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Purpose: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC., Materials and Methods: We established a NECTIN4 -specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs., Results: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers., Conclusion: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Drinking water can be a major source of poly- and perfluoroalkyl substance (PFAS) exposure for humans. The lack of historic data on PFAS drinking-water concentrations and consumption patterns are a limiting factor for developing estimates of past exposure. Here, in contribution to a community-scale PFAS health effects study near fire training facilities that contaminated a local aquifer with PFASs, we present a novel water-infrastructure, mass-balance mixing model coupled to a non-steady state, single-compartment toxicokinetic model that used Monte Carlo simulations to estimate the start of PFAS exposure in drinking water for individuals within three PFAS-impacted communities in El Paso County, Colorado. Our modeling focused on perfluorohexane sulfonic acid (PFHxS) because median serum PFHxS concentrations in a sample of local residents ( n = 213) were twelve times the median observed in the U.S. National Health and Nutrition Examination Survey (2015-2016). Modeling results for study participants were grouped according to their community of residence, revealing a median start of exposure for the town of Fountain of 1998 (25-75% interquartile range [IQR], 1992 to 2010), 2006 (IQR 1995 to 2012) for Security, and 2009 (IQR 1996-2012) for Widefield. Based on the towns' locations relative to an identified hydraulically upgradient PFAS source, the modeled exposure sequencing does not completely align with this conceptual flow model, implying the presence of an additional PFAS source for the groundwater between Widefield and Fountain.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The mechanisms underlying the bone disease induced by diabetes are complex and not fully understood; and antiresorptive agents, the current standard of care, do not restore the weakened bone architecture. Herein, we reveal the diabetic bone signature in mice at the tissue, cell, and transcriptome levels and demonstrate that three FDA-approved bone-anabolic agents correct it. Diabetes decreased bone mineral density (BMD) and bone formation, damaged microarchitecture, increased porosity of cortical bone, and compromised bone strength. Teriparatide (PTH), abaloparatide (ABL), and romosozumab/anti-sclerostin antibody (Scl-Ab) all restored BMD and corrected the deteriorated bone architecture. Mechanistically, PTH and more potently ABL induced similar responses at the tissue and gene signature levels, increasing both formation and resorption with positive balance towards bone gain. In contrast, Scl-Ab increased formation but decreased resorption. All agents restored bone architecture, corrected cortical porosity, and improved mechanical properties of diabetic bone; and ABL and Scl-Ab increased toughness, a fracture resistance index. Remarkably, all agents increased bone strength over the healthy controls even in the presence of severe hyperglycemia. These findings demonstrate the therapeutic value of bone anabolic agents to treat diabetes-induced bone disease and suggest the need for revisiting the approaches for the treatment of bone fragility in diabetes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Cytoreductive cystectomy appears to have survival advantages as a part of multimodal approach for well-selected patients with bladder cancer. Patient with clinical lymph node metastases might benefit from surgical consolidation after achieving a measurable response to chemotherapy. The exact role of cytoreductive/consolidative cystectomy is yet to be determined in well-designed prospective trials., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: We report contemporary trends in nationwide incidence of intracerebral hemorrhage (ICH) across demographic and regional strata over a 15-year period., Methods: Utilizing the Nationwide Inpatient Sample (2004-2018) and US Census Bureau data, we calculated ICH incidence rates for age, race/ethnicity, sex, and hospital region sub-cohorts across 5 consecutive 3-year periods (2004-2006 to 2016-2018). We fit Poisson and log binomial regression models to evaluate demographic and regional differences in ICH incidence and trends in prevalence of hypertension and past/current anticoagulant use among hospitalized ICH patients., Results: Overall, the annual incidence rate (95% CI) of ICH per 100 000 was 23.15 (23.10-23.20). The 3-year incidence of ICH (per 100 000) increased from 62.79 in 2004 to 2006 to 78.86 in 2016 to 2018 (adjusted incidence rate ratio, CI: 1.11 [1.02-1.20]), coinciding with increased 3-year prevalence of hypertension and anticoagulant use among hospitalized ICH patients (adjusted risk ratio, CI: hypertension-1.16 [1.15-1.17]; anticoagulant use-2.30 [2.14-2.47]). We found a significant age-time interaction, whereby ICH incidence increased significantly faster among those aged 18 to 44 years (adjusted incidence rate ratio, CI: 1.10 [1.05-1.14]) and 45 to 64 years (adjusted incidence rate ratio, CI: 1.08 [1.03-1.13]), relative to those aged ≥75 years., Conclusions: Rising ICH incidence among young and middle-aged Americans warrants ICH prevention strategies targeting these economically productive age groups.

Objectives: The guidelines of the American Hospital Association encourage transferring intracerebral hemorrhage patients from community hospitals to centers with stroke expertise. However, research on the differences in outcomes between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations have been largely limited to small single-center studies. In this study, we explored the national trends in transferred intracerebral hemorrhage hospitalizations, as well as evaluated the differences, in terms of demographic characteristics, co-morbidity, resource utilization, and outcomes, between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations., Materials and Methods: From the National Inpatient Sample (2004 - 2016), we assessed the linear trends in the proportion of interhospital transfers for intracerebral hemorrhage hospitalizations. We constructed a series of multivariate logistic regression models to explore the association of transfer status with inpatient mortality and discharge disposition, controlling for demographic, clinical, and hospital characteristics. We used survey design variables to report nationally weighted estimates., Results: Among 786,999 hospitalizations, 137,340 (17.5%, 95% CI: 16.4-18.6) were transferred. Overall, interhospital transfers for intracerebral hemorrhage has been increasing over the 12-year period of this study. Patients in transferred hospitalizations were younger, more likely to be white, and more likely to have private insurance. Transferred hospitalizations were associated with significantly lower adjusted odds of inpatient mortality, compared to directly admitted hospitalizations., Conclusions: As the US healthcare system continues shifting towards value-based care, evidence on the short- and long-term outcomes of transfer of intracerebral hemorrhage patients will inform optimal management of intracerebral hemorrhage patients., Competing Interests: Declaration of Competing Interest All authors have declared that they have no conflict of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cognitive impairment (CI) is commonly observed after intracerebral hemorrhage (ICH). While a growing number of studies have explored this association, several evidence gaps persist. This review seeks to investigate the relationship between CI and ICH. Methods: A two-stage systematic review of research articles, clinical trials, and case series was performed. Initial search used the keywords ["Intracerebral hemorrhage" OR "ICH"] AND ["Cognitive Impairment" OR "Dementia OR "Cognitive Decline"] within the PubMed (last accessed November 3rd, 2020) and ScienceDirect (last accessed October 27th, 2020) databases, without publication date limits. Articles that addressed CI and spontaneous ICH were accepted if CI was assessed after ICH. Articles were rejected if they did not independently address an adult human population or spontaneous ICH, didn't link CI to ICH, were an unrelated document type, or were not written in English. A secondary snowball literature search was performed using reviews identified by the initial search. The Agency for Healthcare research and Quality's assessment tool was used to evaluate bias within studies. Rates of CI and contributory factors were investigated. Results: Search yielded 32 articles that collectively included 22,631 patients. Present evidence indicates a high rate of post-ICH CI (65-84%) in the acute phase (<4 weeks) which is relatively lower at 3 (17.3-40.2%) and 6 months (19-63.3%). Longer term follow-up (≥1 year) demonstrates a gradual increase in CI. Advanced age, female sex, and prior stroke were associated with higher rates of CI. Associations between post-ICH CI and cerebral microbleeds, superficial siderosis, and ICH volume also exist. Pre-ICH cognitive assessment was missing in 28% of included studies. The Mini Mental State Evaluation (44%) and Montreal Cognitive Assessment (16%) were the most common cognitive assessments, albeit with variable thresholds and definitions. Studies rarely (<10%) addressed racial and ethnic disparities. Discussion: Current findings suggest a dynamic course of post-ICH cognitive impairment that may depend on genetic, sociodemographic and clinical factors. Methodological heterogeneity prevented meta-analysis, limiting results. There is a need for the methodologies and time points of post-ICH cognitive assessments to be harmonized across diverse clinical and demographic populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Potter, Lioutas, Tano, Pan, Meeks, Woo, Seshadri, Selim and Vahidy.)

Introduction: Persistent knowledge gaps exist as to the extent that preexisting cognitive impairment is a risk factor for susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mortality from the coronavirus disease 2019 (COVID-19). Methods: We conducted a cross-sectional analysis of adults tested for SARS-CoV-2 at a tertiary healthcare system. Cognitive impairment was identified utilizing diagnosis codes (mild cognitive impairment, Alzheimer's disease, vascular, and other dementias) or cognitive impairment-specific medication use. Propensity score (PS) matched analyses were utilized to report odds ratios (OR) and 95% confidence intervals (CI) for association of cognitive impairment with SARS-CoV-2 susceptibility and COVID-19 mortality. Results: Between March-3rd and December-11th, 2020, 179,979 adults were tested, of whom 21,607 (12.0%) tested positive. We identified 6,364 individuals with preexisting cognitive impairment (mean age: 78.5 years, 56.8% females), among whom 843 (13.2%) tested positive and 139 (19.5%) of those hospitalized died. In the pre-PS matched cohort, cognitive impairment was significantly associated with increased SARS-CoV-2 susceptibility (OR, CI: 1.12, 1.04-1.21) and COVID-19 mortality (OR, CI: 2.54, 2.07-3.12). One-to-one matches were identified for 6,192 of 6,364 (97.3%) individuals with prior cognitive impairment and 687 of 712 (96.5%) hospitalized patients with prior cognitive impairment. In the fully balanced post-matched cohort, preexisting cognitive impairment was significantly associated with higher likelihood of SARS-CoV-2 infection (OR, CI: 1.51, 1.35-1.70); however, cognitive impairment did not confer higher risk of COVID-19 mortality (OR, CI: 0.96, 0.73-1.25). Discussion: To mitigate the effects of healthcare catastrophes such as the COVID-19 pandemic, strategies for targeted prevention and risk-stratified comorbidity management are warranted among the vulnerable sub-population living with cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pan, Meeks, Potter, Masdeu, Seshadri, Smith, Ory and Vahidy.)

Purpose: As an alternative to radical cystectomy, tri-modality treatment (TMT) is an effective treatment approach for selected patients with muscle-invasive bladder cancer (MIBC). The purpose of this report is to contribute to the literature by summarizing institutional outcomes of a bladder-preserving TMT approach for patients with MIBC., Methods and Materials: Patients treated with TMT for MIBC from 1998 to 2019 were identified. Patient, disease, and treatment factors were recorded. Overall survival (OS), disease-free survival (DFS), and bladder-preserved DFS were estimated with the Kaplan-Meier method. Prognostic factors were evaluated with Cox proportional hazards regression., Results: Thirty-two patients treated with TMT to a median dose of 64.8 Gy for T2 (78%), T3 (19%), and T4 (3%) disease were followed for a median of 19 months (mean, 36; range, 6-213); 31% had associated carcinoma in situ; 25% had associated hydronephrosis. Cisplatin was the most commonly used chemotherapeutic agent. OS rates were 84% at 1 year and 61% at 5 years. DFS rates were 84% and 61% and bladder-preserved DFS rates were 84% and 60% at 1 year and 5 years, respectively. Salvage cystectomy rates at 1 year and 5 years were 4% and 9%, respectively. Four patients had locally invasive recurrences at 8, 11, 34, and 37 months after initial MIBC diagnosis, 2 of whom underwent salvage radical cystectomy. Ten (31%) patients developed distant disease at a median of 13 months after diagnosis. Unlike local recurrence, distant recurrences were associated with worse OS and hazard ratios of 3.4 ( P  = 0.039)., Conclusions: OS and DFS were comparable to those of published data. Our outcomes support TMT as an effective option for carefully selected patients with MIBC., (© 2021 The Authors.)

A 2.5 yr old female spayed domestic shorthair presented for acute tetraparesis, dull mentation, and fever. MRI and computed tomography identified a thin linear foreign body extending from the caudal nasopharynx through the atlanto-occipital joint and cervicomedullary junction. Signal changes within the musculature were consistent with myositis, edema, and abscessation. Inflammation and edema surrounded the foreign body, and a dorsal cervical myelopathy extended caudally to the level of C6. Computed tomography attenuation values of the foreign body were most consistent with plant material. Euthanasia was performed; postmortem dissection of the soft palate confirmed a plant stem with abscess., (© 2021 by American Animal Hospital Association.)

Purpose: Bladder cancer is initially diagnosed and staged with a transurethral resection of bladder tumor (TURBT). Patient survival is dependent on appropriate sampling of layers of the bladder, but pathology reports are dictated as free text, making large-scale data extraction for quality improvement challenging. We sought to automate extraction of stage, grade, and quality information from TURBT pathology reports using natural language processing (NLP)., Methods: Patients undergoing TURBT were retrospectively identified using the Northwestern Enterprise Data Warehouse. An NLP algorithm was then created to extract information from free-text pathology reports and was iteratively improved using a training set of manually reviewed TURBTs. NLP accuracy was then validated using another set of manually reviewed TURBTs, and reliability was calculated using Cohen's κ., Results: Of 3,042 TURBTs identified from 2006 to 2016, 39% were classified as benign, 35% as Ta, 11% as T1, 4% as T2, and 10% as isolated carcinoma in situ. Of 500 randomly selected manually reviewed TURBTs, NLP correctly staged 88% of specimens (κ = 0.82; 95% CI, 0.78 to 0.86). Of 272 manually reviewed T1 tumors, NLP correctly categorized grade in 100% of tumors (κ = 1), correctly categorized if muscularis propria was reported by the pathologist in 98% of tumors (κ = 0.81; 95% CI, 0.62 to 0.99), and correctly categorized if muscularis propria was present or absent in the resection specimen in 82% of tumors (κ = 0.62; 95% CI, 0.55 to 0.73). Discrepancy analysis revealed pathologist notes and deeper resection specimens as frequent reasons for NLP misclassifications., Conclusion: We developed an NLP algorithm that demonstrates a high degree of reliability in extracting stage, grade, and presence of muscularis propria from TURBT pathology reports. Future iterations can continue to improve performance, but automated extraction of oncologic information is promising in improving quality and assisting physicians in delivery of care.

Background: Baseline sarcopenia or severe lean muscle deficiency is independently associated with increased mortality after cystectomy for muscle-invasive urothelial carcinoma of the bladder (MIUC). The impact of chemotherapy on muscle mass in MIUC patients remains undefined., Objectives: To describe preoperative changes in body composition in MIUC patients receiving platinum-based neoadjuvant chemotherapy (NC)., Methods: Patients with cT2-4 N0-1 M0 UC of the bladder who received NC were identified. Lumbar skeletal muscle index (SMI, cm 2 /m 2 ), visceral adipose index (VAI, cm 2 /m 2 ), and the subcutaneous and intramuscular adipose index (SAI, cm 2 /m 2 ) were calculated using validated methodology (cross sectional area of skeletal muscle/height 2 at L3) from measurement of soft tissue areas on pre- (pre-NC) and post-NC (post-NC) computed tomography. Patients were classified as sarcopenic according to consensus definitions: Male: SMI <55 cm 2 /m 2 , Female: SMI <38.5 cm 2 /m 2 . Pre-NC and post-NC median body mass index (BMI kg/m 2 ), SMI, and adipose indices were compared., Results: The study cohort consisted of 26 patients, with a median age 70 years, including 7 females (27%). Chemotherapy regimens included dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (31%), gemcitabine/cisplatin (62%) and gemcitabine/carboplatin (3.8%) with a median of 3.5 (range 2-6) cycles. Median pre- and post-NC BMI were 27.1 kg/m 2 and 27.2 kg/m 2 ( p  = 0.36). Median pre- and post-NC SMI were 49.1 cm 2 /m 2 and 44.5 ( p  < 0.001) respectively. Median percent change in SMI was -6.4% (range -30% to 10%). Pre-NC, 18 (69%) patients were sarcopenic vs. 21 (81%, p  = 0.002) post-NC. Median time between initiation of chemotherapy and cystectomy was 110 days., Conclusions: We observed a significant decrease in lean muscle mass among MIUC patients treated with platinum-based NC prior to cystectomy, with an associated increase in the prevalence of sarcopenia. Patients undergoing NC may benefit from pre-habilitative interventions to mitigate lean muscle loss prior to cystectomy.

Globalization prompts remote acculturation toward U.S. culture in Jamaica; this study used a bioecological systems approach to examine its proximal impact on nutrition through U.S. cable TV consumption, and maternal influences in the home. Overall, 330 randomly selected adolescent-mother dyads from schools in Kingston, Jamaica (M adolescent&#95;age  = 13.8 years, SD adolescent&#95;age  = 1.8) completed questionnaires reporting American identity and behavioral preferences, daily time spent watching U.S.-produced TV programs, and frequency of eating unhealthy foods. Actor-partner interdependence models revealed that girls' American identity/behavior directly predicted their unhealthy eating, whereas girls' mothers and boys' American identity/behavior indirectly predicted unhealthy eating as mediated by their U.S. TV hours. Additionally, mothers' American identity/behavior predicted daughters' unhealthy eating as mediated by mothers' U.S. TV hours. Remote acculturation theory may facilitate more targeted research and prevention/intervention., (© 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.)

[This corrects the article DOI: 10.1371/journal.pone.0162761.].

In insects, pheromones function as triggers to elicit complex behavior programs, such as courtship and mating behavior. In most species, the neurons tuned to pheromones are localized in a specific subset of olfactory sensilla located on the antenna called trichoid sensilla. In Drosophila there are two classes of trichoid sensilla, at1 sensilla that contain the dendrites of a single neuron that is specifically tuned to the male-specific pheromone 11-cis vaccenyl acetate (cVA), and at4 sensilla that contain three neurons with relatively poorly defined chemical specificity and function. Using a combination of odorant receptor mutant analysis, single sensillum electrophysiology and optogenetics, we have examined the chemical tuning and behavioral consequences of the three at4 olfactory neuron classes. Our results indicate that one class, Or65abc neurons, are unresponsive to cVA pheromone, and function to inhibit courtship behaviors in response to an unknown ligand, while the other two neuron classes, Or88a and Or47b neurons, are sensitive to a diverse array of fly and non-fly odors, and activation of these neurons has little direct impact on courtship behaviors., Competing Interests: The authors have declared that no competing interests exist.

Background: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer., Material and Methods: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors., Results: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively., Conclusions: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer., (Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Lower serum vitamin D levels have been associated with an increased risk of aggressive prostate cancer. Among men with localized prostate cancer, especially with low- or intermediate-risk disease, vitamin D may serve as an important biomarker of disease aggression. The aim of this study was to assess the relationship between adverse pathology at the time of radical prostatectomy and serum 25-hydroxyvitamin D (25-OH D) levels., Methods: This cross-sectional study was carried out from 2009 to 2014, nested within a large epidemiologic study of 1,760 healthy controls and men undergoing prostate cancer screening. In total, 190 men underwent radical prostatectomy in the cohort. Adverse pathology was defined as the presence of primary Gleason 4 or any Gleason 5 disease, or extraprostatic extension. Descriptive and multivariate analyses were performed to assess the relationship between 25-OH D and adverse pathology at the time of prostatectomy., Results: Eighty-seven men (45.8%) in this cohort demonstrated adverse pathology at radical prostatectomy. The median age in the cohort was 64.0 years (interquartile range, 59.0 to 67.0). On univariate analysis, men with adverse pathology at radical prostatectomy demonstrated lower median serum 25-OH D (22.7 v 27.0 ng/mL, P = .007) compared with their counterparts. On multivariate analysis, controlling for age, serum prostate specific antigen, and abnormal digital rectal examination, serum 25-OH D less than 30 ng/mL was associated with increased odds of adverse pathology (odds ratio, 2.64; 95% CI, 1.25 to 5.59; P = .01)., Conclusion: Insufficiency/deficiency of serum 25-OH D is associated with increased odds of adverse pathology in men with localized disease undergoing radical prostatectomy. Serum 25-OH D may serve as a useful biomarker in prostate cancer aggressiveness, which deserves continued study., (© 2016 by American Society of Clinical Oncology.)

The 2012-13 influenza season had an unusually early and severe start in the US, succeeding the record mild 2011-12 influenza season, which occurred during the fourth warmest winter on record. Our analysis of climate and past US influenza epidemic seasons between 1997-98 to present indicates that warm winters tend to be followed by severe epidemics with early onset, and that these patterns are seen for both influenza A and B. We posit that fewer people are infected with influenza during warm winters, thereby leaving an unnaturally large fraction of susceptible individuals in the population going into the next season, which can lead to early and severe epidemics. In the event of continued global warming, warm winters such as that of 2011-12 are expected to occur more frequently. Our results thus suggest that expedited manufacture and distribution of influenza vaccines after mild winters has the potential to mitigate the severity of future influenza epidemics.

Objective: The aim of this study was to examine the relationship between children's experiences of three different types of violence and academic achievement among primary school children in Kingston, Jamaica., Methods: A cross-sectional study of 1300 children in grade 5 [mean (S.D.) age: 11 (0.5) years] from 29 government primary schools in urban areas of Kingston and St. Andrew, Jamaica, was conducted. Academic achievement (mathematics, reading, and spelling) was assessed using the Wide Range Achievement Test. Children's experiences of three types of violence - exposure to aggression among peers at school, physical punishment at school, and exposure to community violence - were assessed by self-report using an interviewer administered questionnaire., Results: Fifty-eight percent of the children experienced moderate or high levels of all three types of violence. Boys had poorer academic achievement and experienced higher levels of aggression among peers and physical punishment at school than girls. Children's experiences of the three types of violence were independently associated with all three indices of academic achievement. There was a dose-response relationship between children's experiences of violence and academic achievement with children experiencing higher levels of violence having the poorest academic achievement and children experiencing moderate levels having poorer achievement than those experiencing little or none., Conclusions: Exposure to three different types of violence was independently associated with poor school achievement among children attending government, urban schools in Jamaica. Programs are needed in schools to reduce the levels of aggression among students and the use of physical punishment by teachers and to provide support for children exposed to community violence., Practice Implications: Children in Jamaica and the wider Caribbean experience significant amounts of violence in their homes, communities, and schools. In this study, we demonstrate a dose-response relationship between primary school children's experiences of three different types of violence and their academic achievement. The study points to the need for validated violence prevention programs to be introduced in Jamaican primary schools. Such programs need to train teachers in appropriate classroom management and discipline strategies and to promote children's social and emotional competence and prevent aggression.

This article provides detailed guidelines for the implementation of systematic method for setting priorities in health research investments that was recently developed by Child Health and Nutrition Research Initiative (CHNRI). The target audience for the proposed method are international agencies, large research funding donors, and national governments and policy-makers. The process has the following steps: (i) selecting the managers of the process; (ii) specifying the context and risk management preferences; (iii) discussing criteria for setting health research priorities; (iv) choosing a limited set of the most useful and important criteria; (v) developing means to assess the likelihood that proposed health research options will satisfy the selected criteria; (vi) systematic listing of a large number of proposed health research options; (vii) pre-scoring check of all competing health research options; (viii) scoring of health research options using the chosen set of criteria; (ix) calculating intermediate scores for each health research option; (x) obtaining further input from the stakeholders; (xi) adjusting intermediate scores taking into account the values of stakeholders; (xii) calculating overall priority scores and assigning ranks; (xiii) performing an analysis of agreement between the scorers; (xiv) linking computed research priority scores with investment decisions; (xv) feedback and revision. The CHNRI method is a flexible process that enables prioritizing health research investments at any level: institutional, regional, national, international, or global.

We created a system that integrates contextual data for selected test results to help providers make appropriate clinical decisions on particular results. The system adds clinical reminders, historical test results, medication dispensing events, and visit information from a regional health information exchange database to create 'Enhanced Laboratory Reports'. The reports are delivered to the provider who ordered the test securely via web-based inbox or facsimile through a clinical messaging system.

When working on social justice issues, it is easy to become overwhelmed by the problems faced. To maintain morale, it helps to be creative, have fun, and see results. In the spring of 2006, we were able to bring together a group of people to document, first hand, the daily experience of being homeless in the City of Toronto. Using photography and story telling, we were able to give voice to a population not often heard. Our powerful images reached out to the public through events and publications. This resulted not only in great coverage and discussion of the important issues we were addressing, but also in a successful and rewarding group project that benefited group members in many ways.

We investigated the duration of humoral responses to dengue virus infection in individuals who recalled experiencing dengue fever-like illnesses at the time of the Second World War, when dengue fever epidemics occurred throughout the Pacific and Southeast Asia. In July 1943 dengue fever reappeared in Hawaii following an interval of 31 years. Over the next 12 months a total of 1498 locally transmitted cases were reported, and at least 46 imported cases were identified, most of which were among members of the military returning from the Pacific Theatre of the war. Serum samples collected in 2005, more than 60 years after onset of symptoms, were tested for the presence of dengue-specific antibodies using a rapid ELISA test, and by plaque reduction neutralization test. Four of seven samples were positive for dengue-specific IgG and demonstrated neutralization titers >or=160 to dengue 1. We describe the existence of dengue-specific antibodies in the serum of people infected more than 60 years earlier.

Proinflammatory cytokines secreted by memory CD8+ and CD4+ T cells are thought to play a direct role in the pathogenesis of dengue virus infection by increasing vascular permeability and thereby inducing the pathophysiologic events associated with dengue hemorrhagic fever and dengue shock syndrome. Severe disease is frequently observed in the setting of secondary infection with heterologous dengue virus serotypes, suggesting a role for cross-reactive memory T cells in the immunopathogenesis of severe disease. We used a large panel of well-characterized dengue virus-specific CD8+ T-cell clones isolated from Pacific Islanders previously infected with dengue virus 1 to examine effector memory function, focusing on a novel dominant HLA-B*5502-restricted NS5(329-337) epitope, and assessed T-cell responses to stimulation with variant peptides representing heterologous serotypes. Variant peptides were differentially recognized by dengue virus 1-specific effector CD8+ cytotoxic T lymphocytes (CTL) in a heterogeneous and clone-specific manner, in which cytolytic function and cytokine secretion could be enhanced, diminished, or abrogated compared with cognate peptide stimulation. Dengue virus-specific CTL stimulated with cognate and variant peptides demonstrated a cytokine response hierarchy of gamma IFN (IFN-gamma) > tumor necrosis factor alpha (TNF-alpha) > interleukin-2 (IL-2), and a subset of clones also produced IL-4 and IL-6. Individual clones demonstrated greater avidity for variant peptides representing heterologous serotypes, including serotypes previously encountered by the subject, and IFN-gamma and TNF-alpha secretion was enhanced by stimulation with these heterologous peptides. Altered antiviral T-cell responses in response to stimulation with heterologous dengue virus serotypes have implications for control of virus replication and for disease pathogenesis.

Eighty-nine mothers attending post-natal clinics at the University Hospital of the West Indies were interviewed at six weeks postpartum regarding their breast-feeding patterns and problems. Breastfeeding was practised by 97.8% of the mothers, with 29.9% practising exclusive breastfeeding and 70.1% partial breastfeeding. Only two women were solely bottle feeding. The pattern of breastfeeding was not significantly affected by maternal parity, age, education, employment or socioeconomic status. An intention to wean later (at six months) or when the mother felt the baby was 'ready,' was associated with increasing parity, age and further education. Babies who were exclusively breastfed achieved greater weight gain compared with those who partially breastfed but this difference did not achieve statistical significance. Breastfeeding trends appear to have remained stable over the last several years.

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk.

We could find no previous data describing the extent to which eating disorders are a public health problem in Jamaica, and so we carried out two exercises to assess this. We investigated the number of cases of anorexia nervosa (AN) and bulimia nervosa (BN) presenting at the University Hospital of the West Indies (UHWI) between 1985 and 1998, using case records, and carried out a survey among health professionals (psychiatrists, clinical psychologists, paediatricians and nutritionists/dietitians) to determine the number of patients with eating disorders seen by them between 1996 and 1998. We also examined the diagnostic criteria used and correlates of eating disorders. Only two cases of AN were treated at UHWI. Eleven cases each of AN and BN (two males) had presented to the health professionals surveyed, chiefly the psychiatrists. The AN patients ranged in age from 14 to 28 years (mean 20.9 years), and the BN patients from 11 to 35 years (mean 22.2 years). Eating disorders were reported primarily among urban dwellers (76%), and half of the cases were among students. Limiting food intake, excessive exercise and vomiting were the most frequently used methods of weight control. Nine eating disorder patients (41%) were also diagnosed with depression, and five (23%) patients reported previous emotional trauma. The occurrence of eating disorders in Jamaica appears to be very low.

Entrusted with the records for more than 1.5 million patients, the Regenstrief Medical Record System (RMRS) has evolved into a fast and comprehensive data repository used extensively at three hospitals on the Indiana University Medical Center campus and more than 30 Indianapolis clinics. The RMRS routinely captures laboratory results, narrative reports, orders, medications, radiology reports, registration information, nursing assessments, vital signs, EKGs and other clinical data. In this paper, we describe the RMRS data model, file structures and architecture, as well as recent necessary changes to these as we coordinate a collaborative effort among all major Indianapolis hospital systems, improving patient care by capturing city-wide laboratory and encounter data. We believe that our success represents persistent efforts to build interfaces directly to multiple independent instruments and other data collection systems, using medical standards such as HL7, LOINC, and DICOM. Inpatient and outpatient order entry systems, instruments for visit notes and on-line questionnaires that replace hardcopy forms, and intelligent use of coded data entry supplement the RMRS. Physicians happily enter orders, problems, allergies, visit notes, and discharge summaries into our locally developed Gopher order entry system, as we provide them with convenient output forms, choice lists, defaults, templates, reminders, drug interaction information, charge information, and on-line articles and textbooks. To prepare for the future, we have begun wrapping our system in Web browser technology, testing voice dictation and understanding, and employing wireless technology.

The central nucleus of the inferior colliculus (ICc) is a major processing center for the ascending auditory pathways. Gamma-aminobutyric acid (GABA) and excitant amino acids (EAAs) are essential for coding many auditory tasks in the IC. Recently, a number of neurochemical and immunocytochemical studies have suggested an age-related decline in GABAergic inhibition in the ICc, and possibly excitant-amino-acid-mediated excitation as well. The objective of this study was to compare quantitatively changes in the synaptic organization of the ICc among three age groups (3, 19, and 28 months) of Fischer-344 rats. Immunogold electron microscopic methods were used to determine if there were age-related changes in the density, distribution, or morphology of GABA-immunoreactive (+) and GABA-immunonegative (-) synapses in the ICc. The data suggest similar losses of excitatory and inhibitory synapses in the ICc. There were significant reductions in the densities of GABA+ and GABA- synaptic terminals (approximately 30% and approximately 24%, respectively) and synapses (approximately 33% and approximately 26%, respectively) in the ICc of 28-month-old rats relative to 3-month-olds. The numeric values, which were adjusted to consider changes in volume of the IC with age, depict similar effects, although the effect magnitude for the adjusted values was reduced by approximately 9%. For both types of synapses, the decreases did not differ significantly from each other. The reductions in synaptic numbers appeared, to be related to a similar numeric decline in dendrites, in particular those with calibers of between 0.5 and 1.5 microm. The number and distribution of synaptic terminals on the remaining dendrites of GABA- neurons appeared not to undergo major age-related changes. GABA+ neurons, on the other hand, may have evolved patterns of synaptic and dendritic change during aging in which the distribution of synaptic terminals shifts to dendrites of larger caliber. In the 19-month group, the synaptic areas were elevated in terminals apposed to dendrites with calibers of 1.5 microm or less. However, this increase in synaptic size did not persist in the aged animals. No neuronal losses were detectable among the three age groups. Thus, the decrease in GABA and EAAs identified in the IC by previous studies may be attributable to synaptic and dendritic declines, rather than cell loss.

The rain forest canopy is a seamless web through which arboreal creatures efficiently move to reach the edible fruits without any attention to the individual trees. Individual health care computer systems are rich with patient data, but rather than a canopy linking all the trees in the forest, the data "fruit" come from a diverse forest of individual computer "trees"-laboratory systems, word processing systems, pharmacy systems, and the like. These different sources of patient information are difficult or impossible to reach by individual physicians, especially from their offices. The World Wide Web and other standardization technology provide physicians and their institutions the tools needed for seamless and secure access to their patients' data and to medical information, when and where they need it. We and others have adopted these tools to combine independent sources of clinical data. Physicians who assist in the purchase of clinical information systems should demand products in their practice settings that are Web enabled, use standard coding systems, and communicate with other computer systems via broadly accepted protocols.

Objective: We investigated whether there was a growth or morbidity response to zinc supplementation., Design: The study was randomized, placebo-controlled, and double-blind., Setting: Children were recruited at clinics in Kingston, Jamaica, and supplemented at home., Subjects: Children selected were singletons aged 6-24 months, and stunted (< -2.0 s.d. length for age, NCHS references). They were stratified by sex and age and randomly assigned to receive zinc supplement (n = 31) or placebo (n = 30). Four children were excluded because of hospitalization; all others had all measurements. Adequately nourished children (n = 24) were recruited from a well-baby clinic., Interventions: The supplement provided 5 mg elemental zinc in a syrup daily for 12 weeks; the placebo comprised the syrup only., Main Outcome Measures: Caretakers were interviewed to obtain social background data, number of clinic visits and hospitalizations. Anthropometric measurements were done on enrolment, and after 6 weeks, 12 weeks and 12 months. Children's health was determined by weekly questionnaire to caretakers of the undernourished groups during the supplementation period., Results: The supplemented and placebo groups were similar on enrolment. The adequately nourished children were from significantly better socio-economic circumstances. Mean initial hair zinc content was 5.5 +/- 4.8 mumol/g (supplemented group) and 6.7 +/- 12.1 mumol/g (placebo)(n.s.). Regression analyses showed that there were no significant effects of supplementation on length, height or head circumference, nor on the incidence of any morbidity symptom. Mean duration of the episodes was significantly shorter for skin rashes in the supplemented group compared with the control group (ANCOVA, P = 0.02), and longer for vomiting (P = 0.02). The incidence of hospitalization was significantly greater in the control group (Fisher's exact test, P = 0.02)., Conclusions: Zinc supplementation reduced the hospitalizations which probably reflect severity of morbidity, but did not improve growth.

It is frequently assumed that undernutrition in young children leads to poor development through reduced activity. 3 groups of 26 1-year-old stunted children were studied: nutritional supplementation, supplementation with psychosocial stimulation, and controls. 26 nonstunted comparison children were also studied. Activity levels were measured by extensive observation in the homes, and development using 4 subscales of the Griffith's Mental Development Scales. Initially, stunted children were less active than nonstunted ones (p < .01), but after 6 months they caught up regardless of treatment. The mental ages of the stunted children were lower than those of the nonstunted children initially, and improved with either treatment. Initially, activity levels made a significant contribution to the variance in the locomotor subscale only, but not 6 months later. Activity did not predict change in development over 6 or 12 months, nor did change in activity over 6 months predict change in development over 12 months.

At the Indiana University Hospital (IUH) site on the Indianapolis campus, HL7 version 2.1 is being implemented via a TCP/IP LAN, (using the "Minimal" Lower Layer Protocol). HL7 is currently being used to convey record-oriented lab results from the local clinical laboratory system to a clinical database system via an intelligent router, which also provides store and forward capabilities. The database application displays the lab results in a variety of configurable formats to clinical users.

Although all children have the potential for becoming destructively involved with psychoactive drugs, there is considerable evidence that youngsters with particular kinds of psychologic and family problems are at high risk for chemical dependency. These include youngsters with developmental deficiencies that interfere with their capacity to master the environment. Children with a strong family history of alcoholism or drug abuse also seem to be at high risk. Obviously, there is some overlap between these two groups, not only because parental drug abuse and alcoholism may damage the fetus, but because chemically dependent parents are more likely to abuse or neglect their children because of the impact of their own illness on their functioning as parents. In addition, families in which drug use is modeled as a typical behavior are more likely to produce adolescents who use drugs, although rigid rules against drug use are relatively ineffective in preventing adolescents from experimenting with drugs. Finally, certain behavior patterns in young childhood--particularly severe aggressiveness, rebelliousness, and learning problems at school--seem to be correlated with the development of chemical dependency during adolescence.

Because of the differences in informational needs among medical practices, medical record systems should be flexible. The use of data base management and use-oriented command languages helps to achieve flexibility. The Regenstrief Medical Record System is based upon a data base management system and two user-oriented command languages (the RDB Command Language and CARE). Most batch reports, file maintenance procedures, and ad hoc retrievals can be specified by the user by means of these two languages. This means that the user can specify which reports he wants and how they should look. Daily on-line activities are performed by application programs. The data base system also provides flexibility to these programs since the content and format of many of the display screens are defined by statements that are similar to the command language statements and are stored within a text file. The Regenstrief Medical Record System now carries records for 60,000 patients.