found to be 0.594 and 0.399, respectively. The null hypotheses were accepted for 83% of examined data, therefore, the model could be used to predict gamma dose rates based on geological formation and soil type information. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

    USGS Publications Warehouse

    Gutreuter, S.; Boogaard, M.A.

    2007-01-01

    Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

  20. Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

    PubMed Central

    Iwasaki, Hiroshi

    2014-01-01

    The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height) or train-of-four ratio (TOFR) as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245. PMID:24672542

  1. A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation.

    PubMed

    Andrews, Louise M; Hesselink, Dennis A; van Gelder, Teun; Koch, Birgit C P; Cornelissen, Elisabeth A M; Brüggemann, Roger J M; van Schaik, Ron H N; de Wildt, Saskia N; Cransberg, Karlien; de Winter, Brenda C M

    2017-07-05

    Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM(®)) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.

  2. PREDICTION OF OUTCOME IN SCHIZOPHRENIA USING THE SUBJECTIVE RESPONSE TO A TEST DOSE OF A NEUROLEPTIC

    PubMed Central

    Borde, Milind; Davis, Elizabeth J.B.; Sharma, L.N.

    1991-01-01

    SUMMARY Twenty four patients meeting R.D.C. criteria for schizophrenia were assessed using the B.P.R.S. before starting neuroleptics. They were then given a standardized test dose of haloperidol. Their subjective response to the test dose was assessed 4 hours later by a blind rater. The B.P.R.S. ratings were repeated after 3 weeks of neuroleptic treatment. A dysphoric response to the test dose was associated with a poor therapeutic outcome. The implications of these findings are discussed. PMID:21897458

  3. IL-6 is an independent predictive factor of drug survival after dose escalation of infliximab in patients with rheumatoid arthritis.

    PubMed

    Takasugi, Koji; Nishida, Keiichiro; Natsumeda, Masamitsu; Yamashita, Misuzu; Yamamoto, Wataru; Ezawa, Kazuhiko

    2017-08-22

    We aimed to investigate factors predictive of increased serum infliximab (IFX) concentration with improvement of disease activity, as well as better 1-year continuation rate after dose escalation, in patients with rheumatoid arthritis (RA) who showed inadequate response to 3 mg/kg IFX. Among 42 patients allotted to receive 3 mg/kg IFX, 13 patients showed adequate response (DAS28 < 3.2) and 29 patients required dose escalation to 4.5 or 6 mg/kg after inadequate response (DAS28 ≥ 3.2) to 3 mg/kg IFX. DAS28, mHAQ, serum level of CRP, interleukin (IL)-6, IL-17, anti-infliximab antibody (AIA) titers and IFX concentration before and on average 2.7 months after dose escalation were examined to explore the baseline factors predictive of a clinically beneficial increase of serum IFX concentration and drug survival. One year after IFX dose escalation, 25 patients completed the study protocol, and 16 patients (64%) continued to show a good response for one year, while 9 patients (36%) required switching of biologics because of inadequate response. Multivariate analyses revealed that a serum IL-6 level of less than 4.0 pg/mL at baseline was the only factor predictive of a clinically beneficial increase of serum IFX concentration in patients who required dose escalation. Receiver operating characteristic analysis revealed that 5.16 pg/mL of IL-6 was the cut-off value with sensitivity 0.833 and specificity of 0.769 (95%CI for AUC: 0.712-1.006). In patients with IL-6 levels of less than 5.16 pg/mL at baseline, the serum IFX concentration significantly increased after dose escalation with adequate response. The 1-year drug survival rates of patients with IL-6 levels less than 5.16 pg/mL and in those with levels greater than or equal to 5.16 pg/mL at baseline were 83.3% and 30.8%, respectively (log-rank test, p = .011). The results of our study indicated that a baseline serum level of IL-6 below 5.16 pg/mL might be a predictive factor for a

  4. Dose-Volume Parameters Predict for the Development of Chest Wall Pain After Stereotactic Body Radiation for Lung Cancer

    SciTech Connect

    Mutter, Robert W.; Liu Fan; Abreu, Andres; Yorke, Ellen; Jackson, Andrew; Rosenzweig, Kenneth E.

    2012-04-01

    Purpose: Chest wall (CW) pain has recently been recognized as an important adverse effect of stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). We developed a dose-volume model to predict the development of this toxicity. Methods and Materials: A total of 126 patients with primary, clinically node-negative NSCLC received three to five fractions of SBRT to doses of 40-60 Gy and were prospectively followed. The dose-absolute volume histograms of two different definitions of the CW as an organ at risk (CW3cm and CW2cm) were examined for all 126 patients. Results: With a median follow-up of 16 months, the 2-year estimated actuarial incidence of Grade {>=} 2 CW pain was 39%. The median time to onset of Grade {>=} 2 CW pain (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) was 9 months. There was no predictive advantage for biologically corrected dose over physical dose. Neither fraction number (p = 0.07) nor prescription dose (p = 0.07) were significantly correlated with the development of Grade {>=} 2 CW pain. Cox Proportional Hazards analysis identified significant correlation with a broad range of dose-volume combinations, with the CW volume receiving 30 Gy (V30) as one of the strongest predictors (p < 0.001). CW2cm consistently enabled better prediction of CW toxicity. When a physical dose of 30 Gy was received by more than 70 cm{sup 3} of CW2cm, there was a significant correlation with Grade {>=} 2 CW pain (p = 0.004). Conclusions: CW toxicity after SBRT is common and long-term follow-up is needed to identify affected patients. A volume of CW {>=} 70 cm{sup 3} receiving 30 Gy is significantly correlated with Grade {>=} 2 CW pain. We are currently applying this constraint at our institution for patients receiving thoracic SBRT. An actuarial atlas of our data is provided as an electronic supplement to facilitate data-sharing and meta-analysis relating to CW pain.

  5. Using body mass index to predict optimal thyroid dosing after thyroidectomy.

    PubMed

    Ojomo, Kristin A; Schneider, David F; Reiher, Alexandra E; Lai, Ngan; Schaefer, Sarah; Chen, Herbert; Sippel, Rebecca S

    2013-03-01

    Current postoperative thyroid replacement dosing is weight based, with adjustments made after thyroid-stimulating hormone values. This method can lead to considerable delays in achieving euthyroidism and often fails to accurately dose over- and underweight patients. Our aim was to develop an accurate dosing method that uses patient body mass index (BMI) data. A retrospective review of a prospectively collected thyroid database was performed. We selected adult patients undergoing thyroidectomy, with benign pathology, who achieved euthyroidism on thyroid hormone supplementation. Body mass index and euthyroid dose were plotted and regression was used to fit curves to the data. Statistical analysis was performed using STATA 10.1 software (Stata Corp). One hundred twenty-two patients met inclusion criteria. At initial follow-up, only 39 patients were euthyroid (32%). Fifty-three percent of patients with BMI >30 kg/m(2) were overdosed, and 46% of patients with BMI <25 kg/m(2) were underdosed. The line of best fit demonstrated an overall quadratic relationship between BMI and euthyroid dose. A linear relationship best described the data up to a BMI of 50. Beyond that, the line approached 1.1 μg/kg. A regression equation was derived for calculating initial levothyroxine dose (μg/kg/d = -0.018 × BMI + 2.13 [F statistic = 52.7, root mean square error of 0.24]). The current standard of weight-based thyroid replacement fails to appropriately dose underweight and overweight patients. Body mass index can be used to more accurately dose thyroid hormone using a simple formula. Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  6. Are phantoms useful for predicting the potential of dose reduction in full-field digital mammography?

    NASA Astrophysics Data System (ADS)

    Gennaro, Gisella; Katz, Luc; Souchay, Henri; Alberelli, Claudio; di Maggio, Cosimo

    2005-04-01

    A phantom study was performed in full-field digital mammography to investigate the opportunity and the magnitude of a possible dose reduction that would leave the image quality above the accepted thresholds associated with some classical phantoms. This preliminary work is intended to lay the groundwork for a future clinical study on the impact of dose reduction on clinical results. Three different mammography phantoms (ACR RMI 156, CIRS 11A and CDMAM 3.4) were imaged by a full-field digital mammography unit (GE Senographe 2000D) at different dose levels. Images were rated by three observers with softcopy reading and scoring methods specific to each phantom. Different types of data analysis were applied to the ACR (American College of Radiology) and the other two phantoms, respectively. With reference to the minimum acceptance score in screen/film accreditation programmes, the ACR phantom showed that about 45% dose reduction could be applied, while keeping the phantom scores above that threshold. A relative comparison was done for CIRS and CDMAM, for which no threshold is defined. CIRS scoring remained close to the reference level down to 40% dose reduction, the inter- and intra-observer variability being the main source of uncertainty. Contrast-detail curves provided by CDMAM overlapped down to 50% dose reduction, at least for object contrast values ranging between 30% and 3%. This multi-phantom study shows the potential of further reducing the dose in full-field digital mammography beyond the current values. A common dose reduction factor around 50% seems acceptable for all phantoms. However, caution is required before extrapolating the results for clinical use, given the limitations of these widely used phantoms, mainly related to their limited dynamic range and uniform background.

  7. The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review

    PubMed Central

    2016-01-01

    Background Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. Objective To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. Methods In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. Results We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Conclusion Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is

  8. Development of a novel individualized warfarin dose algorithm based on a population pharmacokinetic model with improved prediction accuracy for Chinese patients after heart valve replacement

    PubMed Central

    Zhu, Yu-bin; Hong, Xian-hua; Wei, Meng; Hu, Jing; Chen, Xin; Wang, Shu-kui; Zhu, Jun-rong; Yu, Feng; Sun, Jian-guo

    2017-01-01

    The gene-guided dosing strategy of warfarin generally leads to over-dose in patients at doses lower than 2 mg/kg, and only 50% of individual variability in daily stable doses can be explained. In this study, we developed a novel population pharmacokinetic (PK) model based on a warfarin dose algorithm for Han Chinese patients with valve replacement for improving the dose prediction accuracy, especially in patients with low doses. The individual pharmacokinetic (PK) parameter - apparent clearance of S- and R-warfarin (CLs) was obtained after establishing and validating the population PK model from 296 recruited patients with valve replacement. Then, the individual estimation of CLs, VKORC1 genotypes, the steady-state international normalized ratio (INR) values and age were used to describe the maintenance doses by multiple linear regression for 144 steady-state patients. The newly established dosing algorithm was then validated in an independent group of 42 patients and was compared with other dosing algorithms for the accuracy and precision of prediction. The final regression model developed was as follows: Dose=-0.023×AGE+1.834×VKORC1+0.952×INR+2.156×CLs (the target INR value ranges from 1.8 to 2.5). The validation of the algorithm in another group of 42 patients showed that the individual variation rate (71.6%) was higher than in the gene-guided dosing models. The over-estimation rate in patients with low doses (<2 mg/kg) was lower than the other dosing methods. This novel dosing algorithm based on a population PK model improves the predictive performance of the maintenance dose of warfarin, especially for low dose (<2 mg/d) patients. PMID:28216623

  9. Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

    PubMed

    Shi, J Q; Wang, B; Will, E J; West, R M

    2012-11-20

    We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

  10. Benchmarking B-cell epitope prediction with quantitative dose-response data on antipeptide antibodies: towards novel pharmaceutical product development.

    PubMed

    Caoili, Salvador Eugenio C

    2014-01-01

    B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data.

  11. Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

    PubMed Central

    Caoili, Salvador Eugenio C.

    2014-01-01

    B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID:24949474

  12. A New Drug Combinatory Effect Prediction Algorithm on the Cancer Cell Based on Gene Expression and Dose-Response Curve.

    PubMed

    Goswami, C Pankaj; Cheng, L; Alexander, P S; Singal, A; Li, L

    2015-02-01

    Gene expression data before and after treatment with an individual drug and the IC20 of dose-response data were utilized to predict two drugs' interaction effects on a diffuse large B-cell lymphoma (DLBCL) cancer cell. A novel drug interaction scoring algorithm was developed to account for either synergistic or antagonistic effects between drug combinations. Different core gene selection schemes were investigated, which included the whole gene set, the drug-sensitive gene set, the drug-sensitive minus drug-resistant gene set, and the known drug target gene set. The prediction scores were compared with the observed drug interaction data at 6, 12, and 24 hours with a probability concordance (PC) index. The test result shows the concordance between observed and predicted drug interaction ranking reaches a PC index of 0.605. The scoring reliability and efficiency was further confirmed in five drug interaction studies published in the GEO database.

  13. The Diagnostic Apathia Scale predicts a dose-remission relationship of T-PEMF in treatment-resistant depression.

    PubMed

    Bech, Per; Lunde, Marianne; Lauritzen, Lise; Straasø, Birgit; Lindberg, Lone; Vinberg, Maj; Undén, Mogens; Hellström, Lone Christina; Dissing, Steen; Larsen, Erik Roj

    2015-02-01

    The aim of this study was to evaluate the predictive validity of the apathy subsyndrome in patients with therapy-resistant depression in the dose-remission study with transcranial pulsating electromagnetic fields (T-PEMF). The apathy subsyndrome consists of the symptoms of fatigue, concentration and memory problems, lack of interests, difficulties in making decisions, and sleep problems. We evaluated 65 patients with therapy-resistant depression. In total, 34 of these patients received placebo T-PEMF in the afternoon and active T-PEMF in the morning, that is, one daily dose. The remaining 31 patients received active T-PEMF twice daily. Duration of treatment was 8 weeks in both groups. The Hamilton Depression Scale (HAM-D17) and the Bech-Rafaelsen Melancholia Scale (MES) were used to measure remission. We also focused on the Diagnostic Apathia Scale, which is based on a mixture of items from the MINI and the HAM-D17/MES. In patients without apathy, the remission rate after T-PEMF was 83.9% versus 58.8% in patients with apathy (p≤0.05). In patients without apathy receiving one active dose daily 94.4% remitted versus 50% for patients with apathy (p≤0.05). In patients without apathy who received two active doses 69.9% remitted versus 66.7% for patients with apathy (p≤0.05). Taking the baseline diagnosis of the apathy syndrome into consideration, we found that in patients without apathy one daily dose of T-PEMF is sufficient, but in patients with apathy two daily doses are necessary. Including the apathy syndrome as predictor in future studies would seem to be clinically relevant.

  14. Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy

    NASA Astrophysics Data System (ADS)

    Lamart, Stephanie; Imran, Rebecca; Simon, Steven L.; Doi, Kazutaka; Morton, Lindsay M.; Curtis, Rochelle E.; Lee, Choonik; Drozdovitch, Vladimir; Maass-Moreno, Roberto; Chen, Clara C.; Whatley, Millie; Miller, Donald L.; Pacak, Karel; Lee, Choonsik

    2013-12-01

    Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg-1 m2) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg-1 m3) and its transverse dimension increased with increasing PI (≈2.5 cm kg-1 m3). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good

  15. Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy

    PubMed Central

    Lamart, Stephanie; Imran, Rebecca; Simon, Steven L.; Doi, Kazutaka; Morton, Lindsay M.; Curtis, Rochelle E.; Lee, Choonik; Drozdovitch, Vladimir; Maass-Moreno, Roberto; Chen, Clara C.; Whatley, Millie; Miller, Donald L.; Pacak, Karel; Lee, Choonsik

    2014-01-01

    Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary Computed Tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm per kg/m2) whereas its craniocaudal dimension decreased with increasing PI (≈ −3.3 cm per kg/m3) and its transverse dimension increased with increasing PI (≈ 2.5 cm per kg/m3). Using the prediction models, we generated three dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated

  16. Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy.

    PubMed

    Lamart, Stephanie; Imran, Rebecca; Simon, Steven L; Doi, Kazutaka; Morton, Lindsay M; Curtis, Rochelle E; Lee, Choonik; Drozdovitch, Vladimir; Maass-Moreno, Roberto; Chen, Clara C; Whatley, Millie; Miller, Donald L; Pacak, Karel; Lee, Choonsik

    2013-12-21

    Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg(-1) m(2)) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg(-1) m(3)) and its transverse dimension increased with increasing PI (≈2.5 cm kg(-1) m(3)). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated

  17. Iron-deficiency anemia in infancy and poorer cognitive inhibitory control at age 10 years

    PubMed Central

    ALGARÍN, CECILIA; NELSON, CHARLES A; PEIRANO, PATRICIO; WESTERLUND, ALISSA; REYES, SUSSANNE; LOZOFF, BETSY

    2013-01-01

    Aim The aim of this study was to assess the effects of iron-deficiency anemia (IDA) in infancy on executive functioning at age 10 years, specifically inhibitory control on the Go/No-Go task. We predicted that children who had IDA in infancy would show poorer inhibitory control. Method We assessed cognitive inhibitory control in 132 Chilean children (mean [SD] age 10y 0mo [1mo]): 69 children had IDA in infancy (45 males, 24 females) and 63 comparison children who did not have IDA (26 males, 37 females). Participants performed the Go/No-Go task with event-related potentials. Group differences in behavioral (accuracy, reaction time) and electrophysiological outcomes (N2 and P300 components) were analyzed using repeated-measures analyses of variance. N2 and P300 are interpreted to reflect attention and resource allocation respectively. Results Relative to comparison participants, children who had IDA in infancy showed slower reaction time (mean [SE], 528.7ms [14.2] vs 485.0ms [15.0], 95% confidence interval [CI] for difference between groups 0.9–86.5); lower accuracy (95.4% [0.5] vs 96.9% [0.6], 95% CI −3.0 to −0.1); longer latency to N2 peak (378.9ms [4.9] vs 356.9ms [5.0], 95% CI 7.5–36.6); and smaller P300 amplitude (4.5μV [0.8] vs 7.6μV [0.9], 95% CI–5.5 to −0.5). Interpretation IDA in infancy was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy. These findings are consistent with the long-lasting effects of early IDA on myelination and/or prefrontal–striatal circuits where dopamine is the major neurotransmitter. PMID:23464736

  18. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants exposed to morphine

    PubMed Central

    Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily WY

    2017-01-01

    Objective To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). Study design A prospective cohort of 136 very preterm neonates (24–32 weeks gestational age) was serially scanned with MRI near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Scales of Motor Development-2 and cognitive outcomes with the Bayley-III at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. Results A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P=0.04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.2% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P=0.30). Greater morphine exposure also predicted poorer motor (P<0.001) and cognitive outcomes (P=0.006) at 18 months CA, an association mediated, in part, by slower brain growth. Conclusions Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. PMID:26763312

  19. Early COPD patients with lung hyperinflation associated with poorer lung function but better bronchodilator responsiveness

    PubMed Central

    Chen, Chunlan; Jian, Wenhua; Gao, Yi; Xie, Yanqing; Song, Yan; Zheng, Jinping

    2016-01-01

    Background It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation. We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation. Methods Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed. Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation. The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD. Results The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV. The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21–5.70, P=0.000–0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages. From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness. Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%–75.3%) and specificities (70.3%–75.7%). Conclusion We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation. PMID:27785008

  20. Thermal therapy in urologic systems: a comparison of arrhenius and thermal isoeffective dose models in predicting hyperthermic injury.

    PubMed

    He, Xiaoming; Bhowmick, Sankha; Bischof, John C

    2009-07-01

    The Arrhenius and thermal isoeffective dose (TID) models are the two most commonly used models for predicting hyperthermic injury. The TID model is essentially derived from the Arrhenius model, but due to a variety of assumptions and simplifications now leads to different predictions, particularly at temperatures higher than 50 degrees C. In the present study, the two models are compared and their appropriateness tested for predicting hyperthermic injury in both the traditional hyperthermia (usually, 43-50 degrees C) and thermal surgery (or thermal therapy/thermal ablation, usually, >50 degrees C) regime. The kinetic parameters of thermal injury in both models were obtained from the literature (or literature data), tabulated, and analyzed for various prostate and kidney systems. It was found that the kinetic parameters vary widely, and were particularly dependent on the cell or tissue type, injury assay used, and the time when the injury assessment was performed. In order to compare the capability of the two models for thermal injury prediction, thermal thresholds for complete killing (i.e., 99% cell or tissue injury) were predicted using the models in two important urologic systems, viz., the benign prostatic hyperplasia tissue and the normal porcine kidney tissue. The predictions of the two models matched well at temperatures below 50 degrees C. At higher temperatures, however, the thermal thresholds predicted using the TID model with a constant R value of 0.5, the value commonly used in the traditional hyperthermia literature, are much lower than those predicted using the Arrhenius model. This suggests that traditional use of the TID model (i.e., R=0.5) is inappropriate for predicting hyperthermic injury in the thermal surgery regime (>50 degrees C). Finally, the time-temperature relationships for complete killing (i.e., 99% injury) were calculated and analyzed using the Arrhenius model for the various prostate and kidney systems.

  1. The calculation of radial dose from heavy ions: predictions of biological action cross sections

    NASA Astrophysics Data System (ADS)

    Katz, Robert; Cucinotta, Francis A.; Zhang, C. X.

    1996-02-01

    The track structure model of heavy ion cross sections was developed by Katz and co-workers in the 1960s. In this model the action cross section is evaluated by mapping the dose-response of a detector to γ rays (modeled from biological target theory) onto the radial dose distribution from δ rays about the path of the ion. This is taken to yield the radial distribution of probability for a "hit" (an interaction leading to an observable end-point). Radial integration of the probability yields the cross section. When different response from ions of different Z having the same stopping power is observed this model may be indicated. Since the 1960s there have been several developments in the computation of the radial dose distribution, in the measurement of these distributions, and in new radiobiological data against which to test the model. The earliest model, by Butts and Katz, made use of simplified δ ray distribution functions, of simplified electron range-energy relations, and neglected angular distributions. Nevertheless it made possible the calculation of cross sections for the inactivation of enzymes and viruses, and allowed extension to tracks in nuclear emulsions and other detectors and to biological cells. It set the pattern for models of observable effects in the matter through which the ion passed. Here we outline subsequent calculations of radial dose which make use of improved knowledge of the electron emission spectrum, the electron range-energy relation, the angular distribution, and some considerations of molecular excitation, of particular interest both close to the path of the ion and the outer limits of electron penetration. These are applied to the modeling of action cross sections for the inactivation of several strains of E-coli and B. subtilis spores where extensive measurements in the "thin-down" region have been made with heavy ion beams. Such calculations serve to test the radial dose calculations at the outer limit of electron penetration

  2. The calculation of radial dose from heavy ions: predictions of biological action cross sections

    NASA Technical Reports Server (NTRS)

    Katz, R.; Cucinotta, F. A.; Zhang, C. X.; Wilson, J. W. (Principal Investigator)

    1996-01-01

    The track structure model of heavy ion cross sections was developed by Katz and co-workers in the 1960s. In this model the action cross section is evaluated by mapping the dose-response of a detector to gamma rays (modeled from biological target theory) onto the radial dose distribution from delta rays about the path of the ion. This is taken to yield the radial distribution of probability for a "hit" (an interaction leading to an observable end-point). Radial integration of the probability yields the cross section. When different response from ions of different Z having the same stopping power is observed this model may be indicated. Since the 1960s there have been several developments in the computation of the radial dose distribution, in the measurement of these distributions, and in new radiobiological data against which to test the model. The earliest model, by Butts and Katz made use of simplified delta ray distribution functions, of simplified electron range-energy relations, and neglected angular distributions. Nevertheless it made possible the calculation of cross sections for the inactivation of enzymes and viruses, and allowed extension to tracks in nuclear emulsions and other detectors and to biological cells. It set the pattern for models of observable effects in the matter through which the ion passed. Here we outline subsequent calculations of radial dose which make use of improved knowledge of the electron emission spectrum, the electron range-energy relation, the angular distribution, and some considerations of molecular excitation, of particular interest both close to the path of the ion and the outer limits of electron penetration. These are applied to the modeling of action cross sections for the inactivation of several strains of E-coli and B. subtilis spores where extensive measurements in the "thin-down" region have been made with heavy ion beams. Such calculations serve to test the radial dose calculations at the outer limit of electron

  3. The calculation of radial dose from heavy ions: predictions of biological action cross sections

    NASA Technical Reports Server (NTRS)

    Katz, R.; Cucinotta, F. A.; Zhang, C. X.; Wilson, J. W. (Principal Investigator)

    1996-01-01

    The track structure model of heavy ion cross sections was developed by Katz and co-workers in the 1960s. In this model the action cross section is evaluated by mapping the dose-response of a detector to gamma rays (modeled from biological target theory) onto the radial dose distribution from delta rays about the path of the ion. This is taken to yield the radial distribution of probability for a "hit" (an interaction leading to an observable end-point). Radial integration of the probability yields the cross section. When different response from ions of different Z having the same stopping power is observed this model may be indicated. Since the 1960s there have been several developments in the computation of the radial dose distribution, in the measurement of these distributions, and in new radiobiological data against which to test the model. The earliest model, by Butts and Katz made use of simplified delta ray distribution functions, of simplified electron range-energy relations, and neglected angular distributions. Nevertheless it made possible the calculation of cross sections for the inactivation of enzymes and viruses, and allowed extension to tracks in nuclear emulsions and other detectors and to biological cells. It set the pattern for models of observable effects in the matter through which the ion passed. Here we outline subsequent calculations of radial dose which make use of improved knowledge of the electron emission spectrum, the electron range-energy relation, the angular distribution, and some considerations of molecular excitation, of particular interest both close to the path of the ion and the outer limits of electron penetration. These are applied to the modeling of action cross sections for the inactivation of several strains of E-coli and B. subtilis spores where extensive measurements in the "thin-down" region have been made with heavy ion beams. Such calculations serve to test the radial dose calculations at the outer limit of electron

  4. Mixed Beam Murine Harderian Gland Tumorigenesis: Predicted Dose-Effect Relationships if neither Synergism nor Antagonism Occurs

    SciTech Connect

    Siranart, Nopphon; Blakely, Eleanor A.; Cheng, Alden; Handa, Naval; Sachs, Rainer K.

    2016-12-01

    Complex mixed radiation fields exist in interplanetary space, and not much is known about their latent effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology. However, for more than a century pharmacologists interested in mixtures of therapeutic drugs have analyzed conceptual, mathematical and practical questions similar to those that arise when analyzing mixed radiation fields, and have shown that simple effect additivity often gives unreasonable predictions when the IDER are curvilinear. Various alternatives to simple effect additivity proposed in radiobiology, pharmacometrics, toxicology and other fields are also known to have important limitations. In this work, we analyze upcoming murine Harderian gland (HG) tumor prevalence mixed-beam experiments, using customized open-source software and published IDER from past single-ion experiments. The upcoming experiments will use acute irradiation and the mixed beam will include components of high atomic number and energy (HZE). We introduce a new alternative to simple effect additivity, "incremental effect additivity", which is more suitable for the HG analysis and perhaps for other end points. We use incremental effect additivity to calculate default predictions for mixture dose-effect relationships, including 95% confidence intervals. We have drawn three main conclusions from this work. 1. It is important to supplement mixed-beam experiments with single-ion experiments, with matching end point(s), shielding and dose timing. 2. For HG tumorigenesis due to a mixed beam, simple effect additivity and incremental effect additivity sometimes give

  5. Multivariate analysis of factors predicting prostate dose in intensity-modulated radiotherapy

    SciTech Connect

    Tomita, Tsuneyuki; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Notogawa, Takuya; Miki, Katsuhito; Nakamura, Kiyonao; Ishigaki, Takashi

    2014-01-01

    We conducted a multivariate analysis to determine relationships between prostate radiation dose and the state of surrounding organs, including organ volumes and the internal angle of the levator ani muscle (LAM), based on cone-beam computed tomography (CBCT) images after bone matching. We analyzed 270 CBCT data sets from 30 consecutive patients receiving intensity-modulated radiation therapy for prostate cancer. With patients in the supine position on a couch with the HipFix system, data for center of mass (COM) displacement of the prostate and the state of individual organs were acquired and compared between planning CT and CBCT scans. Dose distributions were then recalculated based on CBCT images. The relative effects of factors on the variance in COM, dose covering 95% of the prostate volume (D{sub 95%}), and percentage of prostate volume covered by the 100% isodose line (V{sub 100%}) were evaluated by a backward stepwise multiple regression analysis. COM displacement in the anterior-posterior direction (COM{sub AP}) correlated significantly with the rectum volume (δVr) and the internal LAM angle (δθ; R = 0.63). Weak correlations were seen for COM in the left-right (R = 0.18) and superior-inferior directions (R = 0.31). Strong correlations between COM{sub AP} and prostate D{sub 95%} and V{sub 100%} were observed (R ≥ 0.69). Additionally, the change ratios in δVr and δθ remained as predictors of prostate D{sub 95%} and V{sub 100%}. This study shows statistically that maintaining the same rectum volume and LAM state for both the planning CT simulation and treatment is important to ensure the correct prostate dose in the supine position with bone matching.

  6. Multivariate analysis of factors predicting prostate dose in intensity-modulated radiotherapy.

    PubMed

    Tomita, Tsuneyuki; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Notogawa, Takuya; Miki, Katsuhito; Nakamura, Kiyonao; Ishigaki, Takashi

    2014-01-01

    We conducted a multivariate analysis to determine relationships between prostate radiation dose and the state of surrounding organs, including organ volumes and the internal angle of the levator ani muscle (LAM), based on cone-beam computed tomography (CBCT) images after bone matching. We analyzed 270 CBCT data sets from 30 consecutive patients receiving intensity-modulated radiation therapy for prostate cancer. With patients in the supine position on a couch with the HipFix system, data for center of mass (COM) displacement of the prostate and the state of individual organs were acquired and compared between planning CT and CBCT scans. Dose distributions were then recalculated based on CBCT images. The relative effects of factors on the variance in COM, dose covering 95% of the prostate volume (D95%), and percentage of prostate volume covered by the 100% isodose line (V100%) were evaluated by a backward stepwise multiple regression analysis. COM displacement in the anterior-posterior direction (COMAP) correlated significantly with the rectum volume (δVr) and the internal LAM angle (δθ; R = 0.63). Weak correlations were seen for COM in the left-right (R = 0.18) and superior-inferior directions (R = 0.31). Strong correlations between COMAP and prostate D95% and V100% were observed (R ≥ 0.69). Additionally, the change ratios in δVr and δθ remained as predictors of prostate D95% and V100%. This study shows statistically that maintaining the same rectum volume and LAM state for both the planning CT simulation and treatment is important to ensure the correct prostate dose in the supine position with bone matching. Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

  7. Changes in heparin dose response slope during cardiac surgery: possible result in inaccuracy in predicting heparin bolus dose requirement to achieve target ACT.

    PubMed

    Ichikawa, Junko; Mori, Tetsu; Kodaka, Mitsuharu; Nishiyama, Keiko; Ozaki, Makoto; Komori, Makiko

    2017-09-01

    The substantial interpatient variability in heparin requirement has led to the use of a heparin dose response (HDR) technique. The accuracy of Hepcon-based heparin administration in achieving a target activated clotting time (ACT) using an HDR slope remains controversial. We prospectively studied 86 adult patients scheduled for cardiac surgery requiring cardiopulmonary bypass. The total dose of calculated heparin required for patient and pump priming was administered simultaneously to achieve a target ACT of 450 s for HDR on the Hepcon HMS system. Blood samples were obtained after the induction of anesthesia, at 3 min after heparin administration and after the initiation of CPB to measure kaolin ACT, HDR slope, whole-blood heparin concentration based on the HDR slope and anti-Xa heparin concentration, antithrombin and complete blood count. The target ACT of 450 s was not achieved in 68.6% of patients. Compared with patients who achieved the target ACT, those who failed to achieve their target ACT had a significantly higher platelet count at baseline. Correlation between the HDR slope and heparin sensitivity was poor. Projected heparin concentration and anti-Xa heparin concentration are not interchangeable based on the Bland-Altman analysis. It can be hypothesized that the wide discrepancy in HDR slope versus heparin sensitivity may be explained by an inaccurate prediction of the plasma heparin level and/or the change in HDR of individual patients, depending on in vivo factors such as extravascular sequestration of heparin, decreased intrinsic antithrombin activity level and platelet count and/or activity.

  8. Potential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient

    PubMed Central

    Hernandez-Suarez, Dagmar F.; Claudio-Campos, Karla; Mirabal-Arroyo, Javier E.; Torres-Hernández, Bianca A.; López-Candales, Angel; Melin, Kyle; Duconge, Jorge

    2016-01-01

    Deep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives. A case to illustrate the clinical utility of ethno-specific pharmacogenetic testing in warfarin management of a Hispanic patient is reported. A 37-year-old Hispanic Puerto Rican, non-gravid female with past medical history of abnormal uterine bleeding on hormonal contraceptive therapy was evaluated for abdominal pain. Physical exam was remarkable for unspecific diffuse abdominal tenderness, and general initial laboratory results—including coagulation parameters—were unremarkable. A contrast-enhanced computed tomography showed a massive thrombosis of the main portal, splenic, and superior mesenteric veins. On admission the patient was started on oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin. The prediction of an effective warfarin dose of 7.5 mg/day, estimated by using a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics, coincided with the actual patient’s warfarin dose to reach the international normalized ratio target. We speculate that the slow rise in patient’s international normalized ratio observed on the initiation of warfarin therapy, the resulting high risk for thromboembolic events, and the required warfarin dose of 7.5 mg/day are attributable in some part to the presence of the NQO1*2 (g.559C>T, p.P187S) polymorphism, which seems to be significantly associated with resistance to warfarin in Hispanics. By adding genotyping results of this novel variant, the predictive model can inform clinicians better about the optimal warfarin dose in Caribbean Hispanics. The results highlight the potential for pharmacogenetic testing of warfarin to improve patient care. PMID:28210634

  9. Fesoterodine in patients with overactive bladder syndrome: can the severity of baseline urgency urinary incontinence predict dosing requirement?

    PubMed

    Cardozo, Linda; Khullar, Vik; Wang, Joseph T; Guan, Zhonghong; Sand, Peter K

    2010-09-01

    To determine whether baseline urgency urinary incontinence (UUI) episodes predict the need for increased doses of fesoterodine in patients with overactive bladder (OAB), as clinicians would benefit from data that help to predict which patients require higher doses of antimuscarinics to manage UUI episodes. In this pooled analysis of data from two double-blind, placebo-controlled trials, patients were randomized to placebo or fesoterodine 4 or 8 mg for 12 weeks and stratified into tertiles (>0-<2, 2-<4, or > or =4) according to the number of UUI episodes/24 h as recorded in 3-day bladder diaries at baseline. The change in mean UUI episodes/24 h from baseline to end of study was assessed using analysis of covariance. In a post hoc analysis of data from two clinical trials, there were significant reductions from baseline in UUI episodes for fesoterodine 4 and 8 mg vs placebo in patients (n) with >0-<2 (422), 2-<4 (424) and > or =4 (481) UUI episodes at baseline (all P < 0.01). In patients with 2-<4 and > or =4 UUI episodes at baseline, fesoterodine 8 mg gave significantly greater mean reductions (-1.92 and -4.17, respectively) vs fesoterodine 4 mg (-1.43 and -3.31) (P < 0.05). The most common adverse events were dry mouth (placebo, 8%; fesoterodine 4 mg, 19%; and 8 mg, 35%) and constipation (placebo, 2%; fesoterodine 4 mg, 5%; and 8 mg, 6%). Fesoterodine 4 and 8 mg significantly reduced UUI episodes vs placebo; this effect appeared to be greater with fesoterodine 8 mg in patients with > or =2 UUI episodes/24 h at baseline. Fesoterodine was well tolerated, although higher doses increased the incidence of adverse events. These findings might aid the clinical identification of patients with OAB who would most benefit from increasing the dose of fesoterodine from 4 to 8 mg.

  10. Stereotactic Body Radiotherapy for Patients With Unresectable Primary Hepatocellular Carcinoma: Dose-Volumetric Parameters Predicting the Hepatic Complication

    SciTech Connect

    Son, Seok Hyun; Choi, Byung Ock; Ryu, Mi Ryeong; Kang, Young Nam; Jang, Ji Sun; Bae, Si Hyun; Yoon, Seung Kew; Choi, Ihl Bohng; Kang, Ki Mun; Jang, Hong Seok

    2010-11-15

    Purpose: To identify the parameters that predict hepatic toxicity and deterioration of hepatic function. Materials and Methods: A total of 47 patients with small unresectable primary hepatocellular carcinoma received hypofractionated stereotactic body radiotherapy (SBRT) using the CyberKnife. Of those, 36 patients received no other local treatments that could influence hepatic toxicity at least for 3 months after the completion of SBRT. The gross tumor volume (GTV) was 18.3 {+-} 15.9 cm{sup 3} (range, 3.0-81.3 cm{sup 3}), and the total dose administered was 30-39 Gy (median, 36 Gy). To assess the deterioration of hepatic function, we evaluated the presence or absence of the progression of Child-Pugh class (CP class). To identify the parameters of predicting the radiation-induced hepatic toxicity and deterioration of the hepatic function, several clinical and dose-volumetric parameters were evaluated. Results: Of 36 patients, 12 (33%) developed Grade 2 or higher hepatic toxicity and 4 (11%) developed progression of CP class. The multivariate analysis showed that the only significant parameter associated with the progression of CP class was the total liver volume receiving a dose less than 18 Gy (<18 Gy). Conclusions: The progression of CP class after SBRT limits other additional local treatments and also reflects the deterioration of hepatic function. Therefore, it would be important to note that the presence or absence of the progression of CP class is a dose-limiting factor. The total liver volume receiving <18 Gy should be greater than 800 cm{sup 3} to reduce the risk of the deterioration of hepatic function.

  11. SU-F-BRB-10: A Statistical Voxel Based Normal Organ Dose Prediction Model for Coplanar and Non-Coplanar Prostate Radiotherapy

    SciTech Connect

    Tran, A; Yu, V; Nguyen, D; Woods, K; Low, D; Sheng, K

    2015-06-15

    Purpose: Knowledge learned from previous plans can be used to guide future treatment planning. Existing knowledge-based treatment planning methods study the correlation between organ geometry and dose volume histogram (DVH), which is a lossy representation of the complete dose distribution. A statistical voxel dose learning (SVDL) model was developed that includes the complete dose volume information. Its accuracy of predicting volumetric-modulated arc therapy (VMAT) and non-coplanar 4π radiotherapy was quantified. SVDL provided more isotropic dose gradients and may improve knowledge-based planning. Methods: 12 prostate SBRT patients originally treated using two full-arc VMAT techniques were re-planned with 4π using 20 intensity-modulated non-coplanar fields to a prescription dose of 40 Gy. The bladder and rectum voxels were binned based on their distances to the PTV. The dose distribution in each bin was resampled by convolving to a Gaussian kernel, resulting in 1000 data points in each bin that predicted the statistical dose information of a voxel with unknown dose in a new patient without triaging information that may be collectively important to a particular patient. We used this method to predict the DVHs, mean and max doses in a leave-one-out cross validation (LOOCV) test and compared its performance against lossy estimators including mean, median, mode, Poisson and Rayleigh of the voxelized dose distributions. Results: SVDL predicted the bladder and rectum doses more accurately than other estimators, giving mean percentile errors ranging from 13.35–19.46%, 4.81–19.47%, 22.49–28.69%, 23.35–30.5%, 21.05–53.93% for predicting mean, max dose, V20, V35, and V40 respectively, to OARs in both planning techniques. The prediction errors were generally lower for 4π than VMAT. Conclusion: By employing all dose volume information in the SVDL model, the OAR doses were more accurately predicted. 4π plans are better suited for knowledge-based planning than

  12. Calculation and Prediction of the Effect of Respiratory Motion on Whole Breast Radiation Therapy Dose Distributions

    SciTech Connect

    Cao Junsheng; Roeske, John C.; Chmura, Steve J.; Salama, Joseph K.; Shoushtari, Asal N.; Boyer, Arthur L.; Martel, Mary K.

    2009-07-01

    The standard treatment technique used for whole-breast irradiation can result in undesirable dose distributions in the treatment site, leading to skin reaction/fibrosis and pulmonary and cardiac toxicities. Hence, the technique has evolved from conventional wedged technique (CWT) to segment intensity-modulated radiation therapy (SIMRT) and beamlet IMRT (IMRT). However, these newer techniques feature more highly modulated dose distributions that may be affected by respiration. The purpose of this work was to conduct a simple study of the clinical impact of respiratory motion on breast radiotherapy dose distributions for the three treatment planning techniques. The ultimate goal was to determine which patients would benefit most from the use of motion management. Eight patients with early-stage breast cancer underwent a free-breathing (FB) computed tomography (CT) simulation, with medial and lateral markers placed on the skin. Two additional CT scans were obtained at the end of inspiration (EI) and the end of expiration (EE). The FB-CT scan was used to develop treatment plans using each technique. Each plan was then applied to EI and EE-CT scans. Compared with the FB CT scan, the medial markers moved up to 1.8 cm in the anterior-superior direction at the end of inspiration (EI-scan), and on average 8 mm. The CWT and SIMRT techniques were not 'sensitive' to respiratory motion, because the % clinical target volume (CTV) receiving 95% of the prescription dose (V{sub 95%}) remained constant for both techniques. For patients that had large respiratory motion indicated by marker movement >0.6 cm, differences in coverage of the CTV at the V100% between FB and EI for beamlet IMRT plans were on the order of >10% and up to 18%. A linear model was developed to relate the dosimetric coverage difference introduced by respiration with the motion information. With this model, the dosimetric coverage difference introduced by respiratory motion could be evaluated during patient CT

  13. Dose to Larynx Predicts for Swallowing Complications After Intensity-Modulated Radiotherapy

    SciTech Connect

    Caglar, Hale B.; Tishler, Roy B.; Burke, Elaine; Li Yi; Goguen, Laura; Norris, Carl M.; Allen, Aaron M.

    2008-11-15

    Purpose: To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. Methods and Materials: Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Women's Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. Results: A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose-volume metrics, including the volume of the larynx receiving {>=}50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving {>=}50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. Conclusion: Aspiration and stricture are common side effects after

  14. Aging and sequential modulations of poorer strategy effects: An EEG study in arithmetic problem solving.

    PubMed

    Hinault, Thomas; Lemaire, Patrick; Phillips, Natalie

    2016-01-01

    This study investigated age-related differences in electrophysiological signatures of sequential modulations of poorer strategy effects. Sequential modulations of poorer strategy effects refer to decreased poorer strategy effects (i.e., poorer performance when the cued strategy is not the best) on current problem following poorer strategy problems compared to after better strategy problems. Analyses on electrophysiological (EEG) data revealed important age-related changes in time, frequency, and coherence of brain activities underlying sequential modulations of poorer strategy effects. More specifically, sequential modulations of poorer strategy effects were associated with earlier and later time windows (i.e., between 200- and 550 ms and between 850- and 1250 ms). Event-related potentials (ERPs) also revealed an earlier onset in older adults, together with more anterior and less lateralized activations. Furthermore, sequential modulations of poorer strategy effects were associated with theta and alpha frequencies in young adults while these modulations were found in delta frequency and theta inter-hemispheric coherence in older adults, consistent with qualitatively distinct patterns of brain activity. These findings have important implications to further our understanding of age-related differences and similarities in sequential modulations of cognitive control processes during arithmetic strategy execution. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction.

    PubMed

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

  16. Low energy electron generator design and depth dose prediction for micro-superficies tumors treatment purposes

    NASA Astrophysics Data System (ADS)

    Khorshidi, Abdollah; Rajaee, Azimeh; Ahmadinejad, Marjan; Ghoranneviss, Mahmood; Ettelaee, Mehdi

    2014-09-01

    We investigate deposited energy and linear energy transfer (LET) of low energy ejection electrons in air and water layers of a generator design via a plasma source. A structured model of a concave cold cathode electron generator was designed and simulated by using Monte Carlo n-particle version X 2.7.0 (MCNPX) code. A negative dc high voltage was applied to a concave cathode up to -12 kV to determine electron energy activity. Results determined that the geometric dimensions of field size toward the anode increased in relation to the angle of the conic beam, widening the accumulated bulks. The increased field size increased the anode current, which also resulted in an increase of electron energy, a reduction in LET, a stretched build-up area and a dose curve that shifted to a higher depth. The biological effect of low energy electron radiation can be increased with an increase of LET; as the depth dose decreased, the electron energy increased at the same time. The study of electron irradiation as a conic beam from an electron generator may provide an accurate investigation of the indirect effect of low energy electrons on bystander cells.

  17. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    PubMed Central

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model. PMID:26989688

  18. Poorer verbal working memory for a second language selectively impacts academic achievement in university medical students.

    PubMed

    Mann, Collette; Canny, Benedict J; Reser, David H; Rajan, Ramesh

    2013-01-01

    Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50 and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50, showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress - all characteristics of the international students. Local students exhibited significantly lower SNR50 scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50 and the students' Visual/Verbal Learning Style (r = -0.023). Standard multiple regression was carried out to assess

  19. Poorer verbal working memory for a second language selectively impacts academic achievement in university medical students

    PubMed Central

    Canny, Benedict J.; Reser, David H.; Rajan, Ramesh

    2013-01-01

    Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50 ) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50 and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50 , showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress – all characteristics of the international students. Local students exhibited significantly lower SNR50 scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50 and the students’ Visual/Verbal Learning Style (r = −0.023). Standard multiple regression was carried out to

  20. Prescription dose and fractionation predict improved survival after stereotactic radiotherapy for brainstem metastases.

    PubMed

    Leeman, Jonathan E; Clump, David A; Wegner, Rodney E; Heron, Dwight E; Burton, Steven A; Mintz, Arlan H

    2012-07-11

    Brainstem metastases represent an uncommon clinical presentation that is associated with a poor prognosis. Treatment options are limited given the unacceptable risks associated with surgical resection in this location. However, without local control, symptoms including progressive cranial nerve dysfunction are frequently observed. The objective of this study was to determine the outcomes associated with linear accelerator-based stereotactic radiotherapy or radiosurgery (SRT/SRS) of brainstem metastases. We retrospectively reviewed 38 tumors in 36 patients treated with SRT/SRS between February 2003 and December 2011. Treatment was delivered with the Cyberknife™ or Trilogy™ radiosurgical systems. The median age of patients was 62 (range: 28-89). Primary pathologies included 14 lung, 7 breast, 4 colon and 11 others. Sixteen patients (44%) had received whole brain radiation therapy (WBRT) prior to SRT/SRS; ten had received prior SRT/SRS at a different site (28%). The median tumor volume was 0.94 cm3 (range: 0.01-4.2) with a median prescription dose of 17 Gy (range: 12-24) delivered in 1-5 fractions. Median follow-up for the cohort was 3.2 months (range: 0.4-20.6). Nineteen patients (52%) had an MRI follow-up available for review. Of these, one patient experienced local failure corresponding to an actuarial 6-month local control of 93%. Fifteen of the patients with available follow-up imaging (79%) experienced intracranial failure outside of the treatment volume. The median time to distant intracranial failure was 2.1 months. Six of the 15 patients with distant intracranial failure (40%) had received previous WBRT. The actuarial overall survival rates at 6- and 12-months were 27% and 8%, respectively. Predictors of survival included Graded Prognostic Assessment (GPA) score, greater number of treatment fractions, and higher prescription dose. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that

  1. Under pressure: predicting pressurized metered dose inhaler interactions using the atomic force microscope.

    PubMed

    Young, Paul M; Price, Robert; Lewis, David; Edge, Stephen; Traini, Daniela

    2003-06-01

    Drug particulate interactions in pressurized metered dose inhalers (pMDI) may lead to a decrease in aerosolization efficiency and subsequent efficacy in patient treatment. The interactions between salbutamol sulfate (commonly used in Ventolin pMDIs) and a series of pMDI canister materials were investigated using the atomic force microscope (AFM) colloid probe technique. Approximately 4000 individual force-distance curves were determined for a drug probe and three surfaces (10 x 10 mum areas) in situ, in a model propellant. The area under each force-distance curve was integrated to obtain separation energy values. Median separation energy values followed the rank order borosilicate glass > aluminum > PTFE, suggesting PTFE to be the most suitable canister coating.

  2. Clinical dose-volume histogram analysis in predicting radiation pneumonitis in Hodgkin's lymphoma

    SciTech Connect

    Koh, Eng-Siew; Sun, Alexander . E-mail: alex.sun@rmp.uhn.on.ca; Tu Huan Tran; Tsang, Richard; Pintilie, Melania; Hodgson, David C.; Wells, Woodrow; Heaton, Robert; Gospodarowicz, Mary K.

    2006-09-01

    Purpose: To quantify the incidence of radiation pneumonitis (RP) in a modern Hodgkin's lymphoma (HL) cohort, and to identify any clinically relevant parameters that may influence the risk of RP. Methods and Materials: Between January 2003 and February 2005, 64 consecutive HL patients aged 18 years or older receiving radical mediastinal radiation therapy (RT) were retrospectively reviewed. Symptomatic cases of radiation pneumonitis were identified. Dose-volume histogram parameters, including V{sub 13}, V{sub 2}, V{sub 3}, and mean lung dose (MLD), were quantified. Results: At a median follow-up of 2.1 years, the actuarial survival for all patients was 91% at 3 years. There were 2 (2/64) cases of Radiation Therapy Oncology Group (RTOG) Grade 2 RP (incidence 3.1%). Both index cases with corresponding V{sub 2} values of 47.0% and 40.7% were located in the upper quartile (2/16 cases), defined by a V{sub 2} value of {>=}36%, an incidence of 12.5% (p = 0.03). Similarly for total MLD, both index cases with values of 17.6 Gy and 16.4 Gy, respectively, were located in the upper quartile defined by MLD {>=}14.2 Gy, an incidence of 11.8% (2/17 cases, p = 0.02). Conclusions: Despite relatively high V{sub 2} values in this study of HL patients, the incidence of RP was only 3%, lower compared with the lung cancer literature. We suggest the following clinically relevant parameters be considered in treatment plan assessment: a V{sub 2} greater than 36% and an MLD greater than 14 Gy, over and above which the risk of RTOG Grade 2 or greater RP would be considered clinically significant.

  3. Prediction of powdered activated carbon doses for 2-MIB removal in drinking water treatment using a simplified HSDM approach.

    PubMed

    Yu, Jianwei; Yang, Fong-Chen; Hung, Wei-Nung; Liu, Chia-Ling; Yang, Min; Lin, Tsair-Fuh

    2016-08-01

    The addition of powdered activated carbon (PAC) is an effective measure to cope with seasonal taste and odor (T&O) problems caused by 2-methylisoborneol (2-MIB) and trans-1, 10-dimethyl-trans-9-decalol (geosmin) in drinking water. Some T&O problems are episodic in nature, and generally require rapid responses. This paper proposed a simplified approach for the application of the homogenous surface diffusion model (HSDM) to predict the appropriate PAC doses for the removal of 2-MIB. Equilibrium and kinetic experiments were performed for 2-MIB adsorption onto five PACs in three source waters. The simplified HSDM approach was compared with the experimental data, by assigning the Freundlich 1/n value in the range of 0.1-1.0 and obtaining the Freundlich equilibrium parameter K value through a 6-hr adsorption kinetic test. The model describes the kinetic adsorption data very well for all of the tested PACs in different source waters. The results were validated using the data obtained from one full scale water treatment plant, and the differences between the predicted and observed results were within 10% range. This simplified HSDM approach may be applied for the rapid determination of PAC doses for water treatment plants when faced with 2-MIB episodes in source waters. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Predicting the hazardous dose of industrial chemicals in warm-blooded species using machine learning-based modelling approaches.

    PubMed

    Gupta, S; Basant, N; Singh, K P

    2015-06-01

    The hazardous dose of a chemical (HD50) is an emerging and acceptable test statistic for the safety/risk assessment of chemicals. Since it is derived using the experimental toxicity values of the chemical in several test species, it is highly cumbersome, time and resource intensive. In this study, three machine learning-based QSARs were established for predicting the HD50 of chemicals in warm-blooded species following the OECD guidelines. A data set comprising HD50 values of 957 chemicals was used to develop SDT, DTF and DTB QSAR models. The diversity in chemical structures and nonlinearity in the data were verified. Several validation coefficients were derived to test the predictive and generalization abilities of the constructed QSARs. The chi-path descriptors were identified as the most influential in three QSARs. The DTF and DTB performed relatively better than SDT model and yielded r(2) values of 0.928 and 0.959 between the measured and predicted HD50 values in the complete data set. Substructure alerts responsible for the toxicity of the chemicals were identified. The results suggest the appropriateness of the developed QSARs for reliably predicting the HD50 values of chemicals, and they can be used for screening of new chemicals for their safety/risk assessment for regulatory purposes.

  5. Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

    SciTech Connect

    Feng, Felix Y.; Qian Yushen; Stenmark, Matthew H.; Halverson, Schuyler; Blas, Kevin; Vance, Sean; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-15

    Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose {>=}75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

  6. Serum levels of vancomycin: is there a prediction using doses in mg/kg/day or m(2)/day for neonates?

    PubMed

    Romanelli, Roberta Maia de Castro; Anchieta, Lêni Márcia; Fernandes, Juliana Chaves Abreu; Lima, Mariana Antunes Faria; Souza, Taís Marina de; Rosado, Viviane; Clemente, Wanessa Trindade; Camargos, Paulo Augusto Moreira

    2016-01-01

    Coagulase-negative Staphylococcus has been identified as the main nosocomial agent of neonatal late-onset sepsis. However, based on the pharmacokinetics and erratic distribution of vancomycin, recommended empirical dose is not ideal, due to the inappropriate serum levels that have been measured in neonates. The aim of this study was to evaluate serum levels of vancomycin used in newborns and compare the prediction of adequate serum levels based on doses calculated according to mg/kg/day and m(2)/day. This is an observational reprospective cohort at a referral neonatal unit, from 2011 to 2013. Newborns treated with vancomycin for the first episode of late-onset sepsis were included. Total dose in mg/kg/day, dose/m(2)/day, age, weight, body surface and gestational age were identified as independent variables. For predictive analysis of adequate serum levels, multiple linear regressions were performed. The Receiver Operating Characteristic curve for proper serum vancomycin levels was also obtained. A total of 98 patients received 169 serum dosages of the drug, 41 (24.3%) of the doses had serum levels that were defined as appropriate. Doses prescribed in mg/kg/day and dose/m(2)/day predicted serum levels in only 9% and 4% of cases, respectively. Statistical significance was observed with higher doses when the serum levels were considered as appropriate (p<0.001). A dose of 27mg/kg/day had a sensitivity of 82.9% to achieve correct serum levels of vancomycin. Although vancomycin has erratic serum levels and empirical doses cannot properly predict the target levels, highest doses in mg/kg/day were associated with adequate serum levels. Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  7. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

    PubMed

    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  8. Aging effects in sequential modulations of poorer-strategy effects during execution of memory strategies.

    PubMed

    Hinault, Thomas; Lemaire, Patrick; Touron, Dayna

    2017-02-01

    In this study, we asked young adults and older adults to encode pairs of words. For each item, they were told which strategy to use, interactive imagery or rote repetition. Data revealed poorer-strategy effects in both young adults and older adults: Participants obtained better performance when executing better strategies (i.e., interactive-imagery strategy to encode pairs of concrete words; rote-repetition strategy on pairs of abstract words) than with poorer strategies (i.e., interactive-imagery strategy on pairs of abstract words; rote-repetition strategy on pairs of concrete words). Crucially, we showed that sequential modulations of poorer-strategy effects (i.e., poorer-strategy effects being larger when previous items were encoded with better relative to poorer strategies), previously demonstrated in arithmetic, generalise to memory strategies. We also found reduced sequential modulations of poorer-strategy effects in older adults relative to young adults. Finally, sequential modulations of poorer-strategy effects correlated with measures of cognitive control processes, suggesting that these processes underlie efficient trial-to-trial modulations during strategy execution. Differences in correlations with cognitive control processes were also found between older adults and young adults. These findings have important implications regarding mechanisms underlying memory strategy execution and age differences in memory performance.

  9. Isothermal calorimetry: a predictive tool to model drug-propellant interactions in pressurized metered dose systems.

    PubMed

    Ooi, Jesslynn; Gaisford, Simon; Boyd, Ben J; Young, Paul M; Traini, Daniela

    2014-01-30

    The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.

  10. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose

    PubMed Central

    Seeman, P

    2016-01-01

    Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects. PMID:27754480

  11. Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study

    PubMed Central

    Müller, Daniel J.; Ng, Chee H.; Byron, Keith; Berk, Michael; Singh, Ajeet B.

    2017-01-01

    Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n=95), there was a strong concordance (Kendall’s τ-b=0.84, P=0.0001; Cohen’s κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. PMID:27779571

  12. High Fibrinogen in Peripheral Blood Correlates with Poorer Hearing Recovery in Idiopathic Sudden Sensorineural Hearing Loss

    PubMed Central

    Kanzaki, Sho; Sakagami, Masafumi; Hosoi, Hiroshi; Murakami, Shingo; Ogawa, Kaoru

    2014-01-01

    Objectives We used hearing tests and peripheral blood sample analyses to characterize the pathology of idiopathic sudden sensorineural hearing loss (ISSNHL) and to identify possible prognostic factors for predicting recovery of hearing loss. Study Design A retrospective, multicenter trial was conducted. Methods Two hundred three patients examined within 7 days after the onset of ISSNHL received prednisone with lipo-prostaglandin E1. Pure-tone auditory tests were performed before and after treatment with these drugs. Blood tests were performed on blood samples collected during the patients’ initial visit to our clinic. Results In all patients, elevated white blood cell (WBC) counts, fasting blood sugar levels, HgbA1c, and erythrocyte sedimentation rate (ESR) significantly correlated with high hearing threshold measurements obtained on the initial visit. High fibrinogen levels, WBC counts, ESR, and low concentrations of fibrinogen degradation products (FDP) were associated with lower hearing recovery rates. Additionally, different audiogram shapes correlated with different blood test factors, indicating that different pathologies were involved. Conclusions High fibrinogen levels measured within seven days after ISSNHL onset correlated with poorer hearing recovery. This may be a consequence of ischemia or infections in the inner ear. The high WBC counts also observed may therefore reflect an immune response to inner ear damage induced by ischemic changes or infections. Our data indicate that therapeutic strategies should be selected based on the timing of initial treatment relative to ISSNHL onset. PMID:25166620

  13. The predictive factors of α1-D/A adrenoceptor antagonist, naftopidil, dose increase therapy for male lower urinary tract symptoms caused by benign prostatic hyperplasia: INFORM study.

    PubMed

    Tanuma, Yasushi; Tanaka, Yoshinori; Takeyama, Ko; Okamoto, Tomoshi

    2017-01-01

    We evaluated the predictive factors which affect the efficacy of naftopidil 50 mg/day therapy and dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. A total of 92 patients with male lower urinary tract symptoms/benign prostatic hyperplasia were administrated naftopidil 50 mg/day for 4 weeks (50 mg therapy). At week 4, the patients were divided into an effective and an ineffective group (Group E and Group I, respectively). For further 4 weeks, the dosage of naftopidil was increased to 75 mg/day in all patients. At week 8, the patients of Group E and Group I were divided into an effective and an ineffective group (Group EE, Group EI, Group IE, and Group II, respectively). Postvoid residual (PVR) urine volume at baseline was a predictive factor for efficacy of 50 mg therapy. In Group E, change in International Prostate Symptom Score storage symptoms subscore from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. In Group I, change in maximum flow rate from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. The short term of naftopidil 50 mg therapy was ineffective for the patients who had large PVR. The predictive factor of this dose increase therapy might be a dynamic variable in 50 mg/day of dose period, but not a baseline variable at the time of 75 mg/day dosage starts.

  14. Assessment of uncertainties in radiation-induced cancer risk predictions at clinically relevant doses

    SciTech Connect

    Nguyen, J.; Moteabbed, M.; Paganetti, H.

    2015-01-15

    Purpose: Theoretical dose–response models offer the possibility to assess second cancer induction risks after external beam therapy. The parameters used in these models are determined with limited data from epidemiological studies. Risk estimations are thus associated with considerable uncertainties. This study aims at illustrating uncertainties when predicting the risk for organ-specific second cancers in the primary radiation field illustrated by choosing selected treatment plans for brain cancer patients. Methods: A widely used risk model was considered in this study. The uncertainties of the model parameters were estimated with reported data of second cancer incidences for various organs. Standard error propagation was then subsequently applied to assess the uncertainty in the risk model. Next, second cancer risks of five pediatric patients treated for cancer in the head and neck regions were calculated. For each case, treatment plans for proton and photon therapy were designed to estimate the uncertainties (a) in the lifetime attributable risk (LAR) for a given treatment modality and (b) when comparing risks of two different treatment modalities. Results: Uncertainties in excess of 100% of the risk were found for almost all organs considered. When applied to treatment plans, the calculated LAR values have uncertainties of the same magnitude. A comparison between cancer risks of different treatment modalities, however, does allow statistically significant conclusions. In the studied cases, the patient averaged LAR ratio of proton and photon treatments was 0.35, 0.56, and 0.59 for brain carcinoma, brain sarcoma, and bone sarcoma, respectively. Their corresponding uncertainties were estimated to be potentially below 5%, depending on uncertainties in dosimetry. Conclusions: The uncertainty in the dose–response curve in cancer risk models makes it currently impractical to predict the risk for an individual external beam treatment. On the other hand, the ratio

  15. Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated 186Re radionuclides

    NASA Astrophysics Data System (ADS)

    Hrycushko, Brian A.; Ware, Steve; Li, Shihong; Bao, Ande

    2011-09-01

    Crucial to all cancer therapy modalities is a strong correlation between treatment and effect. Predictability of therapy success/failure allows for the optimization of treatment protocol and aids in the decision of whether additional treatment is necessary to prevent tumour progression. This work evaluated the relationship between cancer treatment and effect for intratumoural infusions of liposome-encapsulated 186Re to head and neck squamous cell carcinoma xenografts of nude rats. Absorbed dose calculations using a dose-point kernel convolution technique showed significant intratumoural dose heterogeneity due to the short range of the beta-particle emissions. The use of three separate tumour infusion locations improved dose homogeneity compared to a single infusion location as a result of a more uniform radioactivity distribution. An improved dose-response correlation was obtained when using effective uniform dose (EUD) calculations based on a generic set of radiobiological parameters (R2 = 0.84) than when using average tumour absorbed dose (R2 = 0.22). Varying radiobiological parameter values over ranges commonly used for all types of tumours showed little effect on EUD calculations, which suggests that individualized parameter use is of little significance as long as the intratumoural dose heterogeneity is taken into consideration in the dose-response relationship. The improved predictability achieved when using EUD calculations for this cancer therapy modality may be useful for treatment planning and evaluation.

  16. Greater emotional arousal predicts poorer long-term memory of communication skills in couples.

    PubMed

    Baucom, Brian R; Weusthoff, Sarah; Atkins, David C; Hahlweg, Kurt

    2012-06-01

    Many studies have examined the importance of learning skills in behaviorally based couple interventions but none have examined predictors of long-term memory for skills. Associations between emotional arousal and long-term recall of communication skills delivered to couples during a behaviorally based relationship distress prevention program were examined in a sample of 49 German couples. Fundamental frequency (f(0)), a vocal measure of encoded emotional arousal, was measured during pre-treatment couple conflict. Higher levels of f(0) were linked to fewer skills remembered 11 years after completing the program, and women remembered more skills than men. Implications of results for behaviorally based couple interventions are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Greater emotional arousal predicts poorer long-term memory of communication skills in couples

    PubMed Central

    Baucom, Brian R.; Weusthoff, Sarah; Atkins, David; Hahlweg, Kurt

    2012-01-01

    Many studies have examined the importance of learning skills in behaviorally based couple interventions but none have examined predictors of long-term memory for skills. Associations between emotional arousal and long-term recall of communication skills delivered to couples during a behaviorally based relationship distress prevention program were examined in a sample of 49 German couples. Fundamental frequency (f0), a vocal measure of encoded emotional arousal, was measured during pre-treatment couple conflict. Higher levels of f0 were linked to fewer skills remembered 11 years after completing the program, and women remembered more skills than men. Implications of results for behaviorally based couple interventions are discussed. PMID:22542535

  18. Early interim FDG PET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease-added value of low-dose CT.

    PubMed

    Ilivitzki, Anat; Radan, Lea; Ben-Arush, Miriam; Israel, Ora; Ben-Barak, Ayelet

    2013-01-01

    Interim 18F-FDG PET helps predict outcome and tailor treatment in adults with Hodgkin disease (HD). The purpose of this study was to assess predictive values of interim 18F-FDG PET/CT in children with HD and to define the potential added value to interim PET of low-dose CT. Children were prospectively enrolled August 2002-April 2007. PET/low-dose CT was performed at staging, after 2 cycles, at the end of treatment and during follow-up (mean 45 months). Treatment was unchanged regardless of interim results. PET and low-dose CT were read independently. Of 34 enrolled children (ages 3-17 years), 27 achieved complete response, 4 had progressive disease and 3 had relapse. Interim PET alone had positive and negative predictive values of 67% and 89%, respectively. Interim low-dose CT alone had positive and negative predictive values of 35% and 100%, respectively. Interim PET/CT had positive and negative predictive values of 75% and 96%, respectively. Early interim PET/CT was a good predictor of outcome. Integrated PET and low-dose CT improved the predictive value in children with HD.

  19. Fit and Vigilant: The Relationship between Poorer Aerobic Fitness and Failures in Sustained Attention during Preadolescence

    PubMed Central

    Pontifex, Matthew B.; Scudder, Mark R.; Drollette, Eric S.; Hillman, Charles H.

    2012-01-01

    With the growing trend toward engagement in sedentary behaviors during childhood, a greater understanding of the relationship between cardiorespiratory fitness and cognition during development is of increasing importance. Objective The aim of this investigation was to assess the extent to which failures in sustained attention may underlie deficits in cognition associated with poorer aerobic fitness. Method A sample of 62 preadolescent children between the ages of 9 and 10 years were separated into higher- and lower-fit groups according to their cardiorespiratory fitness. Results Findings indicated that lower-fit children exhibited poorer overall response accuracy during a task requiring aspects of cognitive control relative to their higher-fit counterparts, with a disproportionately greater number of errors of omission, and longer, more frequent sequential errors of omission. Conclusions These findings suggest that poorer vigilance may contribute to deficits in cognitive control associated with poorer aerobic fitness. PMID:22746307

  20. Dosimetric verification of IMAT delivery with a conventional EPID system and a commercial portal dose image prediction tool

    SciTech Connect

    Iori, Mauro; Cagni, Elisabetta; Paiusco, Marta; Munro, Peter; Nahum, Alan E.

    2010-01-15

    Purpose: The electronic portal imaging device (EPID) is a system for checking the patient setup; as a result of its integration with the linear accelerator and software customized for dosimetry, it is increasingly used for verification of the delivery of fixed-field intensity-modulated radiation therapy (IMRT). In order to extend such an approach to intensity-modulated arc therapy (IMAT), the combined use of an EPID system and a portal dose image prediction (PDIP) tool has been investigated. Methods: The dosimetric behavior of an EPID system, mechanically reinforced to maintain its positional stability during the accelerator gantry rotation, has been studied to assess its ability to measure portal dose distributions for IMAT treatment beams. In addition, the PDIP tool of a commercial treatment planning system, commonly used for static IMRT dosimetry, has been validated for simulating the PDIs of IMAT treatment fields. The method has been applied to the delivery verification of 23 treatment fields that were measured in their dual mode of IMRT and IMAT modalities. Results: The EPID system has proved to be appropriate for measuring the PDIs of IMAT fields; additionally the PDIP tool was able to simulate these accurately. The results are quite similar to those obtained for static IMRT treatment verification, although it was necessary to investigate the dependence of the EPID signal and of the accelerator monitor chamber response on variable dose rate. Conclusions: Our initial tests indicate that the EPID system, together with the PDIP tool, is a suitable device for the verification of IMAT plan delivery; however, additional tests are necessary to confirm these results.

  1. Does the pretherapeutic tumor SUV in 68Ga DOTATOC PET predict the absorbed dose of 177Lu octreotate?

    PubMed

    Ezziddin, Samer; Lohmar, Jonas; Yong-Hing, Charlotte J; Sabet, Amir; Ahmadzadehfar, Hojjat; Kukuk, Guido; Biersack, Hans-Jürgen; Guhlke, Stefan; Reichmann, Karl

    2012-06-01

    Selection of candidates for peptide receptor radionuclide therapy (PRRT) is increasingly based on receptor positron emission tomography (PET) imaging, including the common tracer 68Ga DOTATOC. However, no studies have yet compared standardized uptake values (SUVs) and absorbed doses in this field. We retrospectively analyzed a consecutive cohort of 21 patients with 61 evaluable tumor lesions undergoing both pretherapeutic 68Ga DOTATOC-PET/CT (Biograph Duo [Siemens Medical Solutions, Erlangen, Germany]; PET acquisition, 75.3 ± 15.4 minutes postinjection; 117.3 ± 33.9 MBq 68Ga DOTATOC) and PRRT with Lu octreotate (7.47 ± 1.39 GBq; intratherapeutic tumor dosimetry with serial whole-body scans; 1, 2, and 4 days postinjection) at our institution. SUVs were compared with the tumor-absorbed doses per injected activity (D/A0) of the subsequent first treatment cycle. The correlation of SUV and D/A0 was r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P < 0.001. Pancreatic origin and hepatic localization were associated with higher D/A0, and chromogranin A level and Ki-67 index had no influence on SUV or D/A0. High-SUV lesions (SUVmean >15; SUVmax >25) resulted in high D/A0 (>10 Gy/GBq) in 66.7% to 70.8% and low D/A0 (<5 Gy/GBq) in only 8.3% to 12.5% on subsequent PRRT. The mentioned low D/A0 range, on the other hand, was achieved by all lesions with SUVmean <7 or SUVmax <9. Somatostatin receptor PET imaging may predict tumor-absorbed doses. The ability to indicate insufficient target irradiation by a low SUV could aid in selection of appropriate candidates for PRRT. However, larger series are needed to confirm and validate these initial findings.

  2. Low Dose of Some Persistent Organic Pollutants Predicts Type 2 Diabetes: A Nested Case–Control Study

    PubMed Central

    Lee, Duk-Hee; Steffes, Michael W.; Sjödin, Andreas; Jones, Richard S.; Needham, Larry L.; Jacobs, David R.

    2010-01-01

    Background Low doses of some persistent organic pollutants (POPs) associate cross-sectionally with type 2 diabetes, whereas associations with high POP exposures are inconsistent. Objectives We investigated whether several POPs prospectively predict type 2 diabetes within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Methods Participants in this nested case–control study were diabetes free in 1987–1988. By 2005–2006, the 90 controls remained free of diabetes, whereas the 90 cases developed diabetes. Using serum collected in 1987–1988, we measured 8 organochlorine pesticides, 22 polychlorinated biphenyl congeners (PCBs), and 1 polybrominated biphenyl (PBB). We compared POP concentrations from CARDIA and the National Health and Nutrition Examination Survey (NHANES) in 2003–2004. We computed odds ratios (ORs) for incident diabetes using logistic regression analysis. Results Chlorinated POPs in CARDIA in 1987–1988 were much higher than corresponding NHANES 2003-2004 concentrations. POPs showed nonlinear associations with diabetes risk. The highest risk was observed in the second quartiles of trans-nonachlor, oxychlordane, mirex, highly chlorinated PCBs, and PBB153—a finding that suggests low-dose effects. We concentrated risk by summing these POPs and isolated very low concentrations of multiple POPs in the lowest sextile of the sum. The adjusted OR in the second sextile vs. the lowest sextile was 5.3 overall and 20.1 for body mass index ≥ 30 kg/m2. Conclusions Several POPs at low doses similar to current exposure levels may increase diabetes risk, possibly through endocrine disruption. Certain POPs may a play a role in the current epidemic of diabetes, which has been attributed to obesity. PMID:20444671

  3. Standard-Fractionated Radiotherapy for Optic Nerve Sheath Meningioma: Visual Outcome Is Predicted by Mean Eye Dose

    SciTech Connect

    Abouaf, Lucie; Girard, Nicolas; Lefort, Thibaud; D'hombres, Anne; Tilikete, Caroline; Vighetto, Alain; Mornex, Francoise

    2012-03-01

    Purpose: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM. Methods and Materials: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test. Results: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision. Conclusions: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.

  4. Age-related differences in sequential modulations of poorer-strategy effects.

    PubMed

    Lemaire, Patrick; Hinault, Thomas

    2014-01-01

    To determine how younger and older adults modulate execution of strategies across successive trials, we asked participants to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38 × 74). For each problem, they were cued to execute a better versus a poorer strategy. Their performance revealed sequential modulations of poorer-strategy effects (i.e., longer solution times and larger error rates when asked to execute a poorer than a better strategy). That is, poorer-strategy effects were smaller on current problems after using a poorer strategy on preceding problems than after using a better strategy. Moreover, sequential modulations of these poorer-strategy effects were smaller in older than in younger adults, especially older adults with low-cognitive control skills (as measured by conflict adaptation effects in the Simon task). Our findings suggest that these sequential modulations may result from executive control mechanisms, the efficiency of which is known to decrease in older adults. These findings have important implications regarding mechanisms underlying strategy execution and aging effects on strategic variations.

  5. Predicting inadequate bowel preparation for colonoscopy in participants receiving split-dose bowel preparation: development and validation of a prediction score.

    PubMed

    Dik, Vincent K; Moons, Leon M G; Hüyük, Melek; van der Schaar, Peter; de Vos Tot Nederveen Cappel, Wouter H; Ter Borg, Pieter C J; Meijssen, Maarten A C; Ouwendijk, Rob J T H; Le Fèvre, Doris M; Stouten, Merijn; van der Galiën, Onno; Hiemstra, Theo J; Monkelbaan, Jan F; van Oijen, Martijn G H; Siersema, Peter D

    2015-03-01

    Adequate bowel preparation is important for optimal colonoscopy. It is important to identify patients at risk for inadequate bowel preparation because this allows taking precautions in this specific group. To develop a prediction score to identify patients at risk for inadequate bowel preparation who may benefit from an intensified bowel cleansing regimen. Patient and colonoscopy data were prospectively collected, whereas clinical data were retrospectively collected for a total of 1996 colonoscopies in participants who received split-dose bowel preparation. Multivariate logistic regression analyses were conducted in a random two-thirds of the cohort to develop a prediction model. Validation and evaluation of the discriminative power of the prediction model were performed within the remaining one-third of the cohort. Four centers, including one academic and three medium-to-large size nonacademic centers. Consecutive colonoscopies in November and December 2012. Mean age was 57.3 ± 15.9 years, 45.8% were male and indications for colonoscopy were screening and/or surveillance (27%), abdominal symptoms and/or blood loss and/or anemia (60%), inflammatory bowel disease (9%), and others (4%). Colonoscopy. Inadequate bowel preparation defined as Boston Bowel Preparation Scale score <6. A total of 1331 colonoscopies were included in the development cohort, of which 172 (12.9%) had an inadequate bowel preparation. Independent factors included in the prediction model were American Society of Anesthesiologists Physical Status Classification System score ≥3, use of tricyclic antidepressants, use of opioids, diabetes, chronic constipation, history of abdominal and/or pelvic surgery, history of inadequate bowel preparation, and current hospitalization. The discriminative ability of the scale was good, with an area under the curve of 0.77 in the validation cohort. Study design partially retrospective, no data on patient compliance. We developed a validated, easy

  6. SU-D-BRB-01: A Comparison of Learning Methods for Knowledge Based Dose Prediction for Coplanar and Non-Coplanar Liver Radiotherapy

    SciTech Connect

    Tran, A; Ruan, D; Woods, K; Yu, V; Nguyen, D; Sheng, K

    2016-06-15

    Purpose: The predictive power of knowledge based planning (KBP) has considerable potential in the development of automated treatment planning. Here, we examine the predictive capabilities and accuracy of previously reported KBP methods, as well as an artificial neural networks (ANN) method. Furthermore, we compare the predictive accuracy of these methods on coplanar volumetric-modulated arc therapy (VMAT) and non-coplanar 4π radiotherapy. Methods: 30 liver SBRT patients previously treated using coplanar VMAT were selected for this study. The patients were re-planned using 4π radiotherapy, which involves 20 optimally selected non-coplanar IMRT fields. ANNs were used to incorporate enhanced geometric information including liver and PTV size, prescription dose, patient girth, and proximity to beams. The performance of ANN was compared to three methods from statistical voxel dose learning (SVDL), wherein the doses of voxels sharing the same distance to the PTV are approximated by either taking the median of the distribution, non-parametric fitting, or skew-normal fitting. These three methods were shown to be capable of predicting DVH, but only median approximation can predict 3D dose. Prediction methods were tested using leave-one-out cross-validation tests and evaluated using residual sum of squares (RSS) for DVH and 3D dose predictions. Results: DVH prediction using non-parametric fitting had the lowest average RSS with 0.1176(4π) and 0.1633(VMAT), compared to 0.4879(4π) and 1.8744(VMAT) RSS for ANN. 3D dose prediction with median approximation had lower RSS with 12.02(4π) and 29.22(VMAT), compared to 27.95(4π) and 130.9(VMAT) for ANN. Conclusion: Paradoxically, although the ANNs included geometric features in addition to the distances to the PTV, it did not perform better in predicting DVH or 3D dose compared to simpler, faster methods based on the distances alone. The study further confirms that the prediction of 4π non-coplanar plans were more accurate than

  7. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important?

    SciTech Connect

    Macdonald, A. Graham . E-mail: gmacdonald@easynet.co.uk; Keyes, Mira; Kruk, Alexandra; Duncan, Graeme; Moravan, Veronika; Morris, W. James

    2005-09-01

    Purpose: To determine predictive factors for postimplant erectile dysfunction (ED) in a cohort of patients, according to prospectively collected data; specifically, to assess the impact of penile bulb volume and D50 and D95 (dose covering 50% and 95% of the penile bulb volume, respectively) on ED. Methods and Materials: Three hundred forty-two patients were identified who were potent before implant and who had at least 2 years' follow-up. Patient, tumor, treatment, and dosimetric data were collected on all patients. Postimplant ED was defined according to both physician-documented and patient-documented outcome data. Binary logistic regression analysis was used to create multivariable models of predictors for ED at 1, 2, and 3 years after implant. Results: Physician-documented rates of ED were 57%, 48%, and 38% at 1, 2, and 3 years after implant, respectively. Patient-documented rates of ED were 70% and 66% at 1 and 2 years, respectively. Multivariable analyses revealed age and degree of preimplant erectile function to be consistently significant predictors of ED. Use of hormones was significant at the 1-year physician-documented ED endpoint but not thereafter, in keeping with the time course of testosterone recovery. Penile bulb volume, D50, and D95 were not found to be predictive for ED at any time point, in contrast to previous studies. In addition, planning ultrasound target volume, number of needles, and institutional case sequence number were significant predictors of ED at various time points, consistent with a traumatic etiology of ED. Conclusions: We found no evidence to support penile bulb dosimetry as an independent predictive factor for ED after implant, using physician-documented or patient-documented outcomes.

  8. Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism.

    PubMed

    Cerruti, Lena; Bleyzac, Nathalie; Tod, Michel

    2017-09-09

    A simple approach is proposed to predict drug clearance in children when no paediatric data are available for drugs metabolised by cytochromes. The maturation functions of cytochrome activity and binding proteins in plasma were combined with several measures of body size to describe drug clearance increase with age. The complete model and different reduced models were evaluated on a large panel of drug clearance data in children. The parameters of the models were estimated by nonlinear regression. Bias and precision of predictions were determined. Two hundred and ten clearance ratios were available for the analysis, corresponding to 53 drugs mainly eliminated by cytochrome metabolism. The age range was 1.5 day to 16 years and there were 30 values for children aged less than 2 years. Fat-free mass at power 0.75 yielded better results than the other body size descriptor tested. The model with the best fit was based on the fat-free mass ratio, the unbound fraction ratio, maturation functions for cytochromes and no maturation function for clearance by other routes. In children aged less than 2 years, the predictive performances were much better with the final model than with the model based on body surface area. The final model was almost unbiased. This model allows the calculation of the maintenance dose of drugs eliminated mainly by cytochromes. After external validation, it could be used in children aged less than 2 years. In older children, the model reduces to a simple approach based on body surface area or preferably on fat-free mass at power 0.75. The model is not suitable for preterm neonates.

  9. Can I Count on Getting Better? Association between Math Anxiety and Poorer Understanding of Medical Risk Reductions.

    PubMed

    Rolison, Jonathan J; Morsanyi, Kinga; O'Connor, Patrick A

    2016-10-01

    Lower numerical ability is associated with poorer understanding of health statistics, such as risk reductions of medical treatment. For many people, despite good numeracy skills, math provokes anxiety that impedes an ability to evaluate numerical information. Math-anxious individuals also report less confidence in their ability to perform math tasks. We hypothesized that, independent of objective numeracy, math anxiety would be associated with poorer responding and lower confidence when calculating risk reductions of medical treatments. Objective numeracy was assessed using an 11-item objective numeracy scale. A 13-item self-report scale was used to assess math anxiety. In experiment 1, participants were asked to interpret the baseline risk of disease and risk reductions associated with treatment options. Participants in experiment 2 were additionally provided a graphical display designed to facilitate the processing of math information and alleviate effects of math anxiety. Confidence ratings were provided on a 7-point scale. Individuals of higher objective numeracy were more likely to respond correctly to baseline risks and risk reductions associated with treatment options and were more confident in their interpretations. Individuals who scored high in math anxiety were instead less likely to correctly interpret the baseline risks and risk reductions and were less confident in their risk calculations as well as in their assessments of the effectiveness of treatment options. Math anxiety predicted confidence levels but not correct responding when controlling for objective numeracy. The graphical display was most effective in increasing confidence among math-anxious individuals. The findings suggest that math anxiety is associated with poorer medical risk interpretation but is more strongly related to confidence in interpretations. © The Author(s) 2015.

  10. Prediction of warfarin maintenance dose in Han Chinese patients using a mechanistic model based on genetic and non-genetic factors.

    PubMed

    Lu, Yuan; Yang, Jinbo; Zhang, Haiyan; Yang, Jin

    2013-07-01

    Many attempts have been made to predict the warfarin maintenance dose in patients beginning warfarin therapy using a descriptive model based on multiple linear regression. Here we report the first attempt to develop a comprehensive mechanistic model integrating in vitro-in vivo extrapolation (IVIVE) with a pharmacokinetic-pharmacodynamic model to predict the warfarin maintenance dose in Han Chinese patients. The model incorporates demographic factors [sex, age, body weight (BW)] and the genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). Information on the various factors, mean warfarin daily dose and International Normalized Ratio (INR) was available for a cohort of 197 Han Chinese patients. Based on in vitro enzyme kinetic parameters for S-warfarin metabolism, demographic data for Han Chinese and some scaling factors, the S-warfarin clearance (CL) was predicted for patients in the cohort with different CYP2C9 genotypes using IVIVE. The plasma concentration of S-warfarin after a single oral dose was simulated using a one-compartment pharmacokinetic model with first-order absorption and a lag time and was combined with a mechanistic coagulation model to simulate the INR response. The warfarin maintenance dose was then predicted based on the demographic data and genotypes of CYP2C9 and VKORC1 for each patient and using the observed steady-state INR (INRss) as a target value. Finally, sensitivity analysis was carried out to determine which factor(s) affect the warfarin maintenance dose most strongly. The predictive performance of this mechanistic model is not inferior to that of our previous descriptive model. There were significant differences in the mean warfarin daily dose in patients with different CYP2C9 and VKORC1 genotypes. Using IVIVE, the predicted mean CL of S-warfarin for patients with CYP2C9*1/*3 (0.092 l/h, n = 11) was 57 % less than for those with wild-type *1/*1 (0.215 l/h, n

  11. Little Evidence for Usefulness of Biomarkers for Predicting Successful Dose Reduction or Discontinuation of a Biologic Agent in Rheumatoid Arthritis: A Systematic Review

    PubMed Central

    van den Ende, Cornelia H.; Beeren, Fenna M. M.; Been, Evelien M. J.; van den Hoogen, Frank H. J.; den Broeder, Alfons A.

    2017-01-01

    Objective To systematically review studies addressing prediction of successful dose reduction or discontinuation of a biologic agent in rheumatoid arthritis (RA). Methods PubMed, Embase, and Cochrane Library databases were searched for studies that examined the predictive value of biomarkers for successful dose reduction or discontinuation of a biologic agent in RA. Two reviewers independently selected studies, and extracted data and assessed the risk of bias. A biomarker was classified as a “potential predictor” if the univariate association was either strong (odds ratio or hazard ratio >2.0 or <0.5) or statistically significant. For biomarkers that were studied multiple times, qualitative best‐evidence synthesis was performed separately for the prediction of successful dose reduction and discontinuation. Biomarkers that were defined in ≥75% of the studies as potential predictors were regarded as “predictor” for the purposes of our study. Results Of 3,029 nonduplicate articles initially searched, 16 articles regarding 15 cohorts were included in the present study. Overall, 17 biomarkers were studied multiple times for the prediction of successful dose reduction, and 33 for the prediction of successful discontinuation of a biologic agent. Three predictors were identified: higher adalimumab trough level for successful dose reduction and lower Sharp/van der Heijde erosion score and shorter symptom duration at the start of a biologic agent for successful discontinuation. Conclusion The predictive value of a wide variety of biomarkers for successful dose reduction or discontinuation of biologic treatment in RA has been investigated. We identified only 3 biomarkers as predictors, in just 2 studies. The strength of the evidence is limited by the low quality of the included studies and the likelihood of reporting bias and multiple testing. PMID:27696778

  12. Modeling of Salivary Production Recovery After Radiotherapy Using Mixed Models: Determination of Optimal Dose Constraint for IMRT Planning and Construction of Convenient Tools to Predict Salivary Function

    SciTech Connect

    Ortholan, Cecile Chamorey, Emmanuel Phar; Benezery, Karen; Thariat, Juliette; Dassonville, Olivier; Poissonnet, Gilles; Bozec, Alexandre; Follana, Philippe; Peyrade, Frederique; Sudaka, Anne; Gerard, Jean Pierre; Bensadoun, Rene Jean

    2009-01-01

    Purpose: The mathematical relationship between the dose to the parotid glands and salivary gland production needs to be elucidated. This study, which included data from patients included in a French prospective study assessing the benefit of intensity-modulated radiotherapy (RT), sought to elaborate a convenient and original model of salivary recovery. Methods and Materials: Between January 2001 and December 2004, 44 patients were included (35 with oropharyngeal and 9 with nasopharyngeal cancer). Of the 44 patients, 24 were treated with intensity-modulated RT, 17 with three-dimensional conformal RT, and 2 with two-dimensional RT. Stimulated salivary production was collected for {<=}24 months after RT. The data of salivary production, time of follow-up, and dose to parotid gland were modeled using a mixed model. Several models were developed to assess the best-fitting variable for the dose level to the parotid gland. Results: Models developed with the dose to the contralateral parotid fit the data slightly better than those with the dose to both parotids, suggesting that contralateral and ipsilateral parotid glands are not functionally equivalent even with the same dose level to the glands. The best predictive dose-value variable for salivary flow recovery was the volume of the contralateral parotid gland receiving >40 Gy. Conclusion: The results of this study show that the recommendation of a dose constraint for intensity-modulated RT planning should be established at the volume of the contralateral parotid gland receiving >40 Gy rather than the mean dose. For complete salivary production recovery after 24 months, the volume of the contralateral parotid gland receiving >40 Gy should be <33%. Our results permitted us to establish two convenient tools to predict the saliva production recovery function according to the dose received by the contralateral parotid gland.

  13. Abdominal girth and vertebral column length aid in predicting intrathecal hyperbaric bupivacaine dose for elective cesarean section

    PubMed Central

    Wei, Chang-Na; Zhou, Qing-He; Wang, Li-Zhong

    2017-01-01

    can accurately predict the suitable intrathecal hyperbaric bupivacaine dose for elective cesarean section. PMID:28834913

  14. Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients.

    PubMed

    Pastore, Francesco; Conson, Manuel; D'Avino, Vittoria; Palma, Giuseppe; Liuzzi, Raffaele; Solla, Raffaele; Farella, Antonio; Salvatore, Marco; Cella, Laura; Pacelli, Roberto

    2016-01-01

    Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001]. Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.

  15. Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs.

    PubMed

    Jardim, Denis L; Hess, Kenneth R; Lorusso, Patricia; Kurzrock, Razelle; Hong, David S

    2014-01-15

    Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials. ©2013 AACR.

  16. Automated pediatric abdominal effective diameter measurements versus age-predicted body size for normalization of CT dose.

    PubMed

    Cheng, Phillip M; Vachon, Linda A; Duddalwar, Vinay A

    2013-12-01

    There has been increasing interest in adjusting CT radiation dose data for patient body size. A method for automated computation of the abdominal effective diameter of a patient from a CT image has previously only been tested in adult patients. In this work, we tested the method on a set of 128 pediatric patients aged 0.8 to 12.9 years (average 8.0 years, SD = 3.7 years) who had CT abdomen/pelvis exams performed on a Toshiba Aquilion 64 scanner. For this set of patients, age-predicted abdominal effective diameter extrapolated based on data from the International Commission on Radiation Units and Measurements was a relatively poor predictor of measured effective diameter. The mean absolute percentage error between the CTDI normalization coefficient calculated from a manually measured effective diameter and the coefficient determined by age-predicted effective diameter was 12.3 % with respect to a 32 cm phantom (range 0.0-52.8 %, SD 8.7 %) and 12.9 % with respect to a 16 cm phantom (range 0.0-56.4 %, SD 9.2 %). In contrast, there is a close correspondence between the automated and manually measured patient effective diameters, with a mean absolute error of 0.6 cm (error range 0.2-1.3 cm). This correspondence translates into a high degree of correspondence between normalization coefficients determined by automated and manual measurements; the mean absolute percentage error was 2.1 % with respect to a 32 cm phantom (range 0.0-8.1 %, SD = 1.4 %) and 2.3 % with respect to a 16 cm phantom (range 0.0-9.3 %, SD = 1.6 %).

  17. Osteoporosis markers on low-dose lung cancer screening chest computed tomography scans predict all-cause mortality.

    PubMed

    Buckens, C F; van der Graaf, Y; Verkooijen, H M; Mali, W P; Isgum, I; Mol, C P; Verhaar, H J; Vliegenthart, R; Oudkerk, M; van Aalst, C M; de Koning, H J; de Jong, P A

    2015-01-01

    Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. Following a case-cohort design, lung cancer screening trial participants (N = 3,673) who died (N = 196) during a median follow-up of 6 years (inter-quartile range: 5.7-6.3) were identified and added to a random sample of N = 383 from the trial. We assessed vertebral fractures using Genant's semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. The prevalence of vertebral fractures was 35% (95% confidence interval 30-40%) among survivors and 51% (44-58%) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43-2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02-1.15). Vertebral fractures and bone density are independently associated with all-cause mortality. • Lung cancer screening chest computed tomography contains additional, potentially useful information. • Vertebral fractures and bone density are independently predictive of mortality. • This finding has implications for screening and management decisions.

  18. Subjective relative deprivation is associated with poorer physical and mental health.

    PubMed

    Mishra, Sandeep; Carleton, R Nicholas

    2015-12-01

    Substantial epidemiological evidence has shown that income inequality and objective measures of relative deprivation are associated with poorer health outcomes. However, surprisingly little research has examined whether subjective feelings of relative deprivation are similarly linked with poorer health outcomes. The relative deprivation hypothesis suggests that inequality affects health at the individual level through negative consequences of social comparison. We directly examined the relationship between subjective feelings of personal relative deprivation and self-reported physical and mental health in a diverse community sample (n = 328). Results demonstrated that subjective feelings of personal relative deprivation are associated with significantly poorer physical and mental health. These relationships held even when accounting for covariates that have been previously associated with both relative deprivation and health. These results further support the link between relative deprivation and health outcomes and suggest that addressing root causes of relative deprivation may lead to greater individual health. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The predictive factors of α1-D/A adrenoceptor antagonist, naftopidil, dose increase therapy for male lower urinary tract symptoms caused by benign prostatic hyperplasia: INFORM study

    PubMed Central

    Tanuma, Yasushi; Tanaka, Yoshinori; Takeyama, Ko; Okamoto, Tomoshi

    2017-01-01

    Introduction: We evaluated the predictive factors which affect the efficacy of naftopidil 50 mg/day therapy and dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. Materials and Methods: A total of 92 patients with male lower urinary tract symptoms/benign prostatic hyperplasia were administrated naftopidil 50 mg/day for 4 weeks (50 mg therapy). At week 4, the patients were divided into an effective and an ineffective group (Group E and Group I, respectively). For further 4 weeks, the dosage of naftopidil was increased to 75 mg/day in all patients. At week 8, the patients of Group E and Group I were divided into an effective and an ineffective group (Group EE, Group EI, Group IE, and Group II, respectively). Results: Postvoid residual (PVR) urine volume at baseline was a predictive factor for efficacy of 50 mg therapy. In Group E, change in International Prostate Symptom Score storage symptoms subscore from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. In Group I, change in maximum flow rate from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. Conclusions: The short term of naftopidil 50 mg therapy was ineffective for the patients who had large PVR. The predictive factor of this dose increase therapy might be a dynamic variable in 50 mg/day of dose period, but not a baseline variable at the time of 75 mg/day dosage starts. PMID:28794594

  20. Which ear should we choose for cochlear implantation in the elderly: The poorer or the better? Audiometric outcomes, quality of sound, and quality-of-life results.

    PubMed

    Lassaletta, Luis; Calvino, Miryam; Sánchez-Cuadrado, Isabel; Pérez-Mora, Rosa M; Gavilán, Javier

    2015-01-01

    Cochlear implantation in the poorer ear of an elderly patient does not predict poorer post-operative audiological, quality-of-life (QoL), and quality of sound results. To determine whether choosing the 'better' or the 'poorer' ear for cochlear implantation impacts performance outcome in an elderly population. Forty-two out of 73 elderly (≥ 60 years) cochlear implant users with some residual hearing in at least one ear were selected. Three criteria were used to group the patients as 'better' or 'poorer' ear implanted; (C1) based on previous use of hearing aid, (C2) pre-operative PTA, and (C3) pre-operative speech discrimination. The Glasgow Benefit Inventory (GBI) and the Hearing Implant Sound Quality Index (HISQUI) were used to measure QoL and quality of sound, respectively. The mean post-operative PTA was 38.7 ± 7.2 dBHL. In quiet, the mean disyllabic SDS at 65dBSPL was 75.4 ± 18.5, whereas the discrimination of sentences was 95.0% ± 6.9. The mean total GBI score was 30.9 ± 21.8, 92.9% of patients reporting a positive score. The mean HISQUI score was 111.3 ± 36.0, which corresponds to 'moderate' sound quality. No significant differences were found between both groups in terms of audiological outcomes, HISQUI scores or GBI scores when considering each of the three criteria.

  1. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma.

    PubMed

    Merchant, Thomas E; Schreiber, Jane E; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-11-01

    To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm(2)). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help estimate the value of newer methods of irradiation. Copyright © 2014

  2. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation.

    PubMed

    Wakahashi, Kanako; Yamamori, Motohiro; Minagawa, Kentaro; Ishii, Shinichi; Nishikawa, Shinichirou; Shimoyama, Manabu; Kawano, Hiroki; Kawano, Yuko; Kawamori, Yuriko; Sada, Akiko; Matsui, Toshimitsu; Katayama, Yoshio

    2011-08-01

    Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC(0-24h)). In allo-BMT, high AUC(0-24h) (>30 μg h/ml) resulted in no incidence of grade II-IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC(0-24h) less than 30 μg h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC(0-24h) and C(2h), plasma MPA concentration at 2 h after administration was observed. Single point assessment of C(2h) was shown to provide a useful surrogate of AUC(0-24h) to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.

  3. Variable selection models based on multiple imputation with an application for predicting median effective dose and maximum effect

    PubMed Central

    Wan, Y.; Datta, S.; Conklin, D.J.; Kong, M.

    2015-01-01

    The statistical methods for variable selection and prediction could be challenging when missing covariates exist. Although multiple imputation (MI) is a universally accepted technique for solving missing data problem, how to combine the MI results for variable selection is not quite clear, because different imputations may result in different selections. The widely applied variable selection methods include the sparse partial least-squares (SPLS) method and the penalized least-squares method, e.g. the elastic net (ENet) method. In this paper, we propose an MI-based weighted elastic net (MI-WENet) method that is based on stacked MI data and a weighting scheme for each observation in the stacked data set. In the MI-WENet method, MI accounts for sampling and imputation uncertainty for missing values, and the weight accounts for the observed information. Extensive numerical simulations are carried out to compare the proposed MI-WENet method with the other competing alternatives, such as the SPLS and ENet. In addition, we applied the MIWENet method to examine the predictor variables for the endothelial function that can be characterized by median effective dose (ED50) and maximum effect (Emax) in an ex-vivo phenylephrine-induced extension and acetylcholine-induced relaxation experiment. PMID:26412909

  4. A photobleaching-based PDT dose metric predicts PDT efficacy over certain BPD concentration ranges in a three-dimensional model of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Anbil, S.; Rizvi, I.; Celli, J. P.; Alagic, N.; Hasan, T.

    2013-03-01

    Photodynamic therapy (PDT) dosimetry is an active area of study that is motivated by the need to reliably predict treatment outcomes. Implicit dosimetric parameters, such as photosensitizer (PS) photobleaching, may indicate PDT efficacy and could establish a framework to provide patient-customized PDT. Here, tumor destruction and benzoporphryin-derivative (BPD) photobleaching are characterized by systematically varying BPD-light combinations to achieve fixed PDT doses (M * J * cm-2) in a three-dimensional (3D) model of micrometastatic ovarian cancer (OvCa). It is observed that the BPD-light parameters used to construct a given PDT dose significantly impact nodule viability and BPD photobleaching. As a result, PDT dose, when measured by the product of BPD concentration and fluence, does not reliably predict overall efficacy. A PDT dose metric that incorporates a term for BPD photobleaching more robustly predicts PDT efficacy at low concentrations of BPD. These results suggest that PDT dose metrics that are informed by implicit approaches to dosimetry could improve the reliability of PDT-based regimens and provide opportunities for patient-specific treatment planning.

  5. Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

    PubMed Central

    Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

    2015-01-01

    Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state. PMID:25602582

  6. The failure of dose-response models to predict low dose effects: a major challenge for biomedical, toxicological and aging research.

    PubMed

    Calabrese, Edward J

    2006-04-01

    Recent detailed evaluations of the pharmacological, toxicological, and biogerontological literature indicate that the hormetic dose-response is quite common and highly generalizable by biological model, endpoint, and chemical class. Head-to-head comparisons of the hormetic model with the traditional threshold model have revealed the hormetic model to occur with considerably greater frequency in the biomedical literature. Despite these developments, the history of both pharmacology and toxicology reflects a strong acceptance and centralizing of the threshold model concept while profoundly marginalizing of the hormetic dose-response. This commentary will address why the biomedical community especially those in the areas of pharmacology and toxicology made an incorrect judgment that the most fundamental nature of the dose-response was threshold rather than hormetic and why this conclusion has continued to dominate these fields and their numerous applications despite convincing evidence to the contrary. These findings have particular relevance to the area of biogerontology since this discipline often resides at the pharmacological-toxicological interface.

  7. Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

    PubMed Central

    Karaiskos, Ilias; Plachouras, Diamantis; Karvanen, Matti; Pontikis, Konstantinos; Jansson, Britt; Papadomichelakis, Evangelos; Antoniadou, Anastasia; Giamarellou, Helen; Armaganidis, Apostolos; Cars, Otto; Friberg, Lena E.

    2012-01-01

    A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg. PMID:22615285

  8. Estimation of plasma area under the curve for etanidazole (SR 2508) in toxicity prediction and dose adjustment

    SciTech Connect

    Workman, P.; Ward, R.; Maughan, T.S.; Newman, H.F.; Bleehen, N.M.

    1989-07-01

    The hydrophilic 2-nitroimidazole radiosensitizer etanidazole is currently undergoing clinical evaluation. Although considerably less neurotoxic than misonidazole because of its rapid renal clearance and partial exclusion from the nervous system, total dose is limited by peripheral neuropathy. Monitoring plasma etanidazole concentration in patients to determine the area under the curve (AUC0-infinity) has been proposed as a method of predicting patients at risk, and of providing a quantitative basis for dose reduction in such patients. Successful application of this policy requires accurate assessment of AUC0-infinity. We have analyzed plasma data for 18 patients receiving 2 g/m2 etanidazole to determine the errors introduced in the estimation of AUC0-infinity caused by omitting selected time points from the analysis. A 'baseline' AUC0-infinity value was calculated by integration of the rate equation for the 2-compartment model using data points at 0, 15, and 30 min and 1, 2, 4, 8, 12, and 24 hr after the end of infusion. The mean +/- SD area for AUC0-infinity was 502 +/- 152 micrograms ml-1 h (2.35 +/- 0.71 mM.h). Omitting the zero or the 24 hr time point, the average errors were quite small (2.5% in both cases), but errors of up to 16.4 and 7.3%, respectively, were seen for individual patients. Leaving out both the 8 hr and 12 hr points at the same time gave a similar low average error of 2.9%, with a highest error of 7.3%. Omitting all data points after 4 hr, the mean error was 24.7% and 15 of 18 patients had errors in excess of 10%. In addition, failure to correct for infusion time results in an underestimation of AUC0-infinity averaging 4.5% (range 1.9-8.7%). The choice of sampling times for toxicological monitoring will depend upon the accuracy with which the AUC0-infinity must be known. Including all data points between 0 and 24 hr will minimize errors.

  9. Deprivation amplification revisited; or, is it always true that poorer places have poorer access to resources for healthy diets and physical activity?

    PubMed Central

    Macintyre, Sally

    2007-01-01

    Background It has commonly been suggested (including by this author) that individual or household deprivation (for example, low income) is amplified by area level deprivation (for example, lack of affordable nutritious food or facilities for physical activity in the neighbourhood). Discussion The idea of deprivation amplification has some intuitive attractiveness and helps divert attention away from purely individual determinants of diet and physical activity, and towards health promoting or health damaging features of the physical and social environment. Such environmental features may be modifiable, and environmental changes may help promote healthier behaviors. However, recent empirical examination of the distribution of facilities and resources shows that location does not always disadvantage poorer neighbourhoods. This suggests that we need: a) to ensure that theories and policies are based on up-to-date empirical evidence on the socio-economic distribution of neighbourhood resources, and b) to engage in further research on the relative importance of, and interactions between, individual and environmental factors in shaping behavior. Summary In this debate paper I suggest that it may not always be true that poorer neighbourhoods are more likely to lack health promoting resources, and to be exposed to more health damaging resources. The spatial distribution of environmental resources by area socioeconomic status may vary between types of resource, countries, and time periods. It may also be that the presence or absence of resources is less important than their quality, their social meaning, or local perceptions of their accessibility and relevance. PMID:17683624

  10. Children's Executive Functions: Are They Poorer after Very Early Brain Insult

    ERIC Educational Resources Information Center

    Anderson, Vicki; Spencer-Smith, Megan; Coleman, Lee; Anderson, Peter; Williams, Jackie; Greenham, Mardee; Leventer, Richard J.; Jacobs, Rani

    2010-01-01

    Traditionally early brain insult (EBI) has been considered to have better outcome than later injury, consistent with the notion that the young brain is flexible and able to reorganize. Recent research findings question this view, suggesting that EBI might lead to poorer outcome than brain insult at any other age. Exploring this early vulnerability…

  11. Children's Executive Functions: Are They Poorer after Very Early Brain Insult

    ERIC Educational Resources Information Center

    Anderson, Vicki; Spencer-Smith, Megan; Coleman, Lee; Anderson, Peter; Williams, Jackie; Greenham, Mardee; Leventer, Richard J.; Jacobs, Rani

    2010-01-01

    Traditionally early brain insult (EBI) has been considered to have better outcome than later injury, consistent with the notion that the young brain is flexible and able to reorganize. Recent research findings question this view, suggesting that EBI might lead to poorer outcome than brain insult at any other age. Exploring this early vulnerability…

  12. Middle Schools and Poorer Neighbourhoods: Between Effectiveness and the Law, Ethics and Culture Model

    ERIC Educational Resources Information Center

    Acosta, Felicitas

    2006-01-01

    This article presents a series of reflections based on a study of two schools of secondary level in the city of Buenos Aires. The purpose is to identify reasons why some schools in poorer areas obtain higher levels of success for their pupils. The conceptual basis is one of cultural analysis, permitting a contextual and situational perspective…

  13. LETTER TO THE EDITOR: Comments on 'Reconsidering the definition of a dose volume histogram'—dose mass histogram (DMH) versus dose volume histogram (DVH) for predicting radiation-induced pneumonitis

    NASA Astrophysics Data System (ADS)

    Mavroidis, Panayiotis; Plataniotis, Georgios A.; Adamus Górka, Magdalena; Lind, Bengt K.

    2006-12-01

    In a recently published paper (Nioutsikou et al 2005 Phys. Med. Biol. 50 L17) the authors showed that the use of the dose-mass histogram (DMH) concept is a more accurate descriptor of the dose delivered to lung than the traditionally used dose-volume histogram (DVH) concept. Furthermore, they state that if a functional imaging modality could also be registered to the anatomical imaging modality providing a functional weighting across the organ (functional mass) then the more general and realistic concept of the dose-functioning mass histogram (D[F]MH) could be an even more appropriate descriptor. The comments of the present letter to the editor are in line with the basic arguments of that work since their general conclusions appear to be supported by the comparison of the DMH and DVH concepts using radiobiological measures. In this study, it is examined whether the dose-mass histogram (DMH) concept deviated significantly from the widely used dose-volume histogram (DVH) concept regarding the expected lung complications and if there are clinical indications supporting these results. The problem was investigated theoretically by applying two hypothetical dose distributions (Gaussian and semi-Gaussian shaped) on two lungs of uniform and varying densities. The influence of the deviation between DVHs and DMHs on the treatment outcome was estimated by using the relative seriality and LKB models using the Gagliardi et al (2000 Int. J. Radiat. Oncol. Biol. Phys. 46 373) and Seppenwoolde et al (2003 Int. J. Radiat. Oncol. Biol. Phys. 55 724) parameter sets for radiation pneumonitis, respectively. Furthermore, the biological equivalent of their difference was estimated by the biologically effective uniform dose (\\bar{\\bar{D}}) and equivalent uniform dose (EUD) concepts, respectively. It is shown that the relation between the DVHs and DMHs varies depending on the underlying cell density distribution and the applied dose distribution. However, the range of their deviation in

  14. SU-D-201-02: Prediction of Delivered Dose Based On a Joint Histogram of CT and FDG PET Images

    SciTech Connect

    Park, M; Choi, Y; Cho, A; Hwang, S; Cha, J; Lee, N; Yun, M

    2015-06-15

    Purpose: To investigate whether pre-treatment images can be used in predicting microsphere distribution in tumors. When intra-arterial radioembolization using Y90 microspheres was performed, the microspheres were often delivered non-uniformly within the tumor, which could lead to an inefficient therapy. Therefore, it is important to estimate the distribution of microspheres. Methods: Early arterial phase CT and FDG PET images were acquired for patients with primary liver cancer prior to radioembolization (RE) using Y90 microspheres. Tumor volume was delineated on CT images and fused with FDG PET images. From each voxel (3.9×3.9×3.3 mm3) in the tumor, the Hounsfield unit (HU) from the CT and SUV values from the FDG PET were harvested. We binned both HU and SUV into 11 bins and then calculated a normalized joint-histogram in an 11×11 array.Patients also underwent a post-treatment Y90 PET imaging. Radiation dose for the tumor was estimated using convolution of the Y90 distribution with a dose-point kernel. We also calculated a fraction of the tumor volume that received a radiation dose great than 100Gy. Results: Averaged over 40 patients, 55% of tumor volume received a dose greater than 100Gy (range : 1.1 – 100%). The width of the joint histogram was narrower for patients with a high dose. For patients with a low dose, the width was wider and a larger fraction of tumor volume had low HU. Conclusion: We have shown the pattern of joint histogram of the HU and SUV depends on delivered dose. The patterns can predict the efficacy of uniform intra-arterial delivery of Y90 microspheres.

  15. Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats

    PubMed Central

    Howdeshell, Kembra L.; Rider, Cynthia V.; Wilson, Vickie S.; Furr, Johnathan R.; Lambright, Christy R.; Gray, L. Earl

    2015-01-01

    Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10, and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP), and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DAref). In addition, we predicted DA (called DAall) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. DA ref and DA all accurately predicted the observed mixture effect for 11 of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17–100% of F1 males when fetal T production was reduced by about 25–72%, respectively. PMID:26350170

  16. The impact of uncertainties in the CT conversion algorithm when predicting proton beam ranges in patients from dose and PET-activity distributions.

    PubMed

    España, Samuel; Paganetti, Harald

    2010-12-21

    The advantages of a finite range of proton beams can only be partly exploited in radiation therapy unless the range can be predicted in patient anatomy with <2 mm accuracy (for non-moving targets). Monte Carlo dose calculation aims at 1-2 mm accuracy in dose prediction, and proton-induced PET imaging aims at ∼2 mm accuracy in range verification. The latter is done using Monte Carlo predicted PET images. Monte Carlo methods are based on CT images to describe patient anatomy. The dose calculation algorithm and the CT resolution/artifacts might affect dose calculation accuracy. Additionally, when using Monte Carlo for PET range verification, the biological decay model and the cross sections for positron emitter production affect predicted PET images. The goal of this work is to study the effect of uncertainties in the CT conversion on the proton beam range predicted by Monte Carlo dose calculations and proton-induced PET signals. Conversion schemes to assign density and elemental composition based on a CT image of the patient define a unique Hounsfield unit (HU) to tissue parameters relationship. Uncertainties are introduced because there is no unique relationship between HU and tissue parameters. In this work, different conversion schemes based on a stoichiometric calibration method as well as different numbers of tissue bins were considered in three head and neck patients. For Monte Carlo dose calculation, the results show close to zero (<0.5 mm) differences in range using different conversion schemes. Further, a reduction of the number of bins used to define individual tissues down to 13 did not affect the accuracy. In the case of simulated PET images we found a more pronounced sensitivity on the CT conversion scheme with a mean fall-off position variation of about 1 mm. We conclude that proton dose distributions based on Monte Carlo calculation are only slightly affected by the uncertainty on density and elemental composition introduced by unique assignment to

  17. Radiation dose to the tongue and velopharynx predicts acoustic-articulatory changes after chemo-IMRT treatment for advanced head and neck cancer.

    PubMed

    Jacobi, Irene; Navran, Arash; van der Molen, Lisette; Heemsbergen, Wilma D; Hilgers, Frans J M; van den Brekel, Michiel W M

    2016-02-01

    The aim of this study was to investigate to what extent changes in speech after C-IMRT treatment are related to mean doses to the tongue and velopharynx (VP). In 34 patients with advanced hypopharyngeal, nasopharyngeal, or oropharyngeal cancer, changes in speech from pretreatment to 10 weeks and 1 year posttreatment were correlated with mean doses to the base of tongue (BOT), oral cavity (OC) and tonsillar fossa/soft palate (VP). Differences in anteroposterior tongue position, dorsoventral degree of tongue to palate or pharynx constriction, grooving, strength, nasality, and laryngeal rise, were assessed by acoustic changes in three speech sounds that depend on a (post-) alveolar closure or narrowing (/t/, /s/, /z/), three with a tongue to palate/pharyngeal narrowing (/l/, /r/, /u/), and in vowel /a/ at comfortable and highest pitch. Acoustically assessed changes in tongue positioning, shape, velopharyngeal constriction, and laryngeal elevation were significantly related to mean doses to the tongue and velopharynx. The mean dose to BOT predicted changes in anteroposterior tongue positioning from pre- to 10-weeks posttreatment. From pretreatment to 1-year, mean doses to BOT, OC, and VP were related to changes in grooving, strength, laryngeal height, nasality, palatalization, and degree of pharyngeal constriction. Changes in speech are related to mean doses to the base of tongue and velopharynx. The outcome indicates that strength, motility, and the balance between agonist and antagonist muscle forces change significantly after radiotherapy.

  18. From active shape model to active optical flow model: a shape-based approach to predicting voxel-level dose distributions in spine SBRT

    NASA Astrophysics Data System (ADS)

    Liu, Jianfei; Wu, Q. Jackie; Kirkpatrick, John P.; Yin, Fang-Fang; Yuan, Lulin; Ge, Yaorong

    2015-03-01

    Prediction of achievable dose distribution in spine stereotactic body radiation therapy (SBRT) can help in designing high-quality treatment plans to maximally protect spinal cords and to effectively control tumours. Dose distributions at spinal cords are primarily affected by the shapes of adjacent planning target volume (PTV) contours. In this work, we estimate such contour effects and predict dose distributions by exploring active optical flow model (AOFM) and active shape model (ASM). We first collect a sequence of dose sub-images and PTV contours near spinal cords from fifteen SBRT plans in the training dataset. The data collection is then classified into five groups according to the PTV locations in relation to spinal cords. In each group, we randomly choose a dose sub-image as the reference and register all other sub-images to the reference using an optical flow method. AOFM is then constructed by importing optical flow vectors and dose values into the principal component analysis (PCA). Similarly, we build ASM by using PCA on PTV contour points. The correlation between ASM and AOFM is estimated via a stepwise multiple regression model. When predicting dose distribution of a new case, the group is first determined based on the PTV contour. The prediction model of the selected group is used to estimate dose distributions by mapping the PTV contours from the ASM space to the AOFM space. This method was validated on fifteen SBRT plans in the testing dataset. Analysis of dose-volume histograms revealed that the important D2%, D5%, D10% and D0.1cc dosimetric parameters of spinal cords between the prediction and the clinical plans were 11.7  ±  1.7 Gy versus 11.8  ±  1.7 Gy (p = 0.95), 10.9  ±  1.7 Gy versus 11.1  ±  1.9 Gy (p = 0.8295), 10.2  ±  1.6 Gy versus 10.1  ±  1.7 (p = 0.9036) and 11.2  ±  2.0 Gy versus 11.1  ±  2.2 Gy (p = 0.5208), respectively. Here, the ‘cord’ is the spinal cord proper (not the

  19. From active shape model to active optical flow model: a shape-based approach to predicting voxel-level dose distributions in spine SBRT.

    PubMed

    Liu, Jianfei; Wu, Q Jackie; Kirkpatrick, John P; Yin, Fang-Fang; Yuan, Lulin; Ge, Yaorong

    2015-03-07

    Prediction of achievable dose distribution in spine stereotactic body radiation therapy (SBRT) can help in designing high-quality treatment plans to maximally protect spinal cords and to effectively control tumours. Dose distributions at spinal cords are primarily affected by the shapes of adjacent planning target volume (PTV) contours. In this work, we estimate such contour effects and predict dose distributions by exploring active optical flow model (AOFM) and active shape model (ASM). We first collect a sequence of dose sub-images and PTV contours near spinal cords from fifteen SBRT plans in the training dataset. The data collection is then classified into five groups according to the PTV locations in relation to spinal cords. In each group, we randomly choose a dose sub-image as the reference and register all other sub-images to the reference using an optical flow method. AOFM is then constructed by importing optical flow vectors and dose values into the principal component analysis (PCA). Similarly, we build ASM by using PCA on PTV contour points. The correlation between ASM and AOFM is estimated via a stepwise multiple regression model. When predicting dose distribution of a new case, the group is first determined based on the PTV contour. The prediction model of the selected group is used to estimate dose distributions by mapping the PTV contours from the ASM space to the AOFM space. This method was validated on fifteen SBRT plans in the testing dataset. Analysis of dose-volume histograms revealed that the important D2%, D5%, D10% and D0.1cc dosimetric parameters of spinal cords between the prediction and the clinical plans were 11.7 ± 1.7 Gy versus 11.8 ± 1.7 Gy (p = 0.95), 10.9 ± 1.7 Gy versus 11.1 ± 1.9 Gy (p = 0.8295), 10.2 ± 1.6 Gy versus 10.1 ± 1.7 (p = 0.9036) and 11.2 ± 2.0 Gy versus 11.1 ± 2.2 Gy (p = 0.5208), respectively. Here, the ‘cord’ is the spinal cord proper (not the thecal sac) extended 5 mm inferior and superior to the involved

  20. Diabetes Mellitus and Poorer Prognosis in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

    PubMed Central

    Wang, Yan-Gang; Wang, Peng; Wang, Bin; Fu, Zheng-Ju; Zhao, Wen-Juan; Yan, Sheng-Li

    2014-01-01

    Background Previous studies suggested that diabetes mellitus was associated with cancer risk and prognosis, but studies investigating the relationship between diabetes mellitus and survival in patients with hepatocellular carcinoma (HCC) reported inconsistent findings. To derive a more precise estimate of the prognostic role of diabetes mellitus in HCC, we systematically reviewed published studies and carried out a meta-analysis. Methods Eligible articles were identified in electronic databases from their inception through September 16, 2013. To evaluate the correlation between diabetes mellitus and prognosis in HCC, the pooled hazard ratios (HR) and their 95% confidence intervals (95% CI) for poorer overall and disease-free survivals were calculated by standard meta-analysis techniques with fixed-effects or random-effects models. Results 21 studies with a total of 9,767 HCC patients stratifying overall survival and/or disease-free survival in HCC patients by diabetes mellitus status were eligible for meta-analysis. 20 studies with a total of 9,727 HCC cases investigated the overall survival, and 10 studies with a total of 2,412 HCC patients investigated the disease-free survival. The pooled HRs for overall survival and disease-free survival were 1.46 (95% CI, 1.29 to 1.66; P<0.001) and 1.57 (95% CI, 1.21 to 2.05; P = 0.001), respectively. The adjusted HRs for overall survival and disease-free survival were 1.55 (95% CI, 1.27 to 1.91; P<0.001) and 2.15 (95% CI, 1.75 to 2.63; P<0.001), respectively. In addition, for patients receiving hepatic resection, diabetes mellitus was associated with both poorer overall survival and poorer disease-free survival, and for patients receiving non-surgical treatment or patients receiving radiofrequency ablation, diabetes mellitus was associated with poorer overall survival. There was no evidence for publication bias. Conclusion Diabetes mellitus is independently associated with both poorer overall survival and poorer disease

  1. Predictive values of urine paraquat concentration, dose of poison, arterial blood lactate and APACHE II score in the prognosis of patients with acute paraquat poisoning.

    PubMed

    Liu, Xiao-Wei; Ma, Tao; Li, Lu-Lu; Qu, Bo; Liu, Zhi

    2017-07-01

    The present study investigated the predictive values of urine paraquat (PQ) concentration, dose of poison, arterial blood lactate and Acute Physiology and Chronic Health Evaluation (APACHE) II score in the prognosis of patients with acute PQ poisoning. A total of 194 patients with acute PQ poisoning, hospitalized between April 2012 and January 2014 at the First Affiliated Hospital of P.R. China Medical University (Shenyang, China), were selected and divided into survival and mortality groups. Logistic regression analysis, receiver operator characteristic (ROC) curve analysis and Kaplan-Meier curve were applied to evaluate the values of urine paraquat (PQ) concentration, dose of poison, arterial blood lactate and (APACHE) II score for predicting the prognosis of patients with acute PQ poisoning. Initial urine PQ concentration (C0), dose of poison, arterial blood lactate and APACHE II score of patients in the mortality group were significantly higher compared with the survival group (all P<0.05). Logistic regression analysis revealed that C0, dose of poison and arterial blood lactate correlated with mortality risk of acute PQ poisoning (all P<0.05). ROC curve analysis suggested that the areas under the curve (AUC) values of C0, dose of poison, arterial blood lactate and APACHE II score in predicting the mortality of patients within 28 days were 0.921, 0.887, 0.808 and 0.648, respectively. The AUC of C0 for predicting early and delayed mortality were 0.890 and 0.764, respectively. The AUC values of urine paraquat concentration the day after poisoning (Csec) and the rebound rate of urine paraquat concentration in predicting the mortality of patients within 28 days were 0.919 and 0.805, respectively. The 28-day survival rate of patients with C0 ≤32.2 µg/ml (42/71; 59.2%) was significantly higher when compared with patients with C0 >32.2 µg/ml (38/123; 30.9%). These results suggest that the initial urine PQ concentration may be the optimal index for predicting the

  2. Poorer glycaemic control in type 1 diabetes is associated with reduced self-management and poorer perceived health: a cross-sectional study.

    PubMed

    Ozcan, Seyda; Amiel, Stephanie A; Rogers, Helen; Choudhary, Pratik; Cox, Alison; de Zoysa, Nicole; Hopkins, David; Forbes, Angus

    2014-10-01

    Many people with type 1 diabetes do not achieve optimal treatment targets despite high patient and professional input. To investigate the reasons underlying suboptimal control we have studied clinical characteristics and self-management behaviours in adults with type 1 diabetes attending a large treatment centre. A questionnaire-based enquiry into self-care behaviours of 380 patients with type 1 diabetes (mean age: 48 (±15) years and mean duration of diabetes: 26 (±15) years), linked with validated measures of impact of treatment on perceived health and hypoglycaemia recognition (Insulin Treatment Satisfaction Questionnaire; and EuroQoL EQ-5D, Gold score) and retrospective case note review of biomedical parameters. The data were analysed using chi-square test, ANOVA, ANCOVA and post-hoc procedures (Tukey's-b) in SPSS-version 18. The minimum significance level was accepted as 0.05. Sixty three percent of participants used multiple daily injections; 36% continuous subcutaneous insulin infusion. Mean HbA1c was 7.7% (±1.2) [61±-10mmol/mol]; 30% had impaired hypoglycaemia awareness (IHA). Factors significantly related to poor glycaemic control with IHA were longer duration of diabetes (p=0.01); less frequent glucose self-monitoring (p=0.05); and low level of patient-set glucose targets (p<0.001). Patients with IHA and poorer control had significantly lower insulin treatment satisfaction (p<0.001); and perceived health (p<0.001). Suboptimal biomedical outcomes in adults with type 1 diabetes attending a specialist intensified insulin therapy clinic are associated with longer duration of diabetes, fewer self-management behaviours and a trend towards poorer perceived health. These data suggest a need for greater emphasis on integration of psychological and self-management support with intensive medical management of type 1 diabetes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

    SciTech Connect

    Gillmann, Clarissa; Jäkel, Oliver; Schlampp, Ingmar; Karger, Christian P.

    2014-04-01

    Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a

  4. Callous-Unemotional Traits are Uniquely Associated with Poorer Peer Functioning in School-Aged Children.

    PubMed

    Haas, Sarah M; Becker, Stephen P; Epstein, Jeffery N; Frick, Paul J

    2017-07-19

    This study examines externalizing symptoms (attention-deficit/hyperactivity disorder [ADHD], conduct problems, and callous-unemotional [CU] traits) in relation to domains of peer functioning (social competence, loneliness, and close friendship quality), with a specific focus on the role of CU traits. One hundred twenty-four elementary students (grades 3-6; 45% boys) completed multiple measures of peer functioning, and teachers completed measures of externalizing symptoms and social competence. After controlling for demographic variables and other externalizing symptoms, CU traits were significantly associated with poorer peer functioning across all variables except for demands of exclusivity in close friendships. ADHD symptoms were also uniquely associated with poorer social functioning across a number of variables. In contrast, conduct problems were at times associated with better social functioning after controlling for the effects of other externalizing problems. These findings bolster the importance of developing and evaluating social skills interventions for children displaying elevated CU traits.

  5. Variation in drug prices at pharmacies: are prices higher in poorer areas?

    PubMed

    Gellad, Walid F; Choudhry, Niteesh K; Friedberg, Mark W; Brookhart, M Alan; Haas, Jennifer S; Shrank, William H

    2009-04-01

    To determine whether retail prices for prescription drugs are higher in poorer areas. The MyFloridarx.com website, which provides retail prescription prices at Florida pharmacies, and median ZIP code income from the 2000 Census. We compared mean pharmacy prices for each of the four study drugs across ZIP code income groups. Pharmacies were classified as either chain pharmacies or independent pharmacies. Prices were downloaded in November 2006. Across the four study drugs, mean prices were highest in the poorest ZIP codes: 9 percent above the statewide average. Independent pharmacies in the poorest ZIP codes charged the highest mean prices. Retail prescription prices appear to be higher in poorer ZIP codes of Florida.

  6. Variation in Drug Prices at Pharmacies: Are Prices Higher in Poorer Areas?

    PubMed Central

    Gellad, Walid F; Choudhry, Niteesh K; Friedberg, Mark W; Brookhart, M Alan; Haas, Jennifer S; Shrank, William H

    2009-01-01

    Objective To determine whether retail prices for prescription drugs are higher in poorer areas. Data Sources The MyFloridarx.com website, which provides retail prescription prices at Florida pharmacies, and median ZIP code income from the 2000 Census. Study Design We compared mean pharmacy prices for each of the four study drugs across ZIP code income groups. Pharmacies were classified as either chain pharmacies or independent pharmacies. Data Collection Prices were downloaded in November 2006. Principal Findings Across the four study drugs, mean prices were highest in the poorest ZIP codes: 9 percent above the statewide average. Independent pharmacies in the poorest ZIP codes charged the highest mean prices. Conclusions Retail prescription prices appear to be higher in poorer ZIP codes of Florida. PMID:19178584

  7. The Observed Variance Between Predicted and Measured Radiation Dose in Breast and Prostate Patients Utilizing an in-vivo Dosimeter

    PubMed Central

    Scarantino, Charles W.; Prestidge, Bradley R.; Anscher, Mitchel S.; Ferree, Carolyn R.; Kearns, William T.; Black, Robert D.; Bolick, Natasha G.; Beyer, Gloria P.

    2008-01-01

    Purpose Report the results of using a permanently implantable dosimeter in radiation therapy: determine specific adverse events, degree of migration, and acquire dose measurements during treatment to determine difference between expected and measured dose. Methods and Materials DVS (Dose Verification System) is a wireless, permanently implantable MOSFET dosimeter using a bidirectional antenna for power and data transfer. The study cohort includes 36 breast (33 received 2 devices) and 29 prostate (21 received 2 devices) cancer patients. A total of 1783 and 1749 daily dose measurements were obtained on breast and prostate patients, respectively. The measurements were compared to the planned expected dose. Bi-weekly CT scans were obtained to evaluate migration and NCI CTCv3 used to evaluate adverse events. Results Only grade I/II adverse events of pain and bleeding were noted. There were only four instances of dosimeter migration of >5mm due to known factors. A deviation of ≥7% in cumulative dose was noted in 7 of 36 (19%) for breast cancer patients. In prostate cancer patients, a ≥7% deviation was noted in 6 of 29 (21%) and 8 of 19 (42%) during initial and boost irradiation, respectively. The two patterns of dose deviation were random and systematic. Some causes for these differences could involve organ movement, patient movement and/or treatment plan considerations. Conclusions The DVS was not associated with significant adverse events or migration. The dosimeter can measure dose in situ on a daily basis. The accuracy and utility of the DVS complements current IGRT and IMRT techniques. PMID:18793963

  8. Predictive Models for Regional Hepatic Function Based upon 99mTc-IDA SPECT and Local Radiation Dose for Physiological Adaptive RT

    PubMed Central

    Wang, Hesheng; Feng, Mary; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2013-01-01

    Purpose High dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed prior to and during the course of RT using 99mTc-labeled immindodiacetic acid (IDA) SPECT could predict regional liver function reserve after RT. Methods and Materials Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans prior to RT, during, and one month after completion of RT. Indocyanine green (ICG) tests (a measure of overall liver function) were performed within 1 day of each scan. 3D volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After co-registration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and post-RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, Dose, Priori and Adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function post-RT. Results The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r = −0.80, p<0.0001), for all time points. Linear correlations between local doses and regional HEFs one month post-RT were significant in 12 patients. In the priori model, regional HEF post-RT was predicted by the planned dose and regional HEF assessed prior to RT (R=0.71, p<0.0001). In the adaptive model, regional HEF post-RT was predicted by regional HEF re-assessed during RT and the remaining planned local dose (R=0.83, p<0.0001). Conclusions 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of

  9. Pharmacokinetic/pharmacodynamic (PK/PD) indices of antibiotics predicted by a semimechanistic PKPD model: a step toward model-based dose optimization.

    PubMed

    Nielsen, Elisabet I; Cars, Otto; Friberg, Lena E

    2011-10-01

    A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitro time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, a dose fractionation study was simulated, using a wide range of total daily doses given as intermittent doses (dosing intervals of 4, 8, 12, or 24 h) or as a constant drug exposure. The time course of the drug concentration (PK model) as well as the bacterial response to drug exposure (in vitro PKPD model) was predicted. Nonlinear least-squares regression analyses determined the PK/PD index (the maximal unbound drug concentration [fC(max)]/MIC, the area under the unbound drug concentration-time curve [fAUC]/MIC, or the percentage of a 24-h time period that the unbound drug concentration exceeds the MIC [fT(>MIC)]) that was most predictive of the effect. The in silico predictions based on the in vitro PKPD model identified the previously determined PK/PD indices, with fT(>MIC) being the best predictor of the effect for β-lactams and fAUC/MIC being the best predictor for the four remaining evaluated drugs. The selection and magnitude of the PK/PD index were, however, shown to be sensitive to differences in PK in subpopulations, uncertainty in MICs, and investigated dosing intervals. In comparison with the use of the PK/PD indices, a model-based approach, where the full time course of effect can be predicted, has a lower sensitivity to study design and allows for PK differences in subpopulations to be considered directly. This study supports the use of PKPD models built from in vitro time-kill curves in the development of optimal dosing regimens for antibacterial drugs.

  10. Predictive models for regional hepatic function based on 99mTc-IDA SPECT and local radiation dose for physiologic adaptive radiation therapy.

    PubMed

    Wang, Hesheng; Feng, Mary; Frey, Kirk A; Ten Haken, Randall K; Lawrence, Theodore S; Cao, Yue

    2013-08-01

    High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver

  11. Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy

    SciTech Connect

    Kim, Tae Hyun; Kim, Dae Yong . E-mail: radiopia@ncc.re.kr; Park, Joong-Won; Kim, Seong Hoon; Choi, Joon-Il; Kim, Hyun Beom; Lee, Woo Jin; Park, Sang Jae; Hong, Eun Kyung; Kim, Chang-Min

    2007-01-01

    Purpose: To identify the dose-volumetric parameters associated with the risk of radiation-induced hepatic toxicity (RIHT) in hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy. Methods and Materials: A total of 105 hepatocellular carcinoma patients underwent three-dimensional conformal radiotherapy (total dose range, 44-58.5 Gy; median, 54). RIHT was scored within 4 months of completing three-dimensional conformal radiotherapy. The dose-volume parameters analyzed were the gross tumor volume; normal liver volume; total liver volume; radiation dose; mean dose to the normal liver; percentage of the normal liver volume receiving {>=}20, {>=}25, {>=}30, {>=}35, and {>=}40 Gy; percentage of the total liver volume receiving {>=}20, {>=}25, {>=}30, {>=}35, and {>=}40 Gy; and the normal tissue complication probability. Results: Of the 105 patients, Grade 1 RIHT was observed in 21 (20.0%), Grade 2 in 7 (6.7%), Grade 3 in 5 (4.8%), and Grade 4 in 1 (1.0%) patient. No fatal Grade 5 RIHT developed. On multivariate analysis for predicting Grade 2 or worse RIHT, the total liver volume receiving {>=}30 Gy was the only significant parameter (p < 0.001). Grade 2 or worse RIHT was observed in only 2 (2.4%) of 85 patients with a total liver volume receiving 30 Gy of {<=}60% and in 11 (55.0%) of 20 patients with >60% (p < 0.001). Conclusion: The total liver volume receiving {>=}30 Gy appears to be a useful dose-volumetric parameter for predicting the risk of RIHT. This volume should be limited to {<=}60% whenever possible to minimize the risk of Grade 2 or worse RIHT.

  12. Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

    PubMed

    Conolly, Rory B; Kimbell, Julia S; Janszen, Derek; Schlosser, Paul M; Kalisak, Darin; Preston, Julian; Miller, Frederick J

    2004-11-01

    Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional dosimetry of formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by the CFD model, with formation of DNA-protein cross-links (DPX) and with cytolethality/regenerative cellular proliferation (CRCP); and (3) use of a two-stage clonal growth model to link DPX and CRCP with tumor formation. With this structure, the prediction of the tumor dose response was extremely sensitive to cell kinetics. The raw dose-response data for CRCP are J-shaped, and use of these data led to a predicted J-shaped dose response for tumors, notwithstanding a concurrent low-dose-linear, directly mutagenic effect of formaldehyde mediated by DPX. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for the human nose with a one-dimensional typical path model for the lower respiratory tract. In other respects, the human model was structurally identical to the rat model. The predicted human dose response for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and rhesus monkey data. The rat dose response for CRCP was used "as is" for the human model, since no preferable alternative was identified. Three

  13. Altered tract-specific white matter microstructure is related to poorer cognitive performance: The Rotterdam Study.

    PubMed

    Cremers, Lotte G M; de Groot, Marius; Hofman, Albert; Krestin, Gabriel P; van der Lugt, Aad; Niessen, Wiro J; Vernooij, Meike W; Ikram, M Arfan

    2016-03-01

    White matter microstructural integrity has been related to cognition. Yet, the potential role of specific white matter tracts on top of a global white matter effect remains unclear, especially when considering specific cognitive domains. Therefore, we determined the tract-specific effect of white matter microstructure on global cognition and specific cognitive domains. In 4400 nondemented and stroke-free participants (mean age 63.7 years, 55.5% women), we obtained diffusion magnetic resonance imaging parameters (fractional anisotropy and mean diffusivity) in 14 white matter tracts using probabilistic tractography and assessed cognitive performance with a cognitive test battery. Tract-specific white matter microstructure in all supratentorial tracts was associated with poorer global cognition. Lower fractional anisotropy in association tracts, primarily the inferior fronto-occipital fasciculus, and higher mean diffusivity in projection tracts, in particular the posterior thalamic radiation, most strongly related to poorer cognition. Altered white matter microstructure related to poorer information processing speed, executive functioning, and motor speed, but not to memory. Tract-specific microstructural changes may aid in better understanding the mechanism of cognitive impairment and neurodegenerative diseases.

  14. Mild cognitive impairment is associated with poorer decision-making in community-based older persons.

    PubMed

    Han, S Duke; Boyle, Patricia A; James, Bryan D; Yu, Lei; Bennett, David A

    2015-04-01

    To test the hypothesis that mild cognitive impairment (MCI) is associated with poorer financial and healthcare decision-making. Community-based epidemiological cohort study. Communities throughout northeastern Illinois. Older persons without dementia from the Rush Memory and Aging Project (N = 730). All participants underwent a detailed clinical evaluation and decision-making assessment using a measure that closely approximates materials used in real-world financial and healthcare settings. This allowed for measurement of total decision-making and financial and healthcare decision-making. Regression models were used to examine whether MCI was associated with a lower level of decision-making. In subsequent analyses, the relationship between specific cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, visuospatial ability) and decision-making was explored in participants with MCI. MCI was associated with lower total, financial, and healthcare decision-making scores after accounting for the effects of age, education, and sex. The effect of MCI on total decision-making was equivalent to the effect of more than 10 additional years of age. Additional models showed that, when considering multiple cognitive systems, perceptual speed accounted for the most variance in decision-making in participants with MCI. Persons with MCI may have poorer financial and healthcare decision-making in real-world situations, and perceptual speed may be an important contributor to poorer decision-making in persons with MCI. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  15. Schizotypal traits are associated with poorer identification of emotions from dynamic stimuli.

    PubMed

    Abbott, Gavin; Byrne, Linda K

    2013-05-15

    Recent research suggests that the emotion recognition difficulties seen in schizophrenia may also be present to a lesser degree in non-clinical individuals who report attenuated expressions of schizophrenia-like symptoms (schizotypy). However, evidence in non-clinical samples primarily comes from studies employing static facial emotion tasks, and it is not clear whether poorer emotion recognition in schizotypy persists when people have access to a broader range of emotional cues more representative of typical face-to-face social interactions. A community sample of 151 adults completed measures of schizotypal traits, IQ, and a task that assessed emotion recognition using dynamic video-based stimuli. Global schizotypy and positive schizotypal traits were each associated with poorer emotion recognition. Negative schizotypy was not associated with emotion recognition overall, but was associated with errors in recognising positive emotions. It appears that poorer emotion recognition in schizotypy is not limited to single-channel stimuli, but can be seen even when multiple emotional cues are available. Thus, individuals with high levels of schizotypal traits, and positive features in particular, may have greater difficulty when it comes to 'reading' the emotions of others in everyday social interactions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma

    SciTech Connect

    Merchant, Thomas E.; Schreiber, Jane E.; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-11-01

    Purpose: To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Methods and Materials: Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm{sup 2}). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. Results: A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. Conclusions: The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help

  17. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    SciTech Connect

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  18. Predicting Dose-Response Relationships of Acute Cadmium Hepatoxicity and Metallothionein Regulation in the Rat Via In Vitro to In Vivo Extrapolation

    DTIC Science & Technology

    2006-02-01

    sensitivity to cadmium- induced hepatotoxicity in Fischer 344 and Sprague-Dawley rats . Toxicol. Sci. 67:329-40. Hoffman, E.O., Cook, J.A., DiLuzio, N.R...Vitro - In Vivo Extrapolation: Predicting Dose- Response Relationship of Acute Hepatotoxicity in the Rat (Rattus norvegicus) .............. 38 Appendix...absence of MT I and MT II has been shown to increase inorganic Cd- induced lethality and 3 hepatotoxicity , whereas gene over-expression causing

  19. Cognitive Results of CANTAB Tests and Their Change Due to the First Dose of Donepezil May Predict Treatment Efficacy in Alzheimer Disease

    PubMed Central

    Kuzmickienė, Jurgita; Kaubrys, Gintaras

    2015-01-01

    Background Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. Material/Methods Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. Results The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57–2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). Conclusions The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors. PMID:26656642

  20. Cognitive Results of CANTAB Tests and Their Change Due to the First Dose of Donepezil May Predict Treatment Efficacy in Alzheimer Disease.

    PubMed

    Kuzmickienė, Jurgita; Kaubrys, Gintaras

    2015-12-14

    BACKGROUND Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. MATERIAL AND METHODS Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. RESULTS The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57-2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). CONCLUSIONS The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors.

  1. Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers

    PubMed Central

    Absalom, A. R.; Lee, M.; Menon, D. K.; Sharar, S. R.; Smet, T. De; Halliday, J.; Ogden, M.; Corlett, P.; Honey, G. D.; Fletcher, P. C.

    2012-01-01

    Background Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models. Methods Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml−1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology. Results For the Domino model, bias, inaccuracy, wobble, and divergence were −2.7%, 33.9%, 24.2%, and 0.1463 % h−1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias. Conclusions Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration PMID:17389691

  2. Analysing risk factors for poorer breast cancer outcomes in residents of lower socioeconomic areas of Australia.

    PubMed

    Roder, David; Zorbas, Helen M; Kollias, James; Pyke, Chris M; Walters, David; Campbell, Ian D; Taylor, Corey; Webster, Fleur

    2014-05-01

    To investigate patient, cancer and treatment factors associated with the residence of female breast cancer patients in lower socioeconomic areas of Australia to better understand factors that may contribute to their poorer cancer outcomes. Bivariable and multivariable analyses were performed using the Breast Quality Audit database of Breast Surgeons of Australia and New Zealand. RESULTS Multivariable regression indicated that patients from lower socioeconomic areas are more likely to live in more remote areas and to be treated at regional than major city centres. Although they appeared equally likely to be referred to surgeons from BreastScreen services as patients from higher socioeconomic areas, they were less likely to be referred as asymptomatic cases from other sources. In general, their cancer and treatment characteristics did not differ from those of women from higher socioeconomic areas, but ovarian ablation therapy was less common for these patients and bilateral synchronous lesions tended to be less frequent than for women from higher socioeconomic areas. The results indicate that patients from lower socioeconomic areas are more likely to live in more remote districts and have their treatment in regional rather than major treatment centres. Their cancer and treatment characteristics appear to be similar to those of women from higher socioeconomic areas, although they are less likely to have ovarian ablation or to be referred as asymptomatic patients from sources other than BreastScreen. What is known about this topic? It is already known from Australian data that breast cancer outcomes are not as favourable for women from areas of socioeconomic disadvantage. The reasons for the poorer outcomes have not been understood. Studies in other countries have also found poorer outcomes in women from lower socioeconomic areas, and in some instances, have attributed this finding to more advanced stages of cancers at diagnosis and more limited treatment. The reasons

  3. Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization.

    PubMed

    Heidari, Pedram; Wehrenberg-Klee, Eric; Habibollahi, Peiman; Yokell, Daniel; Kulke, Matthew; Mahmood, Umar

    2013-12-01

    Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are currently lacking to optimize dosing of octreotide therapy on an individual basis. Multiple factors such as total tumor burden, receptor expression levels, and nontarget organ metabolism/excretion may contribute to a variation in SSTR octreotide occupancy with a given dose among different patients. In this study, we report the development of an imaging method to measure surface SSTR expression and occupancy level using the PET radiotracer (68)Ga-DOTATOC. In an animal model, SSTR occupancy by octreotide was assessed quantitatively with (68)Ga-DOTATOC PET, with the finding that increased occupancy resulted in decreased tumor proliferation rate. The results suggested that quantitative SSTR imaging during octreotide therapy has the potential to determine the fractional receptor occupancy in NETs, thereby allowing octreotide dosing to be optimized readily in individual patients. Clinical trials validating this approach are warranted.

  4. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

    PubMed

    Gharibian, Katherine N; Mueller, Bruce A

    2016-07-01

    Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

  5. Prediction of radiation doses during the dismantling of the pressurized tank from emergency core cooling system of RBMK- 1500 reactor

    SciTech Connect

    Simonis, A.; Poskas, P.; Poskas, G.

    2013-07-01

    Preparation for the decommissioning of the Ignalina Nuclear Power Plant involves multiple problems. Personnel radiation safety during the performance of dismantling activities is one of them. In order to assess the optimal personnel radiation safety, the modelling is performed for large components by the means of computer code 'VISIPLAN 3D ALARA Planning tool' developed by SCK CEN (Belgium). Modelling results of radiation doses during the dismantling of the pressurized tank from the emergency core cooling system (ECCS PT) of RBMK-1500 reactor are presented in this paper. The mass of one ECCS PT is approximately 47.6 tons. The radiological surveys indicate that the inner surface of the ECCS PT is contaminated with radioactive products of corrosion and sediments due to the radioactive water. The assessment of workers exposure was performed to comply with ALARA. The effective doses to the workers were modeled for different strategies of ECCS PT dismantling. The impact of dismantling tools and shielding types and extract ventilation flow rate during the dismantling of ECCS PT on effective doses were analyzed. The total effective personnel doses were obtained by summarizing the effective personnel doses from various sources of exposure, i. e., direct radiation from radioactive equipment, internal radiation due to inhalation of radioactive aerosols, and direct radiation from radioactive aerosols arising during hot cutting in premises. (authors)

  6. Sequential modulations of poorer-strategy effects during strategy execution: an event-related potential study in arithmetic.

    PubMed

    Hinault, Thomas; Dufau, Stéphane; Lemaire, Patrick

    2014-11-01

    When participants accomplish cognitive tasks, they obtain poorer performance if asked to execute a poorer strategy than a better strategy on a given problem. These poorer-strategy effects are smaller following execution of a poorer strategy relative to following a better strategy. To investigate ERP correlates of sequential modulations of poorer-strategy effects, we asked participants (n=20) to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38×74). For each problem, they were cued to execute a better versus a poorer strategy. We found event-related potentials signatures of sequential modulations of poorer-strategy effects in two crucial windows (i.e., between 200 and 550 ms and between 850 and 1250 ms) associated with executive control mechanisms and allowing conflict monitoring between the better and the cued strategy. These results have important implications on theories of strategies as they suggest that sequential modulations of poorer-strategy effects involve earlier as well as later mechanisms of cognitive control during strategy execution. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Predictive Models for Regional Hepatic Function Based on 99mTc-IDA SPECT and Local Radiation Dose for Physiologic Adaptive Radiation Therapy

    SciTech Connect

    Wang, Hesheng; Feng, Mary; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2013-08-01

    Purpose: High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. Methods and Materials: Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose–response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. Results: The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=−0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). Conclusions: 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies

  8. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

    EPA Science Inventory

    Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

  9. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

    EPA Science Inventory

    Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

  10. Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

    PubMed

    Conrado, Daniela J; Krishnaswami, Sriram; Shoji, Satoshi; Kolluri, Sheela; Hey-Hadavi, Judith; McCabe, Dorothy; Rojo, Ricardo; Tammara, Brinda K

    2016-06-01

    PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

  11. Mild Cognitive Impairment is Associated with PoorerDecision Making in Community-Based Older Persons

    PubMed Central

    Duke Han, S.; Boyle, Patricia A.; James, Bryan D.; Yu, Lei; Bennett, David A.

    2015-01-01

    Background/Objectives Financial and healthcare decision making are important for maintaining wellbeing and independence in old age. We tested the hypothesis that Mild Cognitive Impairment (MCI) is associated with poorer decision making in financial and healthcare matters. Design Community-based epidemiologic cohort study. Setting Communities throughout Northeastern Illinois. Participants Participants were 730 older nondemented persons from the Rush Memory and Aging Project. Measurements All participants underwent a detailed clinical evaluation and decision making assessment using a measure that closely approximates materials utilized in real world financial and healthcare settings. This allowed for measurement of total decision making, as well as financial and healthcare decision making. Regression models were used to examine whether the presence of MCI was associated with a lower level of decision making. In subsequent analyses, we explored the relation of specific cognitive systems (i.e., episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability) with decision making in those with MCI. Results Results showed that MCI was associated with lower decision making total scores as well as financial and healthcare scores, respectively, after accounting for the effects of age, education, and sex. The effect of MCI on total decision making was equivalent to the effect of more than 10 additional years of age. Additional models showed that when considering multiple cognitive systems, perceptual speed accounted for the most variance in decision making among participants with MCI. Conclusion Results suggest that persons with MCI may exhibit poorer financial and healthcare decision making in real world situations, and that perceptual speed may be an important contributor to poorer decision making among persons with MCI. PMID:25850350

  12. Disordered Eating Behaviors are Associated with Poorer Diet Quality in Adolescents with Type 1 Diabetes

    PubMed Central

    Tse, Julia; Nansel, Tonja R.; Haynie, Denise L.; Mehta, Sanjeev N.; Laffel, Lori M.B.

    2012-01-01

    Disordered eating behaviors may pose a risk for poor long-term health outcomes in patients with type 1 diabetes (T1D). This cross-sectional study examined relations of disordered eating behaviors with diet quality, diet-related attitudes, and diabetes management in adolescents with T1D (N=151, 48% female). Participants, recruited July 2008 through February 2009, completed 3-day diet records and survey measures, including the Diabetes Eating Problem Survey (DEPS) and measures of eating-related attitudes. Biomedical data were obtained from medical records. Participants scoring >1 SD above the mean DEPS were classified as at-risk for disordered eating. The Healthy Eating Index-2005 was calculated to assess diet quality. ANCOVA was used to test for differences between risk groups in diet quality, eating attitudes, and diabetes management, controlling for age, sex, and BMI percentile. Youth at-risk for disordered eating were more likely to be overweight/obese (59.1% vs. 40.9% p=0.01). The at-risk group had poorer diet quality (p=0.003), as well as higher intake of total (p=0.01) and saturated (p=0.007) fat than the low-risk group. The at-risk group reported lower self-efficacy (p=0.005), greater barriers (p<0.001), and more negative outcome expectations (p<0.001) for healthful eating, as well as worse dietary satisfaction (p=0.004). The at-risk group had lower diabetes adherence (p<0.01), less frequent blood glucose monitoring (p<0.002), and higher HbA1c (p<0.001). The constellation of excess weight, poorer dietary intake, and poorer diabetes management associated with youth at-risk for disordered eating suggests potential risk of future poor health outcomes. Attention should be given to healthful weight management, especially among overweight youth with T1D. PMID:23102180

  13. Poorer self-rated health is associated with elevated inflammatory markers among older adults.

    PubMed

    Christian, Lisa M; Glaser, Ronald; Porter, Kyle; Malarkey, William B; Beversdorf, David; Kiecolt-Glaser, Janice K

    2011-11-01

    Self-rated health is a strong independent predictor of mortality after accounting for objective health status, behavioral risk factors, and sociodemographic characteristics. However, mechanisms underlying this association are largely unexplained. Inflammation has been associated with increased risk of morbidity and mortality in the elderly. The current study aimed to: (1) examine associations between self-rated health and serum inflammatory markers in older adults; (2) examine the relative strength of these associations for self-rated health versus self-rated change in recent health; (3) examine components of self-rated health that may underlie the association between inflammation and global self-rated health. Self-rated health, as measured by the RAND health survey, and serum interleukin (IL)-6 and C-reactive protein (CRP) were assessed among 250 generally healthy older adults (185 women, 65 men; average age=63.8±13.7 years). A series of linear regression analyses demonstrated that poorer self-rated health was significantly associated with higher IL-6 and CRP. These relationships remained after controlling for age, body mass index, gender, and objective health conditions. These associations also remained after controlling for depressive symptoms, neuroticism, perceived change in health over the past year, and health behaviors (smoking, sleep quality, and physical activity). Analyses of RAND component measures demonstrated that poorer physical functioning was significantly associated with IL-6; the relationship between global self-rated health and both IL-6 and CRP remained after accounting for perceived physical functioning. Poorer self-rated health is associated with elevated serum inflammatory markers among generally healthy older adults. The relationship of self-rated health with inflammatory markers is not secondary to depressive symptoms, neuroticism, or recent changes in perceived health. Subjective ratings of health provide important clinical information

  14. Is cigarette smoking in poorer nations highly sensitive to price? Evidence from Russia and China.

    PubMed

    Lance, Peter M; Akin, John S; Dow, William H; Loh, Chung-Ping

    2004-01-01

    We examine cigarette demand in China and Russia using longitudinal micro-level household and community surveys. Previous developing-country price elasticity estimates of around -0.75 have been larger than United States estimates of about -0.4, but the former have relied primarily on aggregate data. In contrast, our micro-level price elasticity estimates in China and Russia range from 0 to -0.15. Thus, raising prices in poorer countries may not reduce smoking to the degree previously suggested.

  15. Low-dose dobutamine adds incremental value to late gadolinium enhancement cardiac magnetic resonance in the prediction of adverse remodelling following acute myocardial infarction.

    PubMed

    Scott, Anne E; Semple, Scott I K; Redpath, Thomas W; Hillis, Graham S

    2013-09-01

    To examine the relative and combined value of late gadolinium enhancement (LGE) and low-dose dobutamine (LDD) cardiac magnetic resonance (CMR) to predict 'adverse remodelling' (AR) following acute myocardial infarction (AMI). Forty-five patients with AMI were recruited. CMR was performed 2-4 days after presentation and at 6 months. Ventricular wall motion and volume were recorded at rest and following dobutamine infusion. Measures of first pass perfusion, persistent microvascular obstruction (PMO), and LGE were obtained following contrast administration. Quantitation was performed using the MEDIS 6.2 software. Regression analysis was employed to determine the univariables and multivariate models most predictive of AR at 6 months. The incremental and relative value of LDD over LGE was investigated. The most predictive univariable was 'volume of PMO' (r = 0.51, r2 = 0.26, P < 0.001). The optimal 'combined' multivariate model, utilizing data from all components, was highly predictive of AR (r = 0.82, r2 = 0.67, P < 0.001). The optimal model using parameters only from the LGE component also predicted remodelling (r = 0.65, r2 = 42.0, P = 0.001) but with less accuracy. In contrast, the optimal model using variables from the LDD component alone predicted remodelling with a similar accuracy to the optimal combined model (r = 0.82, r2 = 0.67, P < 0.001). A comprehensive CMR examination accurately predicts AR following AMI. LDD is superior to LGE CMR in this respect. These data suggest that LDD not only adds incremental value to LGE in the prediction of remodelling post-AMI but also may be utilized alone with the same predictive power.

  16. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients.

    PubMed

    Rostami-Hodjegan, Amin; Amin, Ajmal M; Spencer, Edgar P; Lennard, Martin S; Tucker, Geoffrey T; Flanagan, Robert J

    2004-02-01

    The measurement of plasma clozapine concentrations is useful in assessing compliance, optimizing therapy, and minimizing toxicity. We measured plasma clozapine and norclozapine (N-desmethylclozapine) concentrations in samples from 3782 patients (2648 male, 1127 female). No clozapine was detected in 291 samples (227 patients, median prescribed dose 300 mg/d). In 4963 (50.2 %) samples (2222 patients); plasma clozapine concentration ranged from 10 to 350 ng/mL.Step-wise backward multiple regression analysis (37 % of the total samples) of log10 plasma clozapine concentration against log10 clozapine dose (mg/d), age (year), sex (male = 0, female = 1), cigarette smoking habit (nonsmokers = 0; smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (clozapine metabolic ratio, MR) showed that these covariates explained 48% of the observed variation in plasma clozapine concentration (C = ng/mL x 10-3) (P < 0.001) according to the following equation: log 10 (C) = 0.811 log 10 (dose) + 0.332 (MR) + 69.42 X 10 (-3) (sex) + 2.263 x 10 (-3) (age) + 1.976 x 10(-3) (weight) - 0.171 (smoking habit) - 3.180. This model and its associated confidence intervals were used to develop nomograms of plasma clozapine concentration versus dose for male and female smokers and nonsmokers. Predicted plasma clozapine changes by +48% in nonsmokers, +17% in females, +/-8 % for every 0.1 change in MR (reference 1.32), +/-4% for every 5 years (reference 40 years), and +/-5 % for every 10 kg body weight (reference 80 kg). The nomograms can be used (i) to individualize dosage to achieve a given target plasma clozapine concentration, and (ii) for quantitative evaluation of adherence by estimating the likelihood of an observed concentration being achieved by a given dosage regimen. The model has been validated against published data.

  17. Cervical Gross Tumor Volume Dose Predicts Local Control Using Magnetic Resonance Imaging/Diffusion-Weighted Imaging—Guided High-Dose-Rate and Positron Emission Tomography/Computed Tomography—Guided Intensity Modulated Radiation Therapy

    SciTech Connect

    Dyk, Pawel; Jiang, Naomi; Sun, Baozhou; DeWees, Todd A.; Fowler, Kathryn J.; Narra, Vamsi; Garcia-Ramirez, Jose L.; Schwarz, Julie K.; Grigsby, Perry W.

    2014-11-15

    Purpose: Magnetic resonance imaging/diffusion weighted-imaging (MRI/DWI)-guided high-dose-rate (HDR) brachytherapy and {sup 18}F-fluorodeoxyglucose (FDG) — positron emission tomography/computed tomography (PET/CT)-guided intensity modulated radiation therapy (IMRT) for the definitive treatment of cervical cancer is a novel treatment technique. The purpose of this study was to report our analysis of dose-volume parameters predicting gross tumor volume (GTV) control. Methods and Materials: We analyzed the records of 134 patients with International Federation of Gynecology and Obstetrics stages IB1-IVB cervical cancer treated with combined MRI-guided HDR and IMRT from July 2009 to July 2011. IMRT was targeted to the metabolic tumor volume and lymph nodes by use of FDG-PET/CT simulation. The GTV for each HDR fraction was delineated by use of T2-weighted or apparent diffusion coefficient maps from diffusion-weighted sequences. The D100, D90, and Dmean delivered to the GTV from HDR and IMRT were summed to EQD2. Results: One hundred twenty-five patients received all irradiation treatment as planned, and 9 did not complete treatment. All 134 patients are included in this analysis. Treatment failure in the cervix occurred in 24 patients (18.0%). Patients with cervix failures had a lower D100, D90, and Dmean than those who did not experience failure in the cervix. The respective doses to the GTV were 41, 58, and 136 Gy for failures compared with 67, 99, and 236 Gy for those who did not experience failure (P<.001). Probit analysis estimated the minimum D100, D90, and Dmean doses required for ≥90% local control to be 69, 98, and 260 Gy (P<.001). Conclusions: Total dose delivered to the GTV from combined MRI-guided HDR and PET/CT-guided IMRT is highly correlated with local tumor control. The findings can be directly applied in the clinic for dose adaptation to maximize local control.

  18. Dominant unit CD34+ cell dose predicts engraftment after double-unit cord blood transplantation and is influenced by bank practice.

    PubMed

    Purtill, Duncan; Smith, Katherine; Devlin, Sean; Meagher, Richard; Tonon, Joann; Lubin, Marissa; Ponce, Doris M; Giralt, Sergio; Kernan, Nancy A; Scaradavou, Andromachi; Stevens, Cladd E; Barker, Juliet N

    2014-11-06

    We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34(+) cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34(+) cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34(+) cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34(+) cell counts (r(2) = 0.73). Median CD34(+) cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34(+) cell viability was 92%, 33 (8%) units had <75% viable CD34(+) cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34(+) cell dose and banking practices should be incorporated into CB unit selection.

  19. Dominant unit CD34+ cell dose predicts engraftment after double-unit cord blood transplantation and is influenced by bank practice

    PubMed Central

    Purtill, Duncan; Smith, Katherine; Devlin, Sean; Meagher, Richard; Tonon, Joann; Lubin, Marissa; Ponce, Doris M.; Giralt, Sergio; Kernan, Nancy A.; Scaradavou, Andromachi; Stevens, Cladd E.

    2014-01-01

    We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34+ cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34+ cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34+ cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34+ cell counts (r2 = 0.73). Median CD34+ cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non–Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)–accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34+ cell viability was 92%, 33 (8%) units had <75% viable CD34+ cells. Units from non–Netcord-FACT–accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34+ cell dose and banking practices should be incorporated into CB unit selection. PMID:25185264

  20. Do poorer people have poorer access to local resources and facilities? The distribution of local resources by area deprivation in Glasgow, Scotland☆

    PubMed Central

    Macintyre, Sally; Macdonald, Laura; Ellaway, Anne

    2008-01-01

    It has commonly been suggested that in modern cities individual or household deprivation (for example, low income or education) is amplified by area level deprivation (for example, lack of jobs or good schools), in ways which damage the health of the poorest and increase health inequalities. The aim of this study was to determine the location of a range of resources and exposures by deprivation in a UK city. We examined the location of 42 resources in Glasgow City, Scotland, in 2005–2006, by quintile of small area deprivation. Measures included number per 1000 population, network distance to nearest resource, and percentage of data zones containing at least one of each type of resource. Twelve resources had higher density in, and/or were closer to or more common in, more deprived neighbourhoods: public nurseries, public primary schools, police stations, pharmacies, credit unions, post offices, bus stops, bingo halls, public swimming pools, public sports centres, outdoor play areas, and vacant and derelict land/buildings. Sixteen had higher density in, and/or were closer to, or more common in, more affluent neighbourhoods: public secondary schools, private schools, banks, building societies, museums/art galleries, railway stations, subway stations, tennis courts, bowling greens, private health clubs, private swimming pools, colleges, A & E hospitals, parks, waste disposal sites, and tourist attractions. Private nurseries, Universities, fire stations, general, dental and ophthalmic practices, pawn brokers, ATMs, supermarkets, fast food chains, cafes, public libraries, golf courses, and cinemas showed no clear pattern by deprivation. Thus it appears that in the early 21st century access to resources does not always disadvantage poorer neighbourhoods in the UK. We conclude that we need to ensure that theories and policies are based on up-to-date and context-specific empirical evidence on the distribution of neighbourhood resources, and to engage in further research

  1. Do poorer people have poorer access to local resources and facilities? The distribution of local resources by area deprivation in Glasgow, Scotland.

    PubMed

    Macintyre, Sally; Macdonald, Laura; Ellaway, Anne

    2008-09-01

    It has commonly been suggested that in modern cities individual or household deprivation (for example, low income or education) is amplified by area level deprivation (for example, lack of jobs or good schools), in ways which damage the health of the poorest and increase health inequalities. The aim of this study was to determine the location of a range of resources and exposures by deprivation in a UK city. We examined the location of 42 resources in Glasgow City, Scotland, in 2005-2006, by quintile of small area deprivation. Measures included number per 1000 population, network distance to nearest resource, and percentage of data zones containing at least one of each type of resource. Twelve resources had higher density in, and/or were closer to or more common in, more deprived neighbourhoods: public nurseries, public primary schools, police stations, pharmacies, credit unions, post offices, bus stops, bingo halls, public swimming pools, public sports centres, outdoor play areas, and vacant and derelict land/buildings. Sixteen had higher density in, and/or were closer to, or more common in, more affluent neighbourhoods: public secondary schools, private schools, banks, building societies, museums/art galleries, railway stations, subway stations, tennis courts, bowling greens, private health clubs, private swimming pools, colleges, A & E hospitals, parks, waste disposal sites, and tourist attractions. Private nurseries, Universities, fire stations, general, dental and ophthalmic practices, pawn brokers, ATMs, supermarkets, fast food chains, cafes, public libraries, golf courses, and cinemas showed no clear pattern by deprivation. Thus it appears that in the early 21st century access to resources does not always disadvantage poorer neighbourhoods in the UK. We conclude that we need to ensure that theories and policies are based on up-to-date and context-specific empirical evidence on the distribution of neighbourhood resources, and to engage in further research on

  2. Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

    SciTech Connect

    Vadhavkar, Nikhil; Pham, Christopher; Georgescu, Walter; Deschamps, Thomas; Heuskin, Anne-Catherine; Tang, Jonathan; Costes, Sylvain V.

    2014-09-01

    In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (m). As X-ray dose increases, the probability of having DSB clusters increases as does the probability of misrepair and cell death. Experimental work characterizing the X-ray dose dependence of radiation-induced foci (RIF) in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSBs at the submicron level. Two mechanisms for DSB clustering, namely random coalescence of DSBs versus active movement of DSBs into repair domains are compared and tested. Simulations that best predicted both RIF dose dependence and cell survival after X-ray irradiation favored the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~;;1.55 m sides. Applying the same approach to high-linear energy transfer (LET) ion tracks, we are able to predict experimental RIF/m along tracks with an overall relative error of 12percent, for LET ranging between 30 350 keV/m and for three different ions. Finally, cell death was predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. Relative biological effectiveness (RBE) predictions for cell survival of MCF10A exposed to high-LET showed an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the submicron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. Conversely, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model

  3. Combinatorial DNA damage pairing model based on X-ray-induced foci predicts the dose and LET dependence of cell death in human breast cells.

    PubMed

    Vadhavkar, Nikhil; Pham, Christopher; Georgescu, Walter; Deschamps, Thomas; Heuskin, Anne-Catherine; Tang, Jonathan; Costes, Sylvain V

    2014-09-01

    In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (μm). As X-ray dose increases, the probability of having DSB clusters increases as does the probability of misrepair and cell death. Experimental work characterizing the X-ray dose dependence of radiation-induced foci (RIF) in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSBs at the submicron level. Two mechanisms for DSB clustering, namely random coalescence of DSBs versus active movement of DSBs into repair domains are compared and tested. Simulations that best predicted both RIF dose dependence and cell survival after X-ray irradiation favored the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ∼1.55 μm sides. Applying the same approach to high-linear energy transfer (LET) ion tracks, we are able to predict experimental RIF/μm along tracks with an overall relative error of 12%, for LET ranging between 30-350 keV/μm and for three different ions. Finally, cell death was predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. Relative biological effectiveness (RBE) predictions for cell survival of MCF10A exposed to high-LET showed an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the submicron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. Conversely, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our

  4. Comparison of the predictive abilities of pharmacogenetics-based warfarin dosing algorithms using seven mathematical models in Chinese patients.

    PubMed

    Li, Xi; Liu, Rong; Luo, Zhi-Ying; Yan, Han; Huang, Wei-Hua; Yin, Ji-Ye; Mao, Xiao-Yuan; Chen, Xiao-Ping; Liu, Zhao-Qian; Zhou, Hong-Hao; Zhang, Wei

    2015-01-01

    This study is aimed to find the best predictive model for warfarin stable dosage. Seven models, namely multiple linear regression (MLR), artificial neural network, regression tree, boosted regression tree, support vector regression, multivariate adaptive regression spines and random forest regression, as well as the genetic and clinical data of two Chinese samples were employed. The average predicted achievement ratio and mean absolute error of the algorithms were ranging from 52.31 to 58.08% and 4.25 to 4.84 mg/week in validation samples, respectively. The algorithm based on MLR showed the highest predicted achievement ratio and the lowest mean absolute error. At present, MLR may be still the best model for warfarin stable dosage prediction in Chinese population. Original submitted 10 November 2014; Revision submitted 18 February 2015.

  5. Predicting Grief Reactions One Year Following a Mass University Shooting: Evaluating Dose-Response and Contextual Predictors.

    PubMed

    Smith, Andrew J; Layne, Christopher M; Coyle, Patrick; Kaplow, Julie B; Brymer, Melissa J; Pynoos, Robert S; Jones, Russell T

    2017-10-10

    This study identifies risk factors for grief following a mass school shooting. Participants (N = 1,013) completed online questionnaires 3-4 months (Time 1) and 1 year (Time 2) post-shootings. We tested models predicting Time 2 grief reactions, exploring direct and indirect predictive effects of exposure variables (physical and social proximity) through hypothesized peritraumatic mediators (peritraumatic perceived threat to self or others) while controlling for Time 1 grief and posttraumatic stress (PTS) reactions, pretrauma vulnerabilities. Findings demonstrate that closer social proximity predicted higher levels of Time 2 grief, directly and indirectly through increasing peritraumatic perceived threat to others' safety. Physical proximity and peritraumatic threat to self did not predict Time 2 grief reactions. Implications for grief screening instruments and theory building research through identifying risk factors and causal mechanisms are discussed.

  6. Intraoperative high-dose calcium stimulation test in patients with sporadic medullary thyroid carcinoma is highly accurate in predicting lateral neck metastases.

    PubMed

    De Crea, Carmela; Raffaelli, Marco; Milano, Valentina; Carrozza, Cinzia; Zuppi, Cecilia; Bellantone, Rocco; Lombardi, Celestino Pio

    2016-01-01

    Intraoperative measurement of calcitonin is not highly accurate in predicting the completeness of the operative resection after total thyroidectomy combined with central neck dissection (TT-CND) in patients with medullary thyroid carcinoma (MTC). We evaluated whether an intraoperative, high-dose calcium stimulation test (IO-CST) after TT-CND can predict lateral neck involvement. Eleven patients who underwent primary operation for sporadic MTC were included. High-dose (25 mg/kg) calcium gluconate was administered after TT-CND with calcitonin measured at 2, 5, and 10 minutes after the calcium gluconate infusion. There were 2 males and 9 females (mean age, 51 years; range, 18-88). Three patients showed lateral neck metastases. At a mean follow-up of 7.0 months (range, 2-10), 1 patient showed distant metastases and 1 a slightly increased calcitonin level. After IO-CST, serum calcitonin increased in all the 3 patients with lateral neck metastases, and it remained unchanged or decreased in the other patients without lateral neck metastases. Percent variation of serum calcitonin after IO-CST was 92% in patients with lateral neck metastases and -3.1 ± 4.9% in patients without lateral neck metastases. Calcitonin measurement after IO-CST in patients with sporadic MTC can be highly accurate in predicting lateral neck nodes involvement. These results could represent a stimulus toward the development of a quick calcitonin assay. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Prospective Memory Deficits Are Associated With Poorer Everyday Functioning in Parkinson’s Disease

    PubMed Central

    Pirogovsky, Eva; Woods, Steven Paul; Filoteo, J. Vincent; Gilbert, Paul E.

    2013-01-01

    Although individuals with Parkinson’s disease (PD) evidence moderate deficits in prospective memory (PM), it is not known whether PM deficits confer an increased risk of poorer everyday functioning. In the current study, 33 individuals with PD and 26 demographically similar normal controls (NC) were administered performance-based and self-report measures of PM and everyday functioning, including medication and financial management. As compared to NC, PD participants demonstrated significantly lower scores on performance-based measures of PM and financial capacity, worse performance at a trend level on performance-based medication management and endorsed significantly greater self-reported declines in PM and instrumental activities of daily living (iADLs). In the PD sample, the laboratory measure of PM significantly correlated with performance-based measures of financial capacity and medication management and a self-report measure of medication management. Self-reported PM failures significantly correlated with perceived declines in iADLs, worse medication management, and poorer health-related quality of life. Although future studies are needed to examine the incremental ecological validity of PM in PD, findings from this study extend prior research by providing preliminary evidence that PM impairment may play a significant role in a range of critical everyday functions in PD. PMID:22846463

  8. Hidden losers? The impact of rural refugees and refugee programs on poorer hosts.

    PubMed

    Chambers, R

    1986-01-01

    Refugee relief organizations and refugee studies have refugees as their 1st concern and focus. Adverse impacts of refugees on hosts are relatively neglected. When impacts are considered, they are seen in terms of host country governments, economies, and services rather than people or different groups among host populations. In rural refugee-affected areas, the better-off and more visible hosts usually gain from the presence of refugees and from refugee programs. In contrast, the poorer among the hosts can be hidden losers. This is more so now than in the past, especially where land is scarce and labor relatively abundant. The poorer hosts can lose from competition for food, work, wages, services, and common property resources. Vulnerable hosts also lack refugees' option of sending their weaker dependents to camps and settlements. Development programs in refugee-affected areas and refugee studies will do a disservice if they neglect adverse effects of refugees on vulnerable hosts. These effects further strengthen the case for development to benefit the whole population in refugee-affected areas (author's).

  9. Anxiety and decreased social support underline poorer quality of life of parent living kidney donors.

    PubMed

    Chen, Pinhong; Luo, Qidong; Peng, Longkai

    2015-06-01

    A growing body of published work suggests that the parent-child relationship can be inherently coercive, such that the expectation that a living parent will not hesitate to donate a kidney to their children, makes informed consent difficult if not impossible to ascertain. The present study was designed to explore whether the emotional response and social resources have a similar effect on health-related quality of life among parent and sibling living kidney donors. This was a cross-sectional study. A total of 98 living kidney donors (60 parent donors, 38 sibling donors) completed an assessment including emotional response, social support and quality of life. Depression, anxiety, subjective social support and quality of life scores were much poorer for parent than sibling donors. Parent donors also showed more anxiety and poorer physical functioning than their counterparts in the general population. Hierarchical multiple regression analyses suggested that anxiety and decreased social support in the parent group were negatively associated with physical and mental function. In the sibling group, the main indicator of improved physical state was higher education level. Current results raised new concerns for the quality of life of parent donors as emotional response and social support differentially affected parent versus sibling quality of life. Therefore, stricter standards for physical selection, as well as emotional and supportive intervention, are needed for parent donors. Copyright © 2013 Wiley Publishing Asia Pty Ltd.

  10. Weekly Dose-Volume Parameters of Mucosa and Constrictor Muscles Predict the Use of Percutaneous Endoscopic Gastrostomy During Exclusive Intensity-Modulated Radiotherapy for Oropharyngeal Cancer

    SciTech Connect

    Sanguineti, Giuseppe; Gunn, G. Brandon; Parker, Brent C.; Endres, Eugene J.; Zeng Jing; Fiorino, Claudio

    2011-01-01

    Purpose: To define predictors of percutaneous endoscopic gastrostomy (PEG) use during intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer. Methods and Materials: Data for 59 consecutive patients treated with exclusive IMRT at a single institution were recovered. Of 59 patients, 25 were treated with hyperfractionation (78 Gy, 1.3 Gy per fraction, twice daily; 'HYPER'); and 34 of 59 were treated with a once-daily fractionation schedule (66 Gy, 2.2 Gy per fraction, or 70 Gy, 2 Gy per fraction; 'no-HYPER'). On the basis of symptoms during treatment, a PEG tube could have been placed as appropriate. A number of clinical/dosimetric factors, including the weekly dose-volume histogram of oral mucosa (OM DVHw) and weekly mean dose to constrictors and larynx, were considered. The OM DVHw of patients with and without PEG were compared to assess the most predictive dose-volume combinations. Results: Of 59 patients, 22 needed a PEG tube during treatment (for 15 of 22, {>=}3 months). The best cutoff values for OM DVHw were V9.5 Gy/week <64 cm{sup 3} and V10 Gy/week <54 cm{sup 3}. At univariate analysis, fractionation, mean weekly dose to OM and superior and middle constrictors, and OM DVHw were strongly correlated with the risk of PEG use. In a stepwise multivariate logistic analysis, OM V9.5 Gy/week ({>=}64 vs. <64 cm{sup 3}) was the most predictive parameter (odds ratio 30.8, 95% confidence interval 3.7-254.2, p = 0.0015), confirmed even in the no-HYPER subgroup (odds ratio 21, 95% CI 2.1 confidence interval 210.1, p = 0.01). Conclusions: The risk of PEG use is drastically reduced when OM V9.5-V10 Gy/week is <50-60 cm{sup 3}. These data warrant prospective validation.

  11. Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy

    NASA Astrophysics Data System (ADS)

    Dankers, Frank; Wijsman, Robin; Troost, Esther G. C.; Monshouwer, René; Bussink, Johan; Hoffmann, Aswin L.

    2017-05-01

    In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade  ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC  =  0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

  12. Prediction of the vertebral strength using a finite element model derived from low-dose biplanar imaging: benefits of subject-specific material properties.

    PubMed

    Sapin-de Brosses, Emilie; Jolivet, Erwan; Travert, Christophe; Mitton, David; Skalli, Wafa

    2012-02-01

    A finite element analysis on osteoporotic vertebrae. This study aims to validate subject-specific finite element models (FEMs) derived from a low-dose imaging system (EOS, Biospace Med, France) for the prediction of vertebral strength. The vertebrae are submitted to an eccentric compression force leading to compression and anterior bending. Given the aging population, osteoporosis and vertebral fractures are a major public health issue. A low bone mineral density (BMD) does not always explain incident fractures, and multifactorial analyses are required. In this context, FEMs based on quantitative computed tomography (QCT) have been proposed to predict vertebral strength in vitro or quantify effects of treatments. However, the clinical use of such a model for the in vivo follow-up of the whole spine is limited by the high-radiation dose induced by QCT and the lying position, which does not allow postural assessment with the same modality. Fourteen vertebrae were modeled using a parametric meshing method. The mesh was subject-specific using geometric parameters computed on the 3-dimensional (3D) reconstructions obtained from the EOS biplanar radiographs. The contribution of cortical bone was taken into account by modeling a cortico-cancellous shell whose properties were derived from experimental data. The effect of subject-specific bone Young's moduli derived from EOS vertebral areal BMD was quantified. The 3D position of the point-of-load application and the 3D orientation of the force was faithfully reproduced in the model to compare the predicted strength and experimental strength under the same loading conditions. The relative error of prediction decreased from 43% to 16% (2.5 times) when subject-specific mechanical properties, derived from EOS areal BMD, were implemented in the FEM compared with averaged material properties. The resulting subject-specific FEMs predicted vertebral strength with a level of significance close to the QCT-based models (r adjusted = 0

  13. Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern).

    PubMed

    Williams, Faith M; Rothe, Helga; Barrett, Gordon; Chiodini, Alessandro; Whyte, Jacqueline; Cronin, Mark T D; Monteiro-Riviere, Nancy A; Plautz, James; Roper, Clive; Westerhout, Joost; Yang, Chihae; Guy, Richard H

    2016-04-01

    Threshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual 'dose' applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool. Copyright © 2016 International Life Sciences Institute Europe. Published by Elsevier Inc. All rights reserved.

  14. Prediction of human observer performance in a 2-alternative forced choice low-contrast detection task using channelized Hotelling observer: impact of radiation dose and reconstruction algorithms.

    PubMed

    Yu, Lifeng; Leng, Shuai; Chen, Lingyun; Kofler, James M; Carter, Rickey E; McCollough, Cynthia H

    2013-04-01

    Efficient optimization of CT protocols demands a quantitative approach to predicting human observer performance on specific tasks at various scan and reconstruction settings. The goal of this work was to investigate how well a channelized Hotelling observer (CHO) can predict human observer performance on 2-alternative forced choice (2AFC) lesion-detection tasks at various dose levels and two different reconstruction algorithms: a filtered-backprojection (FBP) and an iterative reconstruction (IR) method. A 35 × 26 cm(2) torso-shaped phantom filled with water was used to simulate an average-sized patient. Three rods with different diameters (small: 3 mm; medium: 5 mm; large: 9 mm) were placed in the center region of the phantom to simulate small, medium, and large lesions. The contrast relative to background was -15 HU at 120 kV. The phantom was scanned 100 times using automatic exposure control each at 60, 120, 240, 360, and 480 quality reference mAs on a 128-slice scanner. After removing the three rods, the water phantom was again scanned 100 times to provide signal-absent background images at the exact same locations. By extracting regions of interest around the three rods and on the signal-absent images, the authors generated 21 2AFC studies. Each 2AFC study had 100 trials, with each trial consisting of a signal-present image and a signal-absent image side-by-side in randomized order. In total, 2100 trials were presented to both the model and human observers. Four medical physicists acted as human observers. For the model observer, the authors used a CHO with Gabor channels, which involves six channel passbands, five orientations, and two phases, leading to a total of 60 channels. The performance predicted by the CHO was compared with that obtained by four medical physicists at each 2AFC study. The human and model observers were highly correlated at each dose level for each lesion size for both FBP and IR. The Pearson's product-moment correlation coefficients

  15. Prediction of human observer performance in a 2-alternative forced choice low-contrast detection task using channelized Hotelling observer: Impact of radiation dose and reconstruction algorithms

    SciTech Connect

    Yu Lifeng; Leng Shuai; Chen Lingyun; Kofler, James M.; McCollough, Cynthia H.; Carter, Rickey E.

    2013-04-15

    Purpose: Efficient optimization of CT protocols demands a quantitative approach to predicting human observer performance on specific tasks at various scan and reconstruction settings. The goal of this work was to investigate how well a channelized Hotelling observer (CHO) can predict human observer performance on 2-alternative forced choice (2AFC) lesion-detection tasks at various dose levels and two different reconstruction algorithms: a filtered-backprojection (FBP) and an iterative reconstruction (IR) method. Methods: A 35 Multiplication-Sign 26 cm{sup 2} torso-shaped phantom filled with water was used to simulate an average-sized patient. Three rods with different diameters (small: 3 mm; medium: 5 mm; large: 9 mm) were placed in the center region of the phantom to simulate small, medium, and large lesions. The contrast relative to background was -15 HU at 120 kV. The phantom was scanned 100 times using automatic exposure control each at 60, 120, 240, 360, and 480 quality reference mAs on a 128-slice scanner. After removing the three rods, the water phantom was again scanned 100 times to provide signal-absent background images at the exact same locations. By extracting regions of interest around the three rods and on the signal-absent images, the authors generated 21 2AFC studies. Each 2AFC study had 100 trials, with each trial consisting of a signal-present image and a signal-absent image side-by-side in randomized order. In total, 2100 trials were presented to both the model and human observers. Four medical physicists acted as human observers. For the model observer, the authors used a CHO with Gabor channels, which involves six channel passbands, five orientations, and two phases, leading to a total of 60 channels. The performance predicted by the CHO was compared with that obtained by four medical physicists at each 2AFC study. Results: The human and model observers were highly correlated at each dose level for each lesion size for both FBP and IR. The

  16. Preliminary experience of a predictive model to define rectal volume and rectal dose during the treatment of prostate cancer.

    PubMed

    Falco, M D; D'Andrea, M; Fedele, D; Barbarino, R; Benassi, M; Giudice, E; Hamoud, E; Ingrosso, G; Ladogana, P; Santarelli, F; Tortorelli, G; Santoni, R

    2011-09-01

    The aim of this study was to define a method to evaluate the total dose delivered to the rectum during the whole treatment course in six patients undergoing irradiation for prostate cancer using an offline definition of organ motion with images from a cone beam CT (CBCT) scanner available on a commercial linear accelerator. Patient set-up was verified using a volumetric three-dimensional CBCT scanner; 9-14 CBCT scans were obtained for each patient. Images were transferred to a commercial treatment planning system for offline organ motion analysis. The shape of the rectums were used to obtain a mean dose-volume histogram (), which was the average of the DVHs of the rectums as they appeared in each verification CBCT. A geometric model of an average rectum (AR) was produced using the rectal contours delineated on the CBCT scans (DVH(AR)). To check whether the first week of treatment was representative of the whole treatment course, we evaluated the DVHs related to only the first five CBCT scans ( and DVH(AR5)). Finally, the influence of a dietary protocol on the goodness of our results was considered. In all six patients the original rectal DVH for the planning CT scan showed higher values than all DVHs. Although the application of the model to a larger set of patients is necessary to confirm this trend, reconstruction of a representative volume of the rectum throughout the entire treatment course seems feasible.

  17. Women with epilepsy have poorer knowledge and skills in child rearing than women without epilepsy.

    PubMed

    Saramma, P P; Sarma, P S; Thomas, Sanjeev V

    2011-09-01

    Epilepsy can negatively impact the child rearing ability of women because of the risk related to seizures, adverse effects of antiepileptic drugs and psychosocial factors. To compare the child rearing knowledge (CRK) and practices (CRP) of women with epilepsy (WWE) with a matched group of women without epilepsy (WWoE). This study was carried out in the Kerala registry of epilepsy and pregnancy (KREP) at Sree Chitra Tirunal Institute for Medical Sciences and Technology in India. We prospectively recruited 100 WWE in first trimester of pregnancy from the KREP and 93 age, education and parity matched pregnant WWoE from the antenatal clinics of the Government medical college Thiruvananthapuram. Their child rearing knowledge (CRK) and practices (CRP) were evaluated with previously validated protocols. The CRK was assessed at the time of enrolment (first trimester of pregnancy) and the CRP was assessed when the baby was three to four months old. Eighty-eight women each from WWE and WWoE had completed the study, over a period of three years. WWE and WWoE were comparable for age (25.56±4.66 and 25.69±4.49 years), pregnancy outcome and type of delivery. WWE had excess fetal loss and postnatal seizures. The CRK was significantly lower for WWE (23.53±6.3) than for WWoE (26.08±5.3). The CRP was significantly lower for WWE (25.01±9.6) than for WWoE (28.14±7.1). WWE performed poorer in all domains of child rearing practices namely feeding, growth and development, cleaning and protection and infant stimulation. Poorer CRK was strongly associated with lower CRP while several demographic and economic characteristics were not relevant. WWE fared poorer in feeding and nursing their babies in spite of having the right knowledge in that domain. This may be due to several undisclosed concerns and social dynamics that need to be addressed while preparing any interventions. Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  18. Basal renal function reserve and mean kidney dose predict future radiation-induced kidney injury in stomach cancer patients.

    PubMed

    Yavas, Guler; Elsurer, Rengin; Yavas, Cagdas; Ata, Ozlem

    2014-02-01

    Adjuvant chemoradiotherapy (CRT) improves the survival in patients with locally advanced stomach cancer. The kidneys are the major dose-limiting organs for radiotherapy (RT) in upper abdominal cancers. We aimed to evaluate the impact of adjuvant CRT on renal function of patients with stomach cancer. Fifty-nine stomach cancer patients who underwent postoperative CRT were included. Demographic parameters (age, gender), and basal and 12th-month biochemical parameters were recorded. Mean kidney dose (MKD) administered was determined. Estimated glomerular filtration rate (eGFR) was calculated by modification of diet in renal disease formula. Fifty-nine patients were recruited (age 60.8 ± 11.9 years; female/male 25/34; follow-up duration 15.6 ± 9.8 months). Twenty-one patients (35.6 %) had basal eGFR <90 ml/min/1.73 m(2). When the basal and 12th-month eGFR was compared, eGFR decreased in 27 patients (45.8 %), whereas eGFR remained stable in 32 (54.2 %) patients. Cox regression analyses revealed that a MKD ≥1,500 cGy and basal eGFR <90 ml/min/1.73 m(2) significantly increased the risk of a decreased eGFR at 12th month (HR = 2.288, 95 % CI 1.009-5.188, p = 0.048 and HR = 2.854, 95 % CI 1.121-7.262, p = 0.028, respectively). MKD ≥1,500 cGy and a basal eGFR <90 ml/min/1.73 m(2) significantly increased the risk of a decreased eGFR at 12th month. We suggest that patients with stomach cancer be evaluated for their basal renal reserve prior to RT, and it may be more convenient to further minimize the dose to the kidneys with more sophisticated RT techniques in patients with stomach cancer, more specifically in patients with decreased renal reserve.

  19. Lesson from Canada's Universal Care: socially disadvantaged patients use more health services, still have poorer health.

    PubMed

    Alter, David A; Stukel, Therese; Chong, Alice; Henry, David

    2011-02-01

    Lower socioeconomic status is commonly related to worse health. If poor access to health care were the only explanation, universal access to care should eliminate the association. We studied 14,800 patients with access to Canada's universal health care system who were initially free of cardiac disease, tracking them for at least ten years and seven months. We found that socially disadvantaged patients used health care services more than did their counterparts with higher incomes and education. We also found that service use by people with lower incomes and less education had little impact on their poorer health outcomes, particularly mortality. Countries contemplating national health insurance cannot rely on universal health care to eliminate historical disparities in outcomes suffered by disadvantaged groups. Universal access can only reduce these disparities. Our findings suggest the need to introduce large-scale preventive strategies early in patients' lives to help change unhealthy behavior.

  20. Evidence of poorer life-course mental health outcomes among veterans of the Korean War cohort.

    PubMed

    Brooks, Matthew Stephen; Fulton, Lawrence

    2010-03-01

    Comparing the outcomes of veterans who served in Korea and those who served elsewhere, we examined the treatment of post-traumatic stress disorder (PTSD), other mental health conditions, psychiatric treatment locations, and six mental health well-being measures. The analytic sample consisted of nationally representative data from the 2001 National Survey of Veterans (NSV). Analyses included multiple logistic regressions that controlled for sociodemographic characteristics. Korean era veterans in the NSV (n = 4030): 1498 served in Korea; 2532 elsewhere during the era. Veterans who served in Korea have notably poorer mental health than those who served elsewhere. These results suggest higher resource needs among aging Korean era veterans. Clinicians, policy makers and the Department of Veterans Affairs should focus on mental health services to older veterans.

  1. Subjective memory complaints are associated with poorer cognitive performance in adults with HIV.

    PubMed

    Kamkwalala, Asante; Hulgan, Todd; Newhouse, Paul

    2017-05-01

    With successful antiretroviral therapy in the US, HIV-positive adults now routinely survive into old age. However, increased life expectancy with HIV introduces the added complication of age-related cognitive decline. Aging with HIV has been associated with poorer cognitive outcomes compared to HIV-negative adults. While up to 50% of older HIV-positive adults will develop some degree of cognitive impairment over their lifetime, cognitive symptoms are often not consistently monitored, until those symptoms are significant enough to impair daily life. In this study we found that subjective memory complaint (SMC) ratings correlated with measurable memory performance impairments in HIV-positive adults, but not HIV-negative adults. As the HIV-positive population ages, structured subjective cognitive assessment may be beneficial to identify the early signs of cognitive impairment, and subsequently allow for earlier interventions to maintain cognitive performance as these adults continue to survive into old age.

  2. Measurement and model prediction of proton-recoil track length distributions in NTA film dosimeters for neutron energy spectroscopy and retrospective dose assessment

    NASA Astrophysics Data System (ADS)

    Taulbee, Timothy D.

    The goal of this research was to determine whether neutron dose reconstruction could be improved through re-analysis of historic NTA films worn by workers in the 1950 through the 1970s. To improve neutron dose reconstruction, the underlying neutron energy spectra is critical in determining the organ dose due to energy dependence of the dose conversion factor as well as the application of radiation weighting factors used in epidemiology and probability of causation calculations. Monte Carlo models of proton-recoil track length distributions were developed and benchmarked against measurement data for both NTA and Ilford films. These models, when applied to several NTA film dosimeter configurations, demonstrated that proton-recoil track length distributions change based upon incident neutron energy. The neutron energy spectra changes that result from the general work environment such as source term and shielding can subsequently be modeled to predict the response of the NTA film dosimeter. An Automatic NTA Film Analyzer has been designed and developed to determine if the difference in proton-recoil track length distributions predicted by the Monte Carlo models could be measured and whether these differences could be correlated to the incident neutron energy spectra. The design required the development of a 2D-3D hybrid track recognition algorithm for a three dimensional analysis of the NTA film in order to accurately determine the proton-recoil track length for subsequent neutron energy determination. NTA films exposed to a plutonium fluoride (PuF4) and polonium boron (PoB) calibration sources were measured and compared. The proton-recoil track lengths were used to reconstruct the incident neutron energy spectra demonstrating the functionality of the analyzer and that reconstruction of the neutron energy spectra from NTA films is feasible. These measurements were compared to the Monte Carlo models and confirmed the applicability of using models to determine the NTA

  3. Late Cardiac Toxicity After Mediastinal Radiation Therapy for Hodgkin Lymphoma: Contributions of Coronary Artery and Whole Heart Dose-Volume Variables to Risk Prediction.

    PubMed

    Hahn, Ezra; Jiang, Haiyan; Ng, Angela; Bashir, Shaheena; Ahmed, Sameera; Tsang, Richard; Sun, Alexander; Gospodarowicz, Mary; Hodgson, David

    2017-08-01

    Mediastinal radiation therapy (RT) for Hodgkin lymphoma (HL) is associated with late cardiotoxicity, but there are limited data to indicate which dosimetric parameters are most valuable for predicting this risk. This study investigated which whole heart dosimetric measurements provide the most information regarding late cardiotoxicity, and whether coronary artery dosimetry was more predictive of this outcome than whole heart dosimetry. A random sample of 125 HL patients treated with mediastinal RT was selected, and 3-dimensional cardiac dose-volume data were generated from historical plans using validated methods. Cardiac events were determined by linking patients to population-based datasets of inpatient and same-day hospitalizations and same-day procedures. Variables collected for the whole heart and 3 coronary arteries included the following: Dmean, Dmax, Dmin, dose homogeneity, V5, V10, V20, and V30. Multivariable competing risk regression models were generated for the whole heart and coronary arteries. There were 44 cardiac events documented, of which 70% were ischemic. The best multivariable model included the following covariates: whole heart Dmean (hazard ratio [HR] 1.09, P=.0083), dose homogeneity (HR 0.94, P=.0034), male sex (HR 2.31, P=.014), and age (HR 1.03, P=.0049). When any adverse cardiac event was the outcome, models using coronary artery variables did not perform better than models using whole heart variables. However, in a subanalysis of ischemic cardiac events only, the model using coronary artery variables was superior to the whole heart model and included the following covariates: age (HR 1.05, P<.001), volume of left anterior descending artery receiving 5 Gy (HR 0.98, P=.003), and volume of left circumflex artery receiving 20 Gy (HR 1.03, P<.001). In addition to higher mean heart dose, increasing inhomogeneity in cardiac dose was associated with a greater risk of late cardiac effects. When all types of cardiotoxicity were evaluated, the

  4. Fracture-Dislocations Demonstrate Poorer Postoperative Functional Outcomes Among Pronation External Rotation IV Ankle Fractures.

    PubMed

    Warner, Stephen J; Schottel, Patrick C; Hinds, Richard M; Helfet, David L; Lorich, Dean G

    2015-06-01

    Pronation external rotation (PER) ankle fractures are relatively uncommon but serious ankle injuries. Although recent studies have demonstrated good outcomes of PER IV fractures after operative treatment, the effect of dislocation on functional outcomes has not yet been evaluated. The objective of this study was to compare short-term functional outcomes in PER IV ankle fractures with and without dislocation. Our database of ankle fractures surgically treated using an anatomic fixation approach by the senior author from 2003 to 2013 was reviewed. All PER IV ankle fracture patients older than 18 years with a minimum of 12 months of follow-up, including Foot and Ankle Outcome Score (FAOS), were included for analysis. Patient demographics, injury characteristics, FAOS, ankle range of motion (ROM), and rate of postoperative complications were compared in PER IV fractures with and without dislocation. Of the 47 PER IV fractures included for analysis, 20 (43%) were fracture-dislocations and 27 (57%) had no dislocation. Mean age of the study cohort was 49 years (range, 24-91 years). The fracture-dislocation cohort demonstrated significantly poorer FAOS (symptoms, 46 vs 70, P = .002; pain, 56 vs 82, P < .001; activities of daily living, 61 vs 84, P = .002; sports, 37 vs 59, P = .036; quality of life, 25 vs 59, P < .001) than the nondislocation cohort. Articular malreduction (33% vs 14%, P = .147) was also more common in the PER IV dislocation group. Rates of syndesmotic malreduction (44% vs 48%, P = .951) were similar between PER IV fractures with and without dislocation. PER IV fracture-dislocations had higher rates of articular malreduction and demonstrated statistically poorer functional outcomes than PER IV fractures with no dislocation. Dislocation in this select subset of ankle fracture patients likely represents a higher energy injury resulting in substantial articular damage and should spur appropriate preoperative patient counseling by the orthopaedic surgeon

  5. Dexterous Manipulation Is Poorer at Older Ages and Is Dissociated From Decline of Hand Strength

    PubMed Central

    Dayanidhi, Sudarshan

    2014-01-01

    Background. The ability to dynamically control fingertip force vector magnitude and direction is critical for dexterous manipulation. We quantified the dynamic control of fingertip forces to examine how dexterous manipulation declines with age. Methods. The strength–dexterity (SD) test measures fingertip forces during compression of a slender spring prone to instability and buckling. The greatest sustained compression (designed to be under 3 N), and force dynamics therein, have been shown to be simple and quick measures of dynamic dexterous manipulation ability. We measured pinch strength and strength–dexterity test in a cross-sectional population of 98 people from 18 to 89 years of age. Results. Dexterous manipulation ability is poorer at older ages, beginning in middle age (p < .001), with greater decline past 65 years of age. Fingertip force dynamics during spring compression and stabilization show a deterioration of neuromuscular control with age. Importantly, this novel detection of decline in dynamic manipulation ability is not correlated with, and thus cannot be entirely explained by, the known decline in pinch strength. We also measured standardized tests of dexterity in participants older than 45, and discuss how the strength–dexterity test uniquely captures features of sensorimotor capabilities for dexterous manipulation in this adult population. Conclusions. Starting in middle age, changes in the functional interactions among sensory, motor, and neural capabilities result in measurably poorer dynamic dexterous manipulation. This deterioration of neuromuscular control motivates and enables future studies to understand the physiological bases for this functional decline so critical to activities of daily living and quality of life. PMID:24610868

  6. Dexterous manipulation is poorer at older ages and is dissociated from decline of hand strength.

    PubMed

    Dayanidhi, Sudarshan; Valero-Cuevas, Francisco J

    2014-09-01

    The ability to dynamically control fingertip force vector magnitude and direction is critical for dexterous manipulation. We quantified the dynamic control of fingertip forces to examine how dexterous manipulation declines with age. The strength-dexterity (SD) test measures fingertip forces during compression of a slender spring prone to instability and buckling. The greatest sustained compression (designed to be under 3 N), and force dynamics therein, have been shown to be simple and quick measures of dynamic dexterous manipulation ability. We measured pinch strength and strength-dexterity test in a cross-sectional population of 98 people from 18 to 89 years of age. Dexterous manipulation ability is poorer at older ages, beginning in middle age (p < .001), with greater decline past 65 years of age. Fingertip force dynamics during spring compression and stabilization show a deterioration of neuromuscular control with age. Importantly, this novel detection of decline in dynamic manipulation ability is not correlated with, and thus cannot be entirely explained by, the known decline in pinch strength. We also measured standardized tests of dexterity in participants older than 45, and discuss how the strength-dexterity test uniquely captures features of sensorimotor capabilities for dexterous manipulation in this adult population. Starting in middle age, changes in the functional interactions among sensory, motor, and neural capabilities result in measurably poorer dynamic dexterous manipulation. This deterioration of neuromuscular control motivates and enables future studies to understand the physiological bases for this functional decline so critical to activities of daily living and quality of life. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Poorer breast cancer survival outcomes in males than females might be attributable to tumor subtype

    PubMed Central

    Zhu, Shan; Wu, Juan; Li, Xiang; Liu, Qian; Wei, Wen; Sun, Shengrong

    2016-01-01

    Background & Aims Substantial controversy exists regarding the differences in tumor subtypes between male breast cancer (MBC) and female breast cancer (FBC). This is the largest population-based study to compare MBC and FBC patients. Methods Using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2012, a retrospective, population-based cohort study was conducted to investigate tumor subtype-specific differences in various characteristics, overall survival (OS) and breast cancer-specific mortality (BCSM) between males and females. Results In all, 181,814 BC patients (1,516 male and 180,298 female) were eligible for this study. The male patients were more likely to be black, older, and have lower histological grades, more advanced stages, larger tumors, more lymph node and distant metastases and human epidermal growth factor receptor 2 (HER2)-negative tumors (each p<0.05). A matched analysis showed that the 2-year OS was 91.2% and 93.7% and that the BCSM was 2.2% and 2.5% for male and female patients, respectively. The univariate analysis showed that male triple-negative (TN), hormone receptor (HoR)-positive/HER2-positive and HoR-positive/HER2-negative patients had poorer OS (p <0.01). Meanwhile, the HoR-positive/HER2-positive and TN subtypes were associated with a higher BCSM in MBC patients (p<0.01). The multivariate analysis revealed that TN MBC patients had poorer OS and BCSM (p<0.05). Simultaneously, the results showed that male patients in the HoR-positive/HER2-negative subgroup were less likely to die of BC when adjusting for other factors (p<0.05). Conclusions The analysis of 2-year OS and BCSM among the BC subtypes showed clear differences between MBC and FBC patients with the TN subtype; these differences warrant further investigation PMID:27655704

  8. Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities.

    PubMed

    Contrera, Joseph F

    2011-02-01

    The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 μg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values.

  9. Evaluation of the Cerebral State Index in Cats under Isoflurane Anaesthesia: Dose-Effect Relationship and Prediction of Clinical Signs

    PubMed Central

    Sousa, Joana R.; Ribeiro, Lénio; Ferreira, David A.

    2014-01-01

    The performance of the cerebral state index (CSI) in reflecting different levels of isoflurane anaesthesia was evaluated in ten cats subjected to four end-tidal isoflurane concentrations (EtIso), each maintained for 15 minutes (0.8%, 1.2%, 1.6%, or 2.0% EtIso). The CSI, hemodynamic data, ocular reflexes, and eye position were recorded for each EtIso concentration. Pharmacodynamic analysis of CSI with EtIso was performed, as well as prediction probability analysis with a clinical scale based on the eye reflexes. The CSI values showed great variability. Between all parameters, burst suppression ratio showed the better fitting with the sigmoidal concentration-effect model (R2 = 0.93) followed by CSI (R2 = 0.82) and electromyographic activity (R2 = 0.79). EtIso was the variable with better prediction of the clinical scale of anaesthesia (prediction probability value of 0.94). Although the CSI values decrease with increasing isoflurane concentrations, the huge variability in CSI values may be a strong limitation for its use in cats and it seems to be no better than EtIso as a predictor of clinical signs. PMID:24616823

  10. An Improved Model for Predicting Radiation Pneumonitis Incorporating Clinical and Dosimetric Variables;Lung cancer; Radiation pneumonitis; Dose-volume histogram; Angiotensin converting enzyme inhibitor

    SciTech Connect

    Jenkins, Peter; Watts, Joanne

    2011-07-15

    Purpose: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. Methods and Materials: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. Results: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS{sub 5}). The area under the receiver operator characteristic curve for TFS{sub 5} was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS{sub 5} <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS{sub 5} {>=}2.17. Conclusions: TFS{sub 5} represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.

  11. Single-dose effects on the P3no-go ERP component predict clinical response to stimulants in pediatric ADHD.

    PubMed

    Ogrim, Geir; Aasen, Ida Emilia; Brunner, Jan Ferenc

    2016-10-01

    Approximately 30% of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) and treated with stimulants are considered non-responders (non-REs). Reliable predictors of response are missing. We examined changes in Event-Related Potentials (ERPs) induced by a single dose of stimulant medication in order to predict later clinical response. ERPs were registered twice during performance of a visual cued go/no-go task in 87 ADHD patients (27 girls) aged 8-18years; the second recording on a single dose of stimulant medication, followed by a systematic medication trial lasting 4weeks. Based on the four-week trial, participants were categorized as responders (REs, N=62) or non-REs (N=25). Changes among REs and non-REs in ERP components (cueP3, CNV, P3go, N2no-go, P3no-go) and behavioral-test variables were then compared. REs and non-REs differed significantly in medication-induced changes in P3no-go, cue-P3, CNV, omission errors, reaction time, and reaction-time variability. The largest effect size was found for P3no-go amplitude (p<.001; d=1.76). Changes in P3no-go and omission errors correctly classified 90% of the REs and 76% of the non-REs, when controlling for the age of the participants. Clinical response to stimulants can be predicted by assessing single-dose changes in the P3no-go ERP component amplitude. Changes in P3no-go may be a clinically useful marker of response to stimulants. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

    PubMed Central

    van der Laan, Jan Willem; Buitenhuis, Wenny H. W.; Wagenaar, Laura; Soffers, Ans E. M. F.; van Someren, Eugene P.; Krul, Cyrille A. M.; Woutersen, Ruud A.

    2016-01-01

    In an exercise designed to reduce animal use, we analyzed the results of rat subchronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumor outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred forty-three of the 239 compounds not inducing putative preneoplastic lesions in the subchronic study did not induce tumors in the carcinogenicity study [true negatives (TNs)], whereas 96 compounds were categorized as false negatives (FNs) because tumors were observed in the carcinogenicity study. Of the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumors in the carcinogenicity study [true positives (TPs)], and 19 only showed preneoplastic lesions in subchronic studies but no tumors in the carcinogenicity study [false positives (FPs)]. In addition, we then re-assessed the prediction of the tumor outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN). For 67 compounds, the presence of cellular hyperplasia as evidence for proliferative action could be found (TP). Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92% and the ability to detect carcinogens at 98%. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorized as FN and 1 as FP), thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological properties of compounds in

  13. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography

    PubMed Central

    Abe, Y; Muro, T; Sakanoue, Y; Komatsu, R; Otsuka, M; Naruko, T; Itoh, A; Yoshiyama, M; Haze, K; Yoshikawa, J

    2005-01-01

    Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling. PMID:15797931

  14. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia.

    PubMed

    Khan, N; Hills, R K; Virgo, P; Couzens, S; Clark, N; Gilkes, A; Richardson, P; Knapper, S; Grimwade, D; Russell, N H; Burnett, A K; Freeman, S D

    2017-05-01

    It remains unclear in adult acute myeloid leukaemia (AML) whether leukaemic expression of CD33, the target antigen for gemtuzumab ozogamicin (GO), adds prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correlated with clinical outcomes and benefit from GO including a dose randomisation. CD33 expression associated with genetic subgroups, including lower levels in both adverse karyotype and core-binding factor (CBF)-AML, but was not independently prognostic. When comparing GO versus no GO (n=393, CBF-AMLs excluded) by stratified subgroup-adjusted analysis, patients with lowest quartile (Q1) %CD33-positivity had no benefit from GO (relapse risk, HR 2.41 (1.27-4.56), P=0.009 for trend; overall survival, HR 1.52 (0.92-2.52)). However, from the dose randomisation (NCRI-AML17, n=464, CBF-AMLs included), 6 mg/m(2) GO only had a relapse benefit without increased early mortality in CD33-low (Q1) patients (relapse risk HR 0.64 (0.36-1.12) versus 1.70 (0.99-2.92) for CD33-high, P=0.007 for trend). Thus CD33 expression is a predictive factor for GO effect in adult AML; although GO does not appear to benefit the non-CBF AML patients with lowest CD33 expression a higher GO dose may be more effective for CD33-low but not CD33-high younger adults.

  15. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights.

    PubMed

    Denkins, P; Badhwar, G; Obot, V; Wilson, B; Jejelewo, O

    2001-01-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  16. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights

    NASA Technical Reports Server (NTRS)

    Denkins, P.; Badhwar, G.; Obot, V.; Wilson, B.; Jejelewo, O.

    2001-01-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  17. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights

    NASA Technical Reports Server (NTRS)

    Denkins, P.; Badhwar, G.; Obot, V.; Wilson, B.; Jejelewo, O.

    2001-01-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  18. Feasibility of real-time MR thermal dose mapping for predicting radiofrequency ablation outcome in the myocardium in vivo.

    PubMed

    Toupin, Solenn; Bour, Pierre; Lepetit-Coiffé, Matthieu; Ozenne, Valéry; Denis de Senneville, Baudouin; Schneider, Rainer; Vaussy, Alexis; Chaumeil, Arnaud; Cochet, Hubert; Sacher, Frédéric; Jaïs, Pierre; Quesson, Bruno

    2017-01-25

    Clinical treatment of cardiac arrhythmia by radiofrequency ablation (RFA) currently lacks quantitative and precise visualization of lesion formation in the myocardium during the procedure. This study aims at evaluating thermal dose (TD) imaging obtained from real-time magnetic resonance (MR) thermometry on the heart as a relevant indicator of the thermal lesion extent. MR temperature mapping based on the Proton Resonance Frequency Shift (PRFS) method was performed at 1.5 T on the heart, with 4 to 5 slices acquired per heartbeat. Respiratory motion was compensated using navigator-based slice tracking. Residual in-plane motion and related magnetic susceptibility artifacts were corrected online. The standard deviation of temperature was measured on healthy volunteers (N = 5) in both ventricles. On animals, the MR-compatible catheter was positioned and visualized in the left ventricle (LV) using a bSSFP pulse sequence with active catheter tracking. Twelve MR-guided RFA were performed on three sheep in vivo at various locations in left ventricle (LV). The dimensions of the thermal lesions measured on thermal dose images, on 3D T1-weighted (T1-w) images acquired immediately after the ablation and at gross pathology were correlated. MR thermometry uncertainty was 1.5 °C on average over more than 96% of the pixels covering the left and right ventricles, on each volunteer. On animals, catheter repositioning in the LV with active slice tracking was successfully performed and each ablation could be monitored in real-time by MR thermometry and thermal dosimetry. Thermal lesion dimensions on TD maps were found to be highly correlated with those observed on post-ablation T1-w images (R = 0.87) that also correlated (R = 0.89) with measurements at gross pathology. Quantitative TD mapping from real-time rapid CMR thermometry during catheter-based RFA is feasible. It provides a direct assessment of the lesion extent in the myocardium with precision in the range of one

  19. Preliminary experience of a predictive model to define rectal volume and rectal dose during the treatment of prostate cancer

    PubMed Central

    Falco, M D; D'Andrea, M; Fedele, D; Barbarino, R; Benassi, M; Giudice, E; Hamoud, E; Ingrosso, G; Ladogana, P; Santarelli, F; Tortorelli, G; Santoni, R

    2011-01-01

    Objectives The aim of this study was to define a method to evaluate the total dose delivered to the rectum during the whole treatment course in six patients undergoing irradiation for prostate cancer using an offline definition of organ motion with images from a cone beam CT (CBCT) scanner available on a commercial linear accelerator. Methods Patient set-up was verified using a volumetric three-dimensional CBCT scanner; 9–14 CBCT scans were obtained for each patient. Images were transferred to a commercial treatment planning system for offline organ motion analysis. The shape of the rectums were used to obtain a mean dose–volume histogram (), which was the average of the DVHs of the rectums as they appeared in each verification CBCT. A geometric model of an average rectum (AR) was produced using the rectal contours delineated on the CBCT scans (DVHAR). To check whether the first week of treatment was representative of the whole treatment course, we evaluated the DVHs related to only the first five CBCT scans ( and DVHAR5). Finally, the influence of a dietary protocol on the goodness of our results was considered. Results In all six patients the original rectal DVH for the planning CT scan showed higher values than all DVHs. Conclusion Although the application of the model to a larger set of patients is necessary to confirm this trend, reconstruction of a representative volume of the rectum throughout the entire treatment course seems feasible. PMID:21849366

  20. [High-dose interferon alpha in treatment of patients with malignant melanoma, monitoring of predictive and prognostic biomarkers].

    PubMed

    Vanásková, J; Grim, J; Kopecký, J; Kubala, E; Filip, S

    2011-01-01

    The incidence of malignant melanoma is increasing by about 2-5% per year, exceeding an incidence of all other tumors. Adjuvant immunotherapy with high-dose interferon (HDI) as per the ECOG 1684 trial Kirkwood's schema is still recommended as a standard. HDI should be started within 60 days after a surgical procedure. Meaningful adjuvant immunotherapy is based on radical surgical excision, an investigation of the sentinel node and regional lymph node dissection, if indicated. Current research aims to utilize routinely usable biomarkers in order to define patients who would explicitly profit from HDI. The authors present a review of HDI trials, focusing on the management of adverse effects of HDI and on biomarkers. This review also discusses the initial own experiences at the Oncology Centre in Hradec Králové. Malignant melanoma is a very immunogenic tumour. Immunotherapy with HDI is considered to be the only therapeutic modality so far that has been proven to prolong relapse-free survival and overall survival (in short-time criterion) in adjuvant setting. However, the results of these trials are inconsistent and particular biomarkers of therapeutic response have not been defined yet.

  1. Use of CFU-GM assay for prediction of human maximum tolerated dose of a new antitumoral drug: Yondelis (ET-743).

    PubMed

    Gómez, Susana G; Bueren, Juan A; Faircloth, Glynn; Albella, Beatriz

    2003-01-01

    Acute cytotoxic exposure causes decreases in bone marrow progenitors that precedes the neutrophil nadir. Experiments in animal models reveal a relationship between the reduction in granulocyte-macrophage progenitors (CFU-GM) and the decrease in absolute neutrophil count [Toxicol. Pathol. 21 (1993) 241]. Recently, the prevalidation of a model for predicting acute neutropenia by the CFU-GM assay has been reported [Toxicol. In Vitro 15 (2001) 729]. The model was based on prediction of human MTD by adjusting the animal-derived MTD for the differential sensitivity between CFU-GM from animal species and humans. In this study, this model has been applied on a new antitumoral drug, Yondelis (Ecteinascidin; ET-743). Preclinical studies showed that hematotoxicity was the main side effect in mice, being the MTD of 600 microg/m2 [Drugs Future 21 (1996) 1155]. The sensitivity of myeloid progenitors was higher in mice than in humans, with IC90 values of 0.69+/-0.22 nM and 1.31+/-0.21 nM for murine and human CFU-GMs respectively. This study predicts a human MTD of 1145 microg/m2. The reported human MTD of ET-743 given as a 24-h continuous infusion every 3 weeks is 1800 microg/m2 [J. Clin. Oncol. 19 (2001) 1256]. Since our predicted MTD is within fourfold of the actual MTD (the interspecies variation in tolerated dose due to differences in clearance rates, metabolism pathways and infusion rate) the result confirms the profit of the prediction model.

  2. Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum

    PubMed Central

    Aa, Jiye; Zheng, Tian; Shi, Jian; Li, Mengjie; Wang, Xinwen; Zhao, Chunyan; Xiao, Wenjing; Yu, Xiaoyi; Sun, Runbin; Gu, Rongrong; Zhou, Jun; Wu, Liang; Hao, Gang; Zhu, Xuanxuan; Wang, Guangji

    2012-01-01

    Background Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. Methodology/Principal Findings Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. Conclusions/Significance These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate

  3. Predicting of Effective Dose as Biomarker for Cytotoxicity Using Partial Least Square-Fourier Transform Infrared Spectroscopy (PLS_FTIR).

    PubMed

    Zendehdel, Rezvan; Khodakarim, Soheila; H Shirazi, Farshad

    2015-01-01

    Toxicity bioassays are important tools to determine biological effects of chemical agents on species. The questions remained on, what effects have been imposed on each of the different molecular site of cells by chemical exposure and how to find a pattern for chemical toxicity. To address the questions, HepG2 cell lines were exposed to the different concentrations of cisplatin for 24 hours to result cell mortality in the range of one to one hundred percent. Fourier Transform Infrared spectroscopy (FTIR) has been used in this study to analyze the chemical alterations on HepG2 cell line by cisplatin. Partial least square regression (PLS) analysis was then applied to the FTIR spectrum results to search for a biomarker peak and present the desire cellular effects of cisplatin. The comparison of cellular FTIR spectra after exposure to different concentrations of cisplatin confirmed the binding of cisplatin to DNA through direct interaction of platinum to guanine and thymine bases of DNA. Biochemical Index Spectra (BIS) were defined based on the differences between of normal and cisplatin exposed cells. Information from the BIS was subjected to PLS analysis to trigger any particular relationship between the toxicity spectral response and cisplatin concentration. This approach was capable of predicting the concentration of cisplatin for any particular effects observed in the cellular FTIR spectrum (R(2) = 0.968 ± 0.037). Our work supports the promises that, FTIR can demonstrate the trace of toxicity before the cells dies. Finally, PLS of FTIR data directly predicts the effective concentration of chemicals in particular cellular components.

  4. Superoxide radical-generating compounds activate a predicted promoter site for paraquat-inducible genes of the Chromobacterium violaceum bacterium in a dose-dependent manner.

    PubMed

    Gabriel, J E; Guerra-Slompo, E P; de Souza, E M; de Carvalho, F A L; Madeira, H M F; de Vasconcelos, A T R

    2015-08-21

    The purpose of the present study was to functionally evaluate the influence of superoxide radical-generating compounds on the heterologous induction of a predicted promoter region of open reading frames for paraquat-inducible genes (pqi genes) revealed during genome annotation analyses of the Chromobacterium violaceum bacterium. A 388-bp fragment corresponding to a pqi gene promoter of C. violaceum was amplified using specific primers and cloned into a conjugative vector containing the Escherichia coli lacZ gene without a promoter. Assessments of the expression of the β-galactosidase enzyme were performed in the presence of menadione (MEN) and phenazine methosulfate (PMS) compounds at different final concentrations to evaluate the heterologous activation of the predicted promoter region of interest in C. violaceum induced by these substrates. Under these experimental conditions, the MEN reagent promoted highly significant increases in the expression of the β-galactosidase enzyme modulated by activating the promoter region of the pqi genes at all concentrations tested. On the other hand, significantly higher levels in the expression of the β-galactosidase enzyme were detected exclusively in the presence of the PMS reagent at a final concentration of 50 μg/mL. The findings described in the present study demonstrate that superoxide radical-generating compounds can activate a predicted promoter DNA motif for pqi genes of the C. violaceum bacterium in a dose-dependent manner.

  5. Medicare-VHA dual use is associated with poorer chronic wound healing.

    PubMed

    Bouldin, Erin D; Littman, Alyson J; Wong, Edwin; Liu, Chuan-Fen; Taylor, Leslie; Rice, Kenneth; Reiber, Gayle E

    2016-09-01

    Veterans who use Veterans Health Affairs (VHA) have the option of enrolling in and obtaining care from other non-VA sources. Dual system use may improve care by increasing options or it may result in poorer outcomes because of fragmented care. Our objective was to assess whether dual system use of VHA and Medicare for wound care was associated with chronic wound healing. We conducted a retrospective cohort study of 227 Medicare-enrolled VHA users in the Pacific Northwest who had an incident, chronic lower limb wound between October 1, 2006 and September 30, 2007 identified through VHA chart review. All wounds were followed until resolution or for up to one year. Dual system wound care was identified through Medicare claims during follow-up. We used a proportional hazards model to compare wound healing among VHA-exclusive and dual wound care users, using a time-varying measure of dual use and treating amputation and death as competing risks. About 18.1% of subjects were classified as dual wound care users during follow-up. After adjustment using propensity scores, dual use was associated with a significantly lower hazard of wound healing compared to VHA-exclusive use (HR = 0.63, 95%CI: 0.39-0.99, p = 0.047). Hazards for the competing risks, amputation (HR = 4.23, 95% CI: 1.61-11.15, p = 0.003) and death (HR = 3.08, 95%CI: 1.11-8.56, p = 0.031), were significantly higher for dual users compared to VHA-exclusive users. Results were similar in inverse probability of treatment weighted analyses and in sensitivity analyses that excluded veterans enrolled in a Medicare managed care plan and that used a revised wound resolution date based on Medicare claims data, but were not always statistically significant. Overall, dual wound care use was associated with substantially poorer wound healing compared to VHA-exclusive wound care use. VHA may need to design programs or policies that support and improve care coordination for veterans needing chronic

  6. Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife.

    PubMed

    Cohen-Manheim, Irit; Doniger, Glen Michael; Sinnreich, Ronit; Simon, Ely Samuel; Pinchas, Ronit; Aviv, Abraham; Kark, Jeremy David

    2016-02-01

    Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28-32 and 41-46 years were assessed at ages 48-52 for global cognitive function and its five specific component domains with a NeuroTrax computerized test battery. Multivariable regression and logistic models were applied for cognition treated as a continuous and categorical variable, respectively. We found that LTL attrition (adjusted for sex, baseline LTL and potential confounders including socioeconomic variables) was inversely associated with global cognition (standardized β = -.119, p = .004) and its component domains: information processing speed (β = -.102, p = .024), visual-spatial function (β = -.102, p = .017) and memory (β = -.093, p = .045), but less so for the attention and executive domains. The multivariable-adjusted odds ratio for low global cognition comparing the upper versus lower thirds of LTL attrition was 2.12 (95 % CI 1.11-4.08, p for trend = .023). There was no association of baseline or follow-up LTL with cognition. No effect modification was evident for sex, smoking or inflammatory markers. In conclusion, faster LTL attrition in young adulthood was associated with poorer global and domain-specific cognitive function in midlife, suggesting that more rapid LTL attrition may be predictive of cognitive aging in healthy young adults.

  7. Whole-exome sequencing reveals defective CYP3A4 variants predictive of paclitaxel dose-limiting neuropathy.

    PubMed

    Apellániz-Ruiz, María; Lee, Mi-Young; Sánchez-Barroso, Lara; Gutiérrez-Gutiérrez, Gerardo; Calvo, Isabel; García-Estévez, Laura; Sereno, María; García-Donás, Jesús; Castelo, Beatriz; Guerra, Eva; Leandro-García, Luis J; Cascón, Alberto; Johansson, Inger; Robledo, Mercedes; Ingelman-Sundberg, Magnus; Rodríguez-Antona, Cristina

    2015-01-15

    Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10(-5)). This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. ©2014 American Association for Cancer Research.

  8. Ratios of T lymphocyte subpopulations predict survival of cadaveric renal allografts in adult patients on low dose corticosteroid therapy.

    PubMed

    Van Es, A; Tanke, H J; Baldwin, W M; Oljans, P J; Ploem, J S; Vanes, L A

    1983-04-01

    Peripheral blood T lymphocyte subpopulations were monitored in 45 consecutive adult recipients of cadaveric renal allografts by using monoclonal antibodies and flow cytometrie. All patients were treated with low dose corticosteroids and azathioprine. In 37 patients pre-transplant OKT4/OKT8 ratios were available. Six of 26 patients (23%) with pre-transplant OKT4/OKT8 ratios greater than 1.6 and seven of 11 patients (64%) with pre-transplant OKT4/OKT8 ratio less than or equal to 1.6 lost their graft due to rejection within 6 months. The difference in transplant survival between patients with pre-transplant OKT4/OKT8 ratios greater than 1.6 and less than or equal to 1.6i is just significant (P = 0 . 049 Fishers test). No correlation was found between post-transplant values of individual lymphocyte subpopulations or OKT4/OKT8 ratios and the incidence of subsequent rejection episodes. Forty out of 45 patients suffered one or more rejection episodes which were treated by raising the dosage of prednisone. In 24 of these patients the rejection episode was reversed, leading to a transplant survival of at least 6 months. In these 24 patients the OKT4/OKT8 ratio was greater than 1.6 for at least 3 days before the institution of any rejection treatments. Sixteen patients lost their graft due to rejection within 6 months after transplantation. In 11 of these 16 patients OKT4/OKT8 ratios less than or equal to 1.6 preceded the institution of all rejection treatments for at least 3 days, while in three patients the OKT4/OKT8 ratio was greater than 1.6 before the first rejection episode but this ratio was less than or equal to 1.6 before subsequent rejection episodes. Thus, OKT4/OKT8 ratios greater than 1.i6 correlated with reversible rejection episodes and OKT4/OKT8 ratios less than or equal to 1.6 correlated with irreversible rejection (P less than 0 . 001).

  9. Ratios of T lymphocyte subpopulations predict survival of cadaveric renal allografts in adult patients on low dose corticosteroid therapy.

    PubMed Central

    Van Es, A; Tanke, H J; Baldwin, W M; Oljans, P J; Ploem, J S; Vanes, L A

    1983-01-01

    Peripheral blood T lymphocyte subpopulations were monitored in 45 consecutive adult recipients of cadaveric renal allografts by using monoclonal antibodies and flow cytometrie. All patients were treated with low dose corticosteroids and azathioprine. In 37 patients pre-transplant OKT4/OKT8 ratios were available. Six of 26 patients (23%) with pre-transplant OKT4/OKT8 ratios greater than 1.6 and seven of 11 patients (64%) with pre-transplant OKT4/OKT8 ratio less than or equal to 1.6 lost their graft due to rejection within 6 months. The difference in transplant survival between patients with pre-transplant OKT4/OKT8 ratios greater than 1.6 and less than or equal to 1.6i is just significant (P = 0 . 049 Fishers test). No correlation was found between post-transplant values of individual lymphocyte subpopulations or OKT4/OKT8 ratios and the incidence of subsequent rejection episodes. Forty out of 45 patients suffered one or more rejection episodes which were treated by raising the dosage of prednisone. In 24 of these patients the rejection episode was reversed, leading to a transplant survival of at least 6 months. In these 24 patients the OKT4/OKT8 ratio was greater than 1.6 for at least 3 days before the institution of any rejection treatments. Sixteen patients lost their graft due to rejection within 6 months after transplantation. In 11 of these 16 patients OKT4/OKT8 ratios less than or equal to 1.6 preceded the institution of all rejection treatments for at least 3 days, while in three patients the OKT4/OKT8 ratio was greater than 1.6 before the first rejection episode but this ratio was less than or equal to 1.6 before subsequent rejection episodes. Thus, OKT4/OKT8 ratios greater than 1.i6 correlated with reversible rejection episodes and OKT4/OKT8 ratios less than or equal to 1.6 correlated with irreversible rejection (P less than 0 . 001). PMID:6345032

  10. Lin28 promotes Her2 expression and Lin28/Her2 predicts poorer survival in gastric cancer.

    PubMed

    Wang, Qinchuan; Zhou, Jichun; Guo, Jufeng; Teng, Rongyue; Shen, Jianguo; Huang, Yasheng; Xie, Shuduo; Wei, Qun; Zhao, Wenhe; Chen, Wenjun; Yuan, Xiaoming; Chen, Yongxia; Wang, Linbo

    2014-11-01

    The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (p<0.05 for each). Kaplan-Meier analysis illustrated that both Lin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, p<0.01). Multivariate Cox analysis showed that Lin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.

  11. Long intergenic non-coding RNA 271 is predictive of a poorer prognosis of papillary thyroid cancer

    PubMed Central

    Ma, Ben; Liao, Tian; Wen, Duo; Dong, Chuanpeng; Zhou, Li; Yang, Shuwen; Wang, Yu; Ji, Qinghai

    2016-01-01

    A number of long non-coding RNAs (lncRNAs) have been found to play critical roles in oncogenesis and tumor progression. We aimed to investigate whether lncRNAs could act as prognostic biomarkers for papillary thyroid cancer (PTC) that may assist us in evaluating disease status and prognosis for patients. We found 220 lncRNAs with expression alteration from the annotated 2773 lncRNAs approved by the HUGO gene nomenclature committee in The Cancer Genome Atlas (TCGA) dataset, of which FAM41C, CTBP1-AS2, LINC00271, HAR1A, LINC00310 and HAS2-AS1 were associated with recurrence. After adjusting classical clinicopathogical factors and BRAFV600E mutation, LINC00271 was found to be an independent risk factor for extrathyroidal extension, lymph node metastasis, advanced tumor stage III/IV and recurrence in multivariate analyses. Additionally, LINC00271 expression was significantly downregulated in PTCs versus adjacent normal tissues (P < 0.001). The Gene Set Enrichment Analysis (GSEA) revealed that genes associated with cell adhesion molecules, cell cycle, P53 signaling pathway and JAK/STAT signaling pathway were remarkably enriched in lower-LINC00271 versus higher-LINC00271 tumors. In conclusion, LINC00271 was identified as a possible suppressor gene in PTC in our study, and it may serve as a potential predictor of poor prognoses in PTC. PMID:27833134

  12. Shorter telomere length predicts poorer immunological recovery in virologically suppressed HIV-1-infected patients treated with combined antiretroviral therapy.

    PubMed

    Blanco, José-Ramón; Jarrin, Inma; Martinez, Alfredo; Siles, Eva; Larrayoz, Ignacio M; Cañuelo, Ana; Gutierrez, Félix; Gonzalez-Garcia, Juan; Vidal, Francesc; Moreno, Santiago

    2015-01-01

    Successful combined antiretroviral therapy (cART) does not always result in complete CD4 T-cell recovery despite the effective control of HIV replication. Because telomere dysregulation can lead to an abnormal cell proliferation, we hypothesized that the lack of CD4 recovery may be related to telomere defects; We thus evaluated the association between telomere length (TL) and CD4 T-cell recovery 48 weeks after cART initiation in virologically suppressed patients, and its possible relationship to oxidative stress (OS) and nitrosative stress (NOx) markers. We studied HIV-infected patients on stable cART who achieved a viral load <50 copies per milliliter after 48 weeks of their first cART. Leukocyte TL was measured and categorized into tertiles. We calculated mean increases in CD4 T-cell at 48 weeks from cART initiation and used multivariate linear regression models to estimate differences in mean increases according to tertiles of TL. One hundred thirty-two patients, 86% male, 81% <50 years at cART initiation were studied. Mean increases in CD4 were greater in patients with long TL than in those with medium and short TLs (P = 0.007). After adjustment for sex, age, CD4 T-cell counts, viral load, and hepatitis C infection at cART initiation, differences in mean CD4 T-cell count increases according to TL remained statistically significant (P = 0.02). Additional adjustment for NOx and OS did not change the results. A lower immunological response despite a successful virological response is associated with a shorter TL. The effect is not related to NOx or OS.

  13. Newborn Event-Related Potentials Predict Poorer Pre-Reading Skills in Children at Risk for Dyslexia

    ERIC Educational Resources Information Center

    Guttorm, Tomi K.; Leppanen, Paavo H. T.; Hamalainen, Jarmo A.; Eklund, Kenneth M.; Lyytinen, Heikki J.

    2010-01-01

    Earlier results from the Jyvaskyla Longitudinal Study of Dyslexia showed that newborn event-related potentials (ERPs) of children with and without familial risk for dyslexia were associated with receptive language and verbal memory skills between 2.5 and 5 years of age. We further examined whether these ERPs (responses to synthetic consonant-vowel…

  14. Newborn Event-Related Potentials Predict Poorer Pre-Reading Skills in Children at Risk for Dyslexia

    ERIC Educational Resources Information Center

    Guttorm, Tomi K.; Leppanen, Paavo H. T.; Hamalainen, Jarmo A.; Eklund, Kenneth M.; Lyytinen, Heikki J.

    2010-01-01

    Earlier results from the Jyvaskyla Longitudinal Study of Dyslexia showed that newborn event-related potentials (ERPs) of children with and without familial risk for dyslexia were associated with receptive language and verbal memory skills between 2.5 and 5 years of age. We further examined whether these ERPs (responses to synthetic consonant-vowel…

  15. Long intergenic non-coding RNA 271 is predictive of a poorer prognosis of papillary thyroid cancer.

    PubMed

    Ma, Ben; Liao, Tian; Wen, Duo; Dong, Chuanpeng; Zhou, Li; Yang, Shuwen; Wang, Yu; Ji, Qinghai

    2016-11-11

    A number of long non-coding RNAs (lncRNAs) have been found to play critical roles in oncogenesis and tumor progression. We aimed to investigate whether lncRNAs could act as prognostic biomarkers for papillary thyroid cancer (PTC) that may assist us in evaluating disease status and prognosis for patients. We found 220 lncRNAs with expression alteration from the annotated 2773 lncRNAs approved by the HUGO gene nomenclature committee in The Cancer Genome Atlas (TCGA) dataset, of which FAM41C, CTBP1-AS2, LINC00271, HAR1A, LINC00310 and HAS2-AS1 were associated with recurrence. After adjusting classical clinicopathogical factors and BRAF(V600E) mutation, LINC00271 was found to be an independent risk factor for extrathyroidal extension, lymph node metastasis, advanced tumor stage III/IV and recurrence in multivariate analyses. Additionally, LINC00271 expression was significantly downregulated in PTCs versus adjacent normal tissues (P < 0.001). The Gene Set Enrichment Analysis (GSEA) revealed that genes associated with cell adhesion molecules, cell cycle, P53 signaling pathway and JAK/STAT signaling pathway were remarkably enriched in lower-LINC00271 versus higher-LINC00271 tumors. In conclusion, LINC00271 was identified as a possible suppressor gene in PTC in our study, and it may serve as a potential predictor of poor prognoses in PTC.

  16. Hearing handicap, rather than measured hearing impairment, predicts poorer quality of life over 10 years in older adults.

    PubMed

    Gopinath, Bamini; Schneider, Julie; Hickson, Louise; McMahon, Catherine M; Burlutsky, George; Leeder, Stephen R; Mitchell, Paul

    2012-06-01

    We aimed to determine the prospective association between measured hearing impairment, self-reported hearing handicap and hearing aid use with quality of life. 829 Blue Mountains Hearing Study participants (≥ 55 years) were examined between 1997-1999 and 2007-2009. The shortened version of the hearing handicap inventory was administered. Hearing levels were measured using pure-tone audiometry. Quality of life was assessed using the 36-Item Short-Form Survey (SF-36); higher scores reflect better quality of life. Hearing impairment at baseline compared with no impairment was associated with lower mean SF-36 mental composite score 10 years later (multivariable-adjusted p=0.03). Physical composite score and mean scores for seven of the eight SF-36 domains after 10-year follow-up were significantly lower among participants who self-reported hearing handicap at baseline. Differences in the adjusted means between participants with and without hearing handicap ranged from 2.7 (physical composite score) to 10.4 units ('role limitations due to physical problems' domain). Individuals who developed incident hearing impairment compared to those who did not, had adjusted mean scores 9.5- and 7.7-units lower in the 'role limitation due to physical problems', and 'bodily pain' domains, respectively, at the 10-year follow-up. Hearing aid users versus non-users at baseline showed a 1.82-point (p=0.03) and 3.32-point (p=0.01) increase in SF-36 mental composite score and mental health domain over the 10-year follow-up, respectively. Older adults with self-perceived hearing handicap constitute a potential risk group for overall deterioration in quality of life, while hearing aid use could help improve the well-being of hearing impaired adults. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Self-Assessed Hearing Handicap in Older Adults with Poorer-than-Predicted Speech Recognition in Noise

    ERIC Educational Resources Information Center

    Eckert, Mark A.; Matthews, Lois J.; Dubno, Judy R.

    2017-01-01

    Purpose: Even older adults with relatively mild hearing loss report hearing handicap, suggesting that hearing handicap is not completely explained by reduced speech audibility. Method: We examined the extent to which self-assessed ratings of hearing handicap using the Hearing Handicap Inventory for the Elderly (HHIE; Ventry & Weinstein, 1982)…

  18. Self-Assessed Hearing Handicap in Older Adults with Poorer-than-Predicted Speech Recognition in Noise

    ERIC Educational Resources Information Center

    Eckert, Mark A.; Matthews, Lois J.; Dubno, Judy R.

    2017-01-01

    Purpose: Even older adults with relatively mild hearing loss report hearing handicap, suggesting that hearing handicap is not completely explained by reduced speech audibility. Method: We examined the extent to which self-assessed ratings of hearing handicap using the Hearing Handicap Inventory for the Elderly (HHIE; Ventry & Weinstein, 1982)…

  19. Adverse psychosocial factors predict poorer prognosis in HIV disease: a meta-analytic review of prospective investigations.

    PubMed

    Chida, Yoichi; Vedhara, Kavita

    2009-05-01

    There is a growing epidemiological literature focusing on the association between psychosocial stress and human immunodeficiency virus (HIV) disease progression or acquired immunodeficiency syndrome (AIDS), but inconsistent findings have been published. We aimed to quantify the association between adverse psychosocial factors and HIV disease progression. We searched Medline; PsycINFO; Web of Science; PubMed up to 19 January 2009, and included population studies with a prospective design that investigated associations between adverse psychosocial factors and HIV disease progression or AIDS. Two reviewers independently extracted data on study characteristics, quality, and estimates of associations. The overall meta-analysis examined 36 articles including 100 psychosocial and disease related relationships. It exhibited a small, but robust positive association between adverse psychosocial factors and HIV progression (correlation coefficient as combined size effect 0.059, 95% confidence interval 0.043-0.074, p<0.001). Notably, sensitivity analyses showed that personality types or coping styles and psychological distress were more strongly associated with greater HIV disease progression than stress stimuli per se, and that all of the immunological and clinical outcome indicators (acquired immunodeficiency syndrome stage, CD4+ T-cell decline, acquired immunodeficiency syndrome diagnosis, acquired immunodeficiency syndrome mortality, and human immunodeficiency virus disease or acquired immunodeficiency syndrome symptoms) except for viral load exhibited detrimental effects by adverse psychosocial factors. In conclusion, the current review reveals a robust relationship between adverse psychosocial factors and HIV disease progression. Furthermore, there would appear to be some evidence for particular psychosocial factors to be most strongly associated with HIV disease progression.

  20. Predictive dosimetry for threshold phototoxicity in photodynamic therapy on normal skin: red wavelengths produce more extensive damage than blue at equal threshold doses.

    PubMed

    Tsoukas, M M; Lin, G C; Lee, M S; Anderson, R R; Kollias, N

    1997-04-01

    The goal of this investigation was to establish methodology to determine and prevent phototoxic responses of normal skin to photodynamic therapy (PDT). The drug used was a second-generation photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA). The dependence of skin phototoxicity on drug dose (0.5-2.0 mg/kg), fluence (1.2-390 J/cm2), and wavelength (690 nm and 458 nm) was studied in the New Zealand albino rabbit in the first 5 h after injection. Skin responses were recorded for 2 wk after irradiation. Noninvasive measurements of drug fluorescence were made on unexposed skin sites during the first 5 h after drug injection. Immediate responses to PDT included erythema induced by 458 nm light and blanching induced by 690 nm light. Delayed reactions included edema on the day of exposure, purpura at 24 h, eschar by day 2 or 3, and scar by the end of follow-up. The threshold fluence for immediate responses correlated strongly with the threshold fluence for delayed reactions. The induction of threshold purpura on day 1 was a reliable index for skin phototoxicity that led to necrosis. The minimum purpura dose on day 1 after irradiation increased exponentially with the interval between drug injection and irradiation, independent of irradiation wavelength, for all drug doses. The action spectrum for threshold purpura mimics closely the absorption spectrum of BPD-MA. The in vivo drug fluorescence correlated with skin phototoxicity, thus allowing predictive dosimetry. This model system defines the safety limits for skin phototoxicity of PDT with BPD-MA.

  1. Tobacco may mask poorer episodic memory among young adult cannabis users.

    PubMed

    Schuster, Randi M; Crane, Natania A; Mermelstein, Robin; Gonzalez, Raul

    2015-09-01

    Co-occurring cannabis and tobacco use has become increasingly prevalent among young adults, but it is not clear how tobacco use may alter the neurocognitive profile typically observed among cannabis users. Although there is substantial evidence citing cannabis and tobacco's individual effect on episodic memory and related brain structures, few studies have examined the effect of combined cannabis and tobacco use on memory. This investigation examined relationships between amount of past year cannabis and tobacco use on 4 different indices of episodic memory among a sample of young adults who identified cannabis as their drug of choice. Results indicated that more cannabis use was linked with poorer initial acquisition, total learning, and delayed recall on the Hopkins Verbal Learning Test-Revised, but only among cannabis users who sporadically smoked cigarettes in the past year. Conversely, the amount of past year cannabis use was not associated with episodic memory performance among individuals who more consistently smoked cigarettes in the past year. These differences could not be explained by several relevant potential confounds. These findings provide important insight into a potential mechanism (i.e., attenuation of cognitive decrements) that might reinforce use of both substances and hamper cessation attempts among cannabis users who also smoke cigarettes. Ongoing and future research will help to better understand how co-use of cannabis and tobacco affects memory during acute intoxication and abstinence and the stability of these associations over time. (c) 2015 APA, all rights reserved).

  2. Expression of HIWI in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis

    PubMed Central

    2009-01-01

    Background HIWI, the human homologue of Piwi family, is present in CD34+ hematopoietic stem cells and germ cells, but not in well-differentiated cell populations, indicating that HIWI may play an impotent role in determining or maintaining stemness of these cells. That HIWI expression has been detected in several type tumours may suggest its association with clinical outcome in cancer patients. Methods With the methods of real-time PCR, western blot, immunocytochemistry and immunohistochemistry, the expression of HIWI in three esophageal squamous cancer cell lines KYSE70, KYSE140 and KYSE450 has been characterized. Then, we investigated HIWI expression in a series of 153 esophageal squamous cell carcinomas using immunohistochemistry and explored its association with clinicopathological features. Results The expression of HIWI was observed in tumour cell nuclei or/and cytoplasm in 137 (89.5%) cases, 16 (10.5%) cases were negative in both nuclei and cytoplasm. 86 (56.2%) were strongly positive in cytoplasm, while 49 (32.0%) were strongly positive in nuclei. The expression level of HIWI in cytoplasm of esophageal cancer cells was significantly associated with histological grade (P = 0.011), T stage (P = 0.035), and clinic outcome (P < 0.001), while there was no correlation between the nuclear HIWI expression and clinicopathological features. Conclusion The expression of HIWI in the cytoplasm of esophageal cancer cells is significantly associated with higher histological grade, clinical stage and poorer clinical outcome, indicating its possible involvement in cancer development. PMID:19995427

  3. Poorer physical fitness is associated with reduced structural brain integrity in heart failure.

    PubMed

    Alosco, Michael L; Brickman, Adam M; Spitznagel, Mary Beth; Griffith, Erica Y; Narkhede, Atul; Raz, Naftali; Cohen, Ronald; Sweet, Lawrence H; Colbert, Lisa H; Josephson, Richard; Hughes, Joel; Rosneck, Jim; Gunstad, John

    2013-05-15

    Physical fitness is an important correlate of structural and functional integrity of the brain in healthy adults. In heart failure (HF) patients, poor physical fitness may contribute to cognitive dysfunction and we examined the unique contribution of physical fitness to brain structural integrity among patients with HF. Sixty-nine HF patients performed the Modified Mini Mental State examination (3MS) and underwent brain magnetic resonance imaging. All participants completed the 2-minute step test (2MST), a brief measure of physical fitness. We examined the associations between cognitive performance, physical fitness, and three indices of global brain integrity: total cortical gray matter volume, total white matter volume, and whole brain cortical thickness. Regression analyses adjusting for demographic characteristics, medical variables (e.g., left ventricular ejection fraction), and intracranial volume revealed reduced performance on the 2MST were associated with decreased gray matter volume and thinner cortex (p<.05). Follow up analyses showed that reduced gray matter volume and decreased cortical thickness were associated with poorer 3MS scores (p<.05). Poor physical fitness is common in HF and associated with reduced structural brain integrity. Prospective studies are needed to elucidate underlying mechanisms for the influence of physical fitness on brain health in HF. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning.

    PubMed

    Morgan, Erin E; Doyle, Katie L; Minassian, Arpi; Henry, Brook L; Perry, William; Marcotte, Thomas D; Woods, Steven Paul; Grant, Igor

    2014-12-15

    Methamphetamine (MA) dependence is associated with executive dysfunction, but no studies have evaluated MA-related elevations in neurocognitive intraindividual variability (IIV), an expression of cognitive dyscontrol linked to poor daily functioning in populations with frontal systems injury. We examined IIV during a vigilance task in a well-characterized sample of 35 MA-dependent (MA+) and 55 non-MA using comparison participants (MA-) as part of a larger neuropsychological battery that included self-report and performance-based measures of everyday functioning. A mixed model ANOVA was conducted while controlling for covariates, including factors that differed between the groups (e.g., education) and those with conceptual relevance to IIV: mean reaction time, global cognitive performance, and HIV-infection (which was comparable across groups; p=0.32). This analysis revealed significantly elevated IIV among MA+ relative to MA- individuals that was comparable in magnitude across all trial blocks of the vigilance task. Within the MA group, elevated IIV was associated with executive dysfunction, psychomotor slowing, and recency of MA use, as well as poorer automobile driving simulator performance, worse laboratory-based functional skills, and more cognitive complaints. MA-users are vulnerable to IIV elevation, likely due to cognitive dyscontrol, which may increase their risk of real-world problems.

  5. Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning

    PubMed Central

    Morgan, Erin E.; Doyle, Katie L.; Minassian, Arpi; Henry, Brook; Perry, William; Marcotte, Thomas D.; Woods, Steven Paul; Grant, Igor

    2014-01-01

    Methamphetamine (MA) dependence is associated with executive dysfunction, but no studies have evaluated MA-related elevations in neurocognitive intraindividual variability (IIV), an expression of cognitive dyscontrol linked to poor daily functioning in populations with frontal systems injury. We examined IIV during a vigilance task in a well-characterized sample of 35 MA-dependent (MA+) and 55 non-MA using comparison participants (MA−) as part of a larger neuropsychological battery that included self-report and performance-based measures of everyday functioning. A mixed model ANOVA was conducted while controlling for covariates, including factors that differed between the groups (e.g., education) and those with conceptual relevance to IIV: mean reaction time, global cognitive performance, and HIV-infection (which was comparable across groups; p = .32). This analysis revealed significantly elevated IIV among MA+ relative to MA− individuals that was comparable in magnitude across all trial blocks of the vigilance task. Within the MA group, elevated IIV was associated with executive dysfunction, psychomotor slowing, and recency of MA use, as well as poorer automobile driving simulator performance, worse laboratory-based functional skills, and more cognitive complaints. MA-users are vulnerable to IIV elevation, likely due to cognitive dyscontrol, which may increase their risk of real-world problems. PMID:25081313

  6. Women's poorer satisfaction with their sex lives following gynecologic cancer treatment.

    PubMed

    Lara, Lucia Alves Silva; de Andrade, Jurandyr Moreira; Consolo, Flavio Donaire; Romão, Adriana Peterson Mariano Salata

    2012-06-01

    Gynecologic cancer treatment can lead to anatomical changes in the genitalia that may impair sexual response. As a result, the authors aimed to assess women's self-perceptions of their sex lives following gynecologic cancer treatment and the impact of such treatment on sexual function. Thirty sexually active women were examined. At the first meeting with a physician sex therapist, women were asked about their satisfaction with their sexual activities prior to and after gynecologic cancer treatment, either with a partner or alone, and how many times per month they had sexual intercourse prior to the cancer diagnosis and after treatment. Women reported significantly worse sex lives and a significantly lower frequency of sexual relations following cancer treatment. All participants reported pain on vaginal penetration and feeling uncomfortable in discussing their sexual difficulties with the oncologist. The findings show that women experienced impaired sexual function, as well as poorer quality of sexual function, following gynecologic cancer treatment. Nurses should provide basic guidelines about sexual function to all patients who undergo treatment for gynecologic cancer.

  7. A Novel Method for Predicting Late Genitourinary Toxicity After Prostate Radiation Therapy and the Need for Age-Based Risk-Adapted Dose Constraints

    SciTech Connect

    Ahmed, Awad A.; Egleston, Brian; Alcantara, Pino; Li, Linna; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

    2013-07-15

    Background: There are no well-established normal tissue sparing dose–volume histogram (DVH) criteria that limit the risk of urinary toxicity from prostate radiation therapy (RT). The aim of this study was to determine which criteria predict late toxicity among various DVH parameters when contouring the entire solid bladder and its contents versus the bladder wall. The area under the histogram curve (AUHC) was also analyzed. Methods and Materials: From 1993 to 2000, 503 men with prostate cancer received 3-dimensional conformal RT (median follow-up time, 71 months). The whole bladder and the bladder wall were contoured in all patients. The primary endpoint was grade ≥2 genitourinary (GU) toxicity occurring ≥3 months after completion of RT. Cox regressions of time to grade ≥2 toxicity were estimated separately for the entire bladder and bladder wall. Concordance probability estimates (CPE) assessed model discriminative ability. Before training the models, an external random test group of 100 men was set aside for testing. Separate analyses were performed based on the mean age (≤ 68 vs >68 years). Results: Age, pretreatment urinary symptoms, mean dose (entire bladder and bladder wall), and AUHC (entire bladder and bladder wall) were significant (P<.05) in multivariable analysis. Overall, bladder wall CPE values were higher than solid bladder values. The AUHC for bladder wall provided the greatest discrimination for late bladder toxicity when compared with alternative DVH points, with CPE values of 0.68 for age ≤68 years and 0.81 for age >68 years. Conclusion: The AUHC method based on bladder wall volumes was superior for predicting late GU toxicity. Age >68 years was associated with late grade ≥2 GU toxicity, which suggests that risk-adapted dose constraints based on age should be explored.

  8. Initial misdiagnosis of melanoma located on the foot is associated with poorer prognosis

    PubMed Central

    Sondermann, Wiebke; Zimmer, Lisa; Schadendorf, Dirk; Roesch, Alexander; Klode, Joachim; Dissemond, Joachim

    2016-01-01

    Abstract Acral melanoma has been reported to be associated with poorer outcomes than melanoma occurring on other cutaneous sites. It has been suggested that part of this disparity in outcomes may be related to delay in diagnosis. Therefore, we have analyzed the rate of misdiagnoses in patients with melanoma located on the foot and have characterized the influence on the clinical course and survival of the patients. A prospective, computerized melanoma database at the Skin Cancer Center of the University Hospital Essen, Germany was used to identify patients with histologically confirmed melanoma located on the foot between 2002 and July 2013 for subsequent analysis. A cohort of 151 patients diagnosed with primary melanoma located on the foot was identified. One hundred seven patients qualified for subsequent analysis. Forty-two patients were male (39.3%) and 65 (60.7%) were female; the mean age at first diagnosis was 61.6 years (median 66 years). The youngest patient was 19 years, the oldest 88 years old. Of the 107 patients analyzed, 32 (30%) were initially misdiagnosed. Misdiagnoses included chronic wounds, nevi, hematoma, fungal infections, warts, and paronychia. Misdiagnosis caused a median delay in diagnosis of 9 months. The 5-year disease-free survival rate (47.8% vs 72.7%) and the 5-year overall survival rate (63.5% vs 88.4%) were statistically significant lower in the misdiagnosis cohort. The awareness of potentially overlooked melanoma located on the foot has to increase among physicians. To improve early detection and, thus, the prognosis of patients with melanoma located on the foot, taking a biopsy from any suspicious lesion should be taken into consideration as soon as possible. PMID:27442685

  9. [Poorer diabetes control among the immigrant population than among the autochthonous population].

    PubMed

    Soler-González, Jorge; Marsal, Josep Ramon; Serna, Caty; Real, Jordi; Cruz, Inés; López, Albert

    2013-01-01

    Ethnic differences are known to exist in the prevalence of diabetes, but little is known about possible differences in the degree of diabetes control among ethnic groups. The aim of this study was to determine whether there are differences in diabetes detection and control between immigrants and the autochthonous population in our health region. We performed a cross-sectional, observational, population-based study of all patients diagnosed with diabetes mellitus type 2 registered and treated in 2010. We analyzed diabetes quality indicators and used multivariate logistic regression models adjusted for age, sex and number of visits. The adjustment method was forced and the absence of collinearity was identified through the ROC curve and Hosmer and Lemeshow's test. There were 77,999 autochthonous patients (6,846 diabetics) and 30,748 immigrant patients (415 diabetics). A total of 8.78% of the autochthonous patients were diabetic versus 1.35% of immigrants (p <0.001). HbA1c <7.5% was found in 68.04% of the native population compared with 54.76% of immigrants. The probability of achieving optimal HbA1c control was 27% lower in immigrants (adjusted OR=0.73), while the probability of achieving good HbA1c control was 30% lower in the immigrant cohort. The model showed moderate discrimination (ROC =0.65 and Hosmer and Lemeshow's contrast, p>0.05). Diabetes control and quality indicators are poorer in some immigrant groups. Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.

  10. Pretransplant transcriptome profiles identify among kidneys with delayed graft function those with poorer quality and outcome.

    PubMed

    Mas, Valeria R; Scian, Mariano J; Archer, Kellie J; Suh, Jihee L; David, Krystle G; Ren, Qing; Gehr, Todd W B; King, Anne L; Posner, Marc P; Mueller, Thomas F; Maluf, Daniel G

    2011-01-01

    Robust biomarkers are needed to identify donor kidneys with poor quality associated with inferior early and longer-term outcome. The occurrence of delayed graft function (DGF) is most often used as a clinical outcome marker to capture poor kidney quality. Gene expression profiles of 92 preimplantation biopsies were evaluated in relation to DGF and estimated glomerular filtration rate (eGFR) to identify preoperative gene transcript changes associated with short-term function. Patients were stratified into those who required dialysis during the first week (DGF group) versus those without (noDGF group) and subclassified according to 1-month eGFR of >45 mL/min (eGFR(hi)) versus eGFR of ≤45 mL/min (eGFR(lo)). The groups and subgroups were compared in relation to clinical donor and recipient variables and transcriptome-associated biological pathways. A validation set was used to confirm target genes. Donor and recipient characteristics were similar between the DGF versus noDGF groups. A total of 206 probe sets were significant between groups (P < 0.01), but the gene functional analyses failed to identify any significantly affected pathways. However, the subclassification of the DGF and noDGF groups identified 283 probe sets to be significant among groups and associated with biological pathways. Kidneys that developed postoperative DGF and sustained an impaired 1-month function (DGF(lo) group) showed a transcriptome profile of significant immune activation already preimplant. In addition, these kidneys maintained a poorer transplant function throughout the first-year posttransplant. In conclusion, DGF is a poor marker for organ quality and transplant outcome. In contrast, preimplant gene expression profiles identify "poor quality" grafts and may eventually improve organ allocation.

  11. Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease.

    PubMed

    Smith, Megan M; Mills, James A; Epping, Eric A; Westervelt, Holly J; Paulsen, Jane S

    2012-09-01

    Depression is associated with more severe cognitive deficits in many neurological disorders, though the investigation of this relationship in Huntington disease (HD) has been limited. This study examined the relationship between depressive symptom severity and measures of executive functioning, learning/memory, and attention in prodromal HD. Participants (814 prodromal HD, 230 gene-negative) completed a neuropsychological test battery and the Beck Depression Inventory-II (BDI-II). Based on the BDI-II, there were 637 participants with minimal depression, 89 with mild depression, 61 with moderate depression, and 27 with severe depression in the prodromal HD group. ANCOVA (controlling for age, sex, and education) revealed that performance on SDMT, Trails B, Hopkins Verbal Learning Test--Revised (HVLT-R) Immediate Recall, and Stroop interference was significantly different between the BDI-II severity groups, with the moderate and severe groups performing worse than the minimal and mild groups. There were no significant differences between the BDI-II severity groups for Trails A or HVLT-R Delayed Recall. Linear regression revealed that both gene status and depression severity were significant predictors of performance on all cognitive tests examined, with contributions of BDI-II and gene status comparable for Trails A, SDMT, and Stroop interference. Gene status had a higher contribution for HVLT-R Immediate and Delayed Recall and Trails B. Our results suggest that depressive symptom severity is related to poorer cognitive performance in individuals with prodromal HD. Though there are currently no approved therapies for cognitive impairment in HD, our findings suggest that depression may be a treatable contributor to cognitive impairment in this population.

  12. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis

    PubMed Central

    Edwards, S M; Evans, D G R; Hope, Q; Norman, A R; Barbachano, Y; Bullock, S; Kote-Jarai, Z; Meitz, J; Falconer, A; Osin, P; Fisher, C; Guy, M; Jhavar, S G; Hall, A L; O'Brien, L T; Gehr-Swain, B N; Wilkinson, R A; Forrest, M S; Dearnaley, D P; Ardern-Jones, A T; Page, E C; Easton, D F; Eeles, R A

    2010-01-01

    Background: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. Methods: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan–Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. Results: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. Conclusion: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease. PMID:20736950

  13. Under-use of migrants' employment skills linked to poorer mental health.

    PubMed

    Reid, Alison

    2012-04-01

    Since the mid-1990s Australia's immigration program has focused on encouraging skilled migration. This study investigated skill usage in three longitudinal studies of immigrants to Australia and examined if there is an association with mental health status. Three Longitudinal Surveys of Immigrants to Australia (LSIA), with multiple data collection waves, were conducted between 1994 and 2006. Some 5,192 primary applicants participated in LSIA1, 3,124 in LSIA2 and 9,865 in LSIA3. Data collected included demographics and employment history in all surveys as well as mental health in LSIA1 and 2. Among migrants in LSIA 1, 49% reported working in jobs in which they used their skills sometimes, rarely or never, 3½ years after immigrating. This was not solely explained by English language proficiency as 47% of migrants who reported speaking English well or very well did not use their qualifications in their job. Migrants who did not use their job qualifications at wave three had a worse GHQ-12 score at wave three after adjusting for age, sex, country of birth and highest educational qualification. There was no difference in wave one or wave two GHQ-12 score between those who did or did not use their job qualifications at wave three. The pattern was similar for those migrants in LSIA 2. There is a large under-utilisation of employment skills in the migrant population in Australia up to 3½ years after immigrating. This is associated with poorer mental health. © 2012 The Authors. ANZJPH © 2012 Public Health Association of Australia.

  14. Poorer Prognosis of Primary Signet-Ring Cell Carcinoma of the Breast Compared with Mucinous Carcinoma

    PubMed Central

    Lin, Qingzhong; Chen, Gang; Lu, Jianping; Zeng, Yi; Hu, Dan; Huang, Kai; Lin, Zhiwu; Yan, Jun

    2016-01-01

    Primary signet-ring cell carcinoma (PSRCC) of the breast is a rare entity and classified under mucin producing tumors in the WHO classification. However, little is known about the clinicopathological characteristics and clinical outcomes of PSRCC as opposed to mucinous carcinoma. Eleven patients with PSRCC in our center from 1995 to 2010 were evaluated in this study, as compared to 50 cases of mucinous breast cancer (MBC) during the same period. The clinicopathologic features of PSRCC compared to MBC were assessed. Furthermore, overall survival (OS) and disease-free survival (DFS) were calculated at 5 years of follow up. Patients with PSRCC showed more frequent lymphatic metastasis, higher Ki67 labeling index and more advanced stage disease than that of MBC (P = 0.018, p = 0.023, P = 0.000, respectively), although there was no difference in age, tumor size, and ER, PR expression between PSRCC and MBC. In addition, PSRCC was associated with simultaneous vimentin upregulation and E-cadherin downregulation. The 5-year OS of PSRCC (54.5%) was significantly lower than that of MBC (88%) (P = 0.004). Similarly, the DFS of PSRCC was poorer than that of MBC significantly (5-year DFS: 27.3% vs. 80%, P = 0.000). Conclusions Our results confirmed the more aggressive behavior of PSRCC compared to MBC. This tumor is frequently associated with more frequent lymphatic metastasis, higher Ki67 labeling index, more advanced stage disease as well as simultaneous vimentin upregulation and E-cadherin downregulation. Different management guidelines should be considered for the two types. PMID:27583684

  15. Initial misdiagnosis of melanoma located on the foot is associated with poorer prognosis.

    PubMed

    Sondermann, Wiebke; Zimmer, Lisa; Schadendorf, Dirk; Roesch, Alexander; Klode, Joachim; Dissemond, Joachim

    2016-07-01

    Acral melanoma has been reported to be associated with poorer outcomes than melanoma occurring on other cutaneous sites. It has been suggested that part of this disparity in outcomes may be related to delay in diagnosis. Therefore, we have analyzed the rate of misdiagnoses in patients with melanoma located on the foot and have characterized the influence on the clinical course and survival of the patients. A prospective, computerized melanoma database at the Skin Cancer Center of the University Hospital Essen, Germany was used to identify patients with histologically confirmed melanoma located on the foot between 2002 and July 2013 for subsequent analysis. A cohort of 151 patients diagnosed with primary melanoma located on the foot was identified. One hundred seven patients qualified for subsequent analysis. Forty-two patients were male (39.3%) and 65 (60.7%) were female; the mean age at first diagnosis was 61.6 years (median 66 years). The youngest patient was 19 years, the oldest 88 years old.Of the 107 patients analyzed, 32 (30%) were initially misdiagnosed. Misdiagnoses included chronic wounds, nevi, hematoma, fungal infections, warts, and paronychia. Misdiagnosis caused a median delay in diagnosis of 9 months. The 5-year disease-free survival rate (47.8% vs 72.7%) and the 5-year overall survival rate (63.5% vs 88.4%) were statistically significant lower in the misdiagnosis cohort.The awareness of potentially overlooked melanoma located on the foot has to increase among physicians.To improve early detection and, thus, the prognosis of patients with melanoma located on the foot, taking a biopsy from any suspicious lesion should be taken into consideration as soon as possible.

  16. Pretransplant Transcriptome Profiles Identify among Kidneys with Delayed Graft Function Those with Poorer Quality and Outcome

    PubMed Central

    Mas, Valeria R; Scian, Mariano J; Archer, Kellie J; Suh, Jihee L; David, Krystle G; Ren, Qing; Gehr, Todd WB; King, Anne L; Posner, Marc P; Mueller, Thomas F; Maluf, Daniel G

    2011-01-01

    Robust biomarkers are needed to identify donor kidneys with poor quality associated with inferior early and longer-term outcome. The occurrence of delayed graft function (DGF) is most often used as a clinical outcome marker to capture poor kidney quality. Gene expression profiles of 92 preimplantation biopsies were evaluated in relation to DGF and estimated glomerular filtration rate (eGFR) to identify preoperative gene transcript changes associated with short-term function. Patients were stratified into those who required dialysis during the first week (DGF group) versus those without (noDGF group) and subclassified according to 1-month eGFR of >45 mL/min (eGFRhi) versus eGFR of ≤45 mL/min (eGFRlo). The groups and subgroups were compared in relation to clinical donor and recipient variables and transcriptome-associated biological pathways. A validation set was used to confirm target genes. Donor and recipient characteristics were similar between the DGF versus noDGF groups. A total of 206 probe sets were significant between groups (P < 0.01), but the gene functional analyses failed to identify any significantly affected pathways. However, the subclassification of the DGF and noDGF groups identified 283 probe sets to be significant among groups and associated with biological pathways. Kidneys that developed postoperative DGF and sustained an impaired 1-month function (DGFlo group) showed a transcriptome profile of significant immune activation already preimplant. In addition, these kidneys maintained a poorer transplant function throughout the first-year posttransplant. In conclusion, DGF is a poor marker for organ quality and transplant outcome. In contrast, preimplant gene expression profiles identify “poor quality” grafts and may eventually improve organ allocation. PMID:21912807

  17. Hyper-responsiveness to acute stress, emotional problems and poorer memory in former preterm children.

    PubMed

    Quesada, Andrea A; Tristão, Rosana M; Pratesi, Riccardo; Wolf, Oliver T

    2014-09-01

    The prevalence of preterm birth (PTB) is high worldwide, especially in developing countries like Brazil. PTB is marked by a stressful environment in intra- as well as extrauterine life, which can affect neurodevelopment and hormonal and physiological systems and lead to long-term negative outcomes. Nevertheless, little is known about PTB and related outcomes later on in childhood. Thus, the goals of the current study were threefold: (1) comparing cortisol and alpha-amylase (sAA) profiles, including cortisol awakening response (CAR), between preterm and full-term children; (2) evaluating whether preterm children are more responsive to acute stress and (3) assessing their memory skills and emotional and behavioral profiles. Basal cortisol and sAA profiles, including CAR of 30 preterm children, aged 6 to 10 years, were evaluated. Further, we assessed memory functions using the Wide Range Assessment of Memory and Learning, and we screened behavior/emotion using the Strengths and Difficulties Questionnaire. The results of preterm children were compared to an age- and sex-matched control group. One week later, participants were exposed to a standardized laboratory stressor [Trier Social Stress Test for Children (TSST-C)], in which cortisol and sAA were measured at baseline, 1, 10 and 25 min after stressor exposure. Preterm children had higher cortisol concentrations at awakening, a flattened CAR and an exaggerated response to TSST-C compared to full-term children. These alterations were more pronounced in girls. In addition, preterm children were characterized by more emotional problems and poorer memory performance. Our findings illustrate the long-lasting and in part sex-dependent effects of PTB on the hypothalamic-pituitary-adrenal (HPA) axis, internalizing behavior and memory. The findings are in line with the idea that early adversity alters the set-point of the HPA axis, thereby creating a more vulnerable phenotype.

  18. FDG-PET/CT Predicts Outcome in Oropharingeal Carcinoma Patients Undergoing Intensity Modulated Radiation Therapy with Dose Escalation to FDG-avid Tumour Volumes.

    PubMed

    Mapelli, Paola; Broggi, Sara; Incerti, Elena; Alongi, Pierpaolo; Kirienko, Margarita; Fiorino, Claudio; Dell Oca, Italo; Fallanca, Federico; Vanoli, Emilia Giovanna; Di Muzio, Nadia Gisella; Gianolli, Luigi; Picchio, Maria

    2017-08-24

    To evaluate the predictive value of FDG-PET/CT parameters on outcome of oropharyngeal squamocellular cancer (OSCC) patients undergoing helical tomotherapy (HTT), with dose escalation to FDG-PET/CT positive tumour volumes using the simultaneous integrated boost (SIB) technique. We analysed 41 patients studied by FDG-PET/CT and treated with radical intent between 2005 and 2014 for OSCC. HTT-SIB was delivered in 30 fractions concomitantly: 69 Gy, as SIB, to the PET-positive volume (biological target volume - BTV-PET), both to the primary tumour (T) and lymph nodes (N), 66 Gy to the T and positive N, 54 Gy to the laterocervical nodes at risk. Selected PET parameters were recovered: maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) obtained with different thresholds (40-50-60% of the SUVmax) for T and N. The correlation between these parameters and the 3-year overall (OS), cancer specific (CSS), disease free (DFS), local relapse free for T and N (LRFS-T and LRFS-N) and distant metastasis free (DMFS) survivals was investigated. The median follow-up was 37 months (range: 3-125). The 3-year OS, CSS, DFS, LRFST, LRFS-N and DMFS were 86%, 88%, 76%, 83%, 88% and 91%, respectively. BTVT+ N>30.9cc and BTV-T>22.4cc were correlated with CSS (p=0.02) and OS (p=0.006) respectively; TLG-T-60>34.6cc was correlated with CSS (p=0.04) and OS (p=0.01). MTV-T-60>4.4cc could predict a higher risk of relapse/death (CSS: p=0.033; hazard ratio (HR) =10.92; OS: p=0.01; HR=16.4; LRFS-T: p=0.02; HR=13.90; LRFS-T+N: p=0.03; HR=6.50). PET parameters predicted survival outcomes and may be considered in the future in the implementation of more personalized treatment schedules in patients affected by OSCC undergoing radiotherapy. FDG-PET/CT dose escalated HTT-SIB allowed very promising 3-year disease control rates in OSCC patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Radiation Transport Modeling and Assessment to Better Predict Radiation Exposure, Dose, and Toxicological Effects to Human Organs on Long Duration Space Flights

    NASA Technical Reports Server (NTRS)

    Denkins, Pamela; Badhwar, Gautam; Obot, Victor

    2000-01-01

    NASA's long-range plans include possible human exploratory missions to the moon and Mars within the next quarter century. Such missions beyond low Earth orbit will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and the missions long, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. The focus of this study is radiation exposure to the blood-forming organs of the NASA astronauts. NASA/JSC developed the Phantom Torso Experiment for Organ Dose Measurements which housed active and passive dosimeters that would monitor and record absorbed radiation levels at vital organ locations. This experiment was conducted during the STS-9 I mission in May '98 and provided the necessary space radiation data for correlation to results obtained from the current analytical models used to predict exposure to the blood-forming organs. Numerous models (i.e., BRYNTRN and HZETRN) have been developed and used to predict radiation exposure. However, new models are continually being developed and evaluated. The Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronomy, is to be used and evaluated as a part of the research activity. It is the intent of this research effort to compare the modeled data to the findings from the STS-9 I mission; assess the accuracy and efficiency of this model; and to determine its usefulness for predicting radiation exposure and developing better guidelines for shielding requirements for long duration manned missions.

  20. High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease: atopy predicts idiopathic diffuse lung injury syndromes.

    PubMed

    Frankovich, J; Donaldson, S S; Lee, Y; Wong, R M; Amylon, M; Verneris, M R

    2001-01-01

    The use of high-dose therapy (HDT) and autologous hematopoietic cell transplantation (AHCT) for children and adolescents with primary refractory and relapsed Hodgkin's disease is increasing. The purpose of this retrospective analysis was to: (1) evaluate the outcome of HDT and AHCT in pediatric patients with Hodgkin's disease, and (2) identify factors that predispose patients to the development of transplantation-related complications. We describe the experiences of 34 pediatric patients from a single institution with primary refractory or relapsed Hodgkin's disease. HDT regimens consisted of cyclophosphamide and etoposide combined with either carmustine, chloroethylcyclohexylnitrosurea, or fractionated total body irradiation. Kaplan-Meier survival predicts that 67% (95% confidence interval [CI] 47%-87%) of patients will be alive and disease-free at 5 years. Nine patients had disease recurrence, of whom 5 relapsed after 1 year (1.5-6.3 years). Five patients succumbed to treatment-related toxicities, of whom 4 died of pulmonary failure. Fifteen patients (44%) developed post-AHCT idiopathic diffuse lung injury syndrome: acute alveolitis (n = 2); diffuse alveolar hemorrhage (n = 2); acute respiratory distress syndrome (n = 2); delayed interstitial pneumonitis (n = 8); and bronchiolitis obliterans (n = 1). The following factors did not predict for the development of a diffuse lung injury syndrome in univariate analysis: prior treatment with bleomycin, pre-HDT pulmonary function tests, and prior thoracic irradiation. Of the patients in our cohort, 44% had a history of atopy (allergic rhinitis and/or asthma). Multivariate logistic analysis revealed that a preexisting history of atopy was highly predictive of idiopathic pulmonary complications (P = .0001, odds ratio = 21, CI 3.6-125). Our experience shows that HDT followed by AHCT results in durable remissions in two thirds of pediatric patients with refractory and relapsed Hodgkin's disease, and a history of atopy is

  1. Prognostic relevance of DHAP dose-density in relapsed Hodgkin lymphoma: an analysis of the German Hodgkin-Study Group.

    PubMed

    Sasse, Stephanie; Alram, Magdalena; Müller, Horst; Smardová, Lenka; Metzner, Bernd; Doehner, Hartmut; Fischer, Thomas; Niederwieser, Dietger W; Schmitz, Norbert; Schäfer-Eckart, Kerstin; Raemaekers, John M M; Schmalz, Oliver; Tresckow, Bastian V; Engert, Andreas; Borchmann, Peter

    2016-05-01

    Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). Based on the results of the HDR2 trial two courses of DHAP and subsequent HDCT/ASCT are the current standard of care in relapsed HL. In order to assess the prognostic relevance of DHAP dose density, we performed a retrospective multivariate analysis of the HDR2 trial (N=266). In addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP>day 22 predicted a significantly poorer progression-free survival (PFS, p=0.0356) and overall survival (OS, p=0.0025). In conclusion, our analysis strongly suggests that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.

  2. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.

    PubMed

    Louisse, Jochem; de Jong, Esther; van de Sandt, Johannes J M; Blaauboer, Bas J; Woutersen, Ruud A; Piersma, Aldert H; Rietjens, Ivonne M C M; Verwei, Miriam

    2010-12-01

    At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.

  3. Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

    PubMed Central

    Gianetti, Jacopo; Parri, Maria Serena; Della Pina, Francesca; Marchi, Federica; Koni, Endrin; De Caterina, Alberto; Maffei, Stefano

    2013-01-01

    Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n = 58) or DD of aspirin and clopidogrel (DD, n = 58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD (P < 0.001). Delta of CEPI-CT (T1 − T0) was significantly related to VWF (P < 0.001) and inversely related to ADAMTS-13 (0.01). Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P = 0.02). HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF. PMID:24453831

  4. Role of vaginal pallor reaction in predicting late vaginal stenosis after high-dose-rate brachytherapy in treatment-naive patients with cervical cancer.

    PubMed

    Yoshida, Ken; Yamazaki, Hideya; Nakamura, Satoaki; Masui, Koji; Kotsuma, Tadayuki; Akiyama, Hironori; Tanaka, Eiichi; Yoshikawa, Nobuhiko; Uesugi, Yasuo; Shimbo, Taiju; Narumi, Yoshifumi; Yoshioka, Yasuo

    2015-07-01

    To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy. We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months). More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade ≥2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade ≥2 vaginal stenosis rate at 3 years at 100% (p=0.001). High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention.

  5. Dose-response patterns for vibration-induced white finger

    PubMed Central

    Griffin, M; Bovenzi, M; Nelson, C

    2003-01-01

    Aims: To investigate alternative relations between cumulative exposures to hand-transmitted vibration (taking account of vibration magnitude, lifetime exposure duration, and frequency of vibration) and the development of white finger (Raynaud's phenomenon). Methods: Three previous studies have been combined to provide a group of 1557 users of powered vibratory tools in seven occupational subgroups: stone grinders, stone carvers, quarry drillers, dockyard caulkers, dockyard boilermakers, dockyard painters, and forest workers. The estimated total operating duration in hours was thus obtained for each subject, for each tool, and for all tools combined. From the vibration magnitudes and exposure durations, seven alternative measurements of cumulative exposure were calculated for each subject, using expressions of the form: dose = ∑amiti, where ai is the acceleration magnitude on tool i, ti is the lifetime exposure duration for tool i, and m = 0, 1, 2, or 4. Results: For all seven alternative dose measures, an increase in dose was associated with a significant increase in the occurrence of vibration-induced white finger, after adjustment for age and smoking. However, dose measures with high powers of acceleration (m > 1) faired less well than measures in which the weighted or unweighted acceleration, and lifetime exposure duration, were given equal weight (m = 1). Dose determined solely by the lifetime exposure duration (without consideration of the vibration magnitude) gave better predictions than measures with m greater than unity. All measures of dose calculated from the unweighted acceleration gave better predictions than the equivalent dose measures usin