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A critique of genomic risk classifiers is potential correlation with readily available clinical data. For these classifiers to enhance clinical decision making, they must demonstrate additional discrimination from clinical variables alone with regards to prognostic and/or predictive value. A 22-gene classifier is increasingly employed to inform treatment decisions in prostate cancer. This study aimed to assess whether its risk score remained independent of available clinical variables when using machine learning (ML) to predict genomic risk score outputs. This was a retrospective study of males with localized prostate cancer treated at one of twenty sites within a single hospital network. Patients whose tumors were sent for genomic risk profiling were eligible. Clinical features including year of biopsy, age, clinical stage, prostate specific antigen (PSA), Gleason score, and National Comprehensive Cancer Network (NCCN) risk group were extracted from the medical record and genomic risk score/category were extracted from the pathology results. Logistic regression for binary classification and linear regression for continuous classification plus 5 ML models were trained to predict the risk score, low-risk disease, and high-risk disease. Model performance was measured using area under the curve (AUC) for binary classification and Spearman rho (ρ) for regression. The best-performing model was explained using SHapley Additive exPlanation (SHAP) values. A total of 354 patients with biopsy specimens obtained between 2010 and 2024 were identified. Median age was 66.7 (IQR = 61.4-73.2). A total of 27.1%, 57.9%, and 15.0% of patients were NCCN low, intermediate, and high risk, respectively. Median genomic risk score was 0.385 (IQR = 0.26-0.58). A total of 57.6%, 18.1%, and 24.3% of patients had genomic risk classified as low, intermediate, and high, respectively. An extreme gradient boosting tree achieved the best performance at predicting genomic risk score (ρ: 0.526; 95% CI = 0.355-0.668). A random forest model achieved the best performance at predicting high-risk (AUC: 0.790; 95% CI = 0.671-0.909) and low-risk (AUC: 0.749; 95% CI = 0.631-0.867) genomic score. The most important variables for predicting risk score were primary Gleason, NCCN risk category, and total Gleason. Risk factors predicting high-risk disease included primary Gleason, NCCN risk group, and total Gleason. For low-risk disease they were primary Gleason, age, and total Gleason. ML predicted the output of genomic risk classifiers with favorable albeit imperfect performance using clinical variables alone. Future analyses should evaluate whether genomic risk classifiers may be particularly useful in the subset of patients whose genomic risk score differs from what was predicted using clinical variables alone. ML in combination with genomic risk should also be evaluated as synergistic tools to predict actuarial outcomes once sufficient follow-up is available. [ABSTRACT FROM AUTHOR]

In the early months of the COVID-19 pandemic, states enacted multiple policies to reduce in-person interactions. Scholars have speculated that these policies may have contributed to adverse mental health outcomes. This study examines potential associations between states' COVID-19 physical distancing policies and working-age (18-64) adults' self-reported mental health. Mental health outcomes (depression, anxiety, worsened mental health, and sought treatment for anxiety or depression) are from the National Wellbeing Survey collected from working-age adults in the United States (U.S.) February 1 to March 18, 2021 (N = 3,804). Data on 12 state policies are from the COVID-19 U.S. State Policy Database. Analyses included logistic regression and Bayesian group index modeling, which identified sets, or "bundles," of policies that were associated with each mental health outcome. Multiple policies (both separately and in bundles) were associated with adverse mental health outcomes, with certain policies (closures and curfews on retail and other businesses) being particularly important. A one-month increase in exposure to respective model-derived physical distancing policy bundles was associated with a 36% increase in the odds of reporting that COVID-19 worsened one's mental health (odds ratio [OR] = 1·36; 95% credible interval [CRI] = 1·01 to 1·80), a 6% increase in the odds of meeting the clinical threshold for anxiety (OR = 1·06; CRI = 0·99 to 1·16), and a 15% increase in the odds of seeking treatment for anxiety or depression (OR = 1·15; CRI = 1·02 to 1·49). To accurately understand the role of states' COVID-19 policies on mental health during the pandemic, researchers must consider how collections of policies might influence outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Context: The Food and Agriculture Organization of the United Nations and the World Health Organization are updating their dietary zinc recommendations for children aged 0 to 3 years., Objective: The aim of this review was to retrieve and synthesize evidence regarding zinc needs for growth as well as zinc losses, absorption, and bioavailability from the diet., Data Sources: MEDLINE, Embase, and Cochrane Library databases were searched electronically from inception to August 2020. Studies assessing the above factors in healthy children aged 0 to 9 years were included, with no limits on study design or language., Data Extraction: Ninety-four studies reporting on zinc content in tissue (n = 27); zinc absorption (n = 47); factors affecting zinc bioavailability (n = 30); and endogenous zinc losses via urine, feces, or integument (n = 40) met the inclusion criteria. Four reviewers extracted data and two reviewers checked for accuracy., Data Analyses: Studies were synthesized narratively, and meta-analyses of zinc losses and gains as well the subgroups of age, type of feeding, country's income, and molar ratio of phytate to zinc were conducted. Meta-analysis revealed an overall mean (95%CI) urinary and endogenous fecal zinc excretion of 17.48 µg/kg/d (11.80-23.15; I2 = 94%) and 0.07 mg/kg/d (0.06-0.08; I2 = 82%), respectively, with a mean fractional zinc absorption of 26.75% (23.69-29.81; I2 = 99%). Subgrouping by age revealed differences in mean values associated with the transition from milk-based diets to solid food during the first 3 years of life., Conclusion: This review synthesizes data that may be used to formulate zinc requirements in young children. Results should be interpreted with caution because of considerable heterogeneity in the evidence., Systematic Review Registration: PROSPERO registration number CRD42020215236., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes can have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0-3 y were identified (from inception to August 2020) in MEDLINE, Embase, and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models were used to generate forest plots to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc compared with placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, serum transferrin receptor, hemoglobin, hematocrit, and the odds of anemia in ≥1 of the subgroups investigated. Lactulose:mannitol ratio was improved with zinc supplementation, and no significant effect was observed on C-reactive protein, erythrocyte superoxide dismutase, zinc protoporphyrin, blood cholesterol, and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Aim: To determine whether higher fibre intakes during childhood or adolescence effect a broad range of intermediate markers of cardiometabolic risk or other health related issues., Materials and Methods: We used online searches up to January 2020 and manual searches to identify prospective observational studies reporting on childhood or adolescent intakes of dietary fibre, vegetables, fruit and refined or whole grains. Outcomes measured later in life were body weight, blood lipids, blood pressure, glycaemia, bone health, cognition, growth and bowel habits. Potential age-specific ranges for dietary fibre were extrapolated from published adult data., Results: We identified 45 publications reporting on 44 354 participants from 30 cohort studies. Mean age at dietary assessment varied from 1 to 19.3 years. Follow-up duration varied from 4 months to 27 years. Although well-conducted studies reported improvements in body weight, blood lipids and glycaemia, the diverse nature of studies precluded meta analysis. The quality of evidence was very low to low given the limited data available per outcome and the inability to synthesize results from multiple studies. Potential dietary fibre intake begins at 13-16 g a day for 2-year-olds and increases until the age of 10 years, when values are comparable with an adult range of 25-30 g a day., Conclusions: Given the inconsistency in findings from cohort studies other than an absence of detrimental effects, it seems appropriate that recommendations regarding childhood fibre intake are extrapolated from relevant adult data., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The positive association between educational attainment and adult health ("the gradient") is stronger in some areas of the United States than in others. Explanations for the geographic pattern have not been rigorously investigated. Grounded in a contextual and life course perspective, this study assesses childhood circumstances (e.g., childhood health, compulsory schooling laws) and adult circumstances (e.g., wealth, lifestyles, economic policies) as potential explanations. Using data on US-born adults aged 50-59 at baseline ( N =13,095) and followed for up to 16 years across the 1998-2014 waves of the Health and Retirement Study, this study examined how and why educational gradients in morbidity, functioning, and mortality vary across nine U.S. regions. The findings indicate that the gradient is stronger in some areas than others partly because of geographic differences in childhood socioeconomic conditions and health, but mostly because of geographic differences in adult circumstances such as wealth, lifestyles, and economic and tobacco policies.

Hepatic late effects are not commonly reported in survivors of childhood leukemia. Four young male patients with acute lymphoblastic leukemia (ALL) were diagnosed with bleeding esophageal varices (EVs) during or shortly after completion of maintenance chemotherapy. EVs were identified from 0 to 60 months after completion of leukemia therapy. All four patients were men between 20 to 24 years old. Hematemesis was the most common presenting symptom. Associated features included splenomegaly, cytopenias, azole therapy, alcohol use, and hepatic iron overload. EVs may be an under-recognized complication of ALL therapy, with adolescent and young adult males at highest risk.

Despite numerous studies on educational disparities in U.S. adult health, explanations for the disparities and their growth over time remain incomplete. We argue that this knowledge gap partly reflects an individualist paradigm in U.S. studies of educational disparities in health. These studies have largely focused on proximal explanations (e.g., individual behaviors) to the neglect of contextual explanations (e.g., economic policies). We draw on contextual theories of health disparities to illustrate how U.S. states, as institutional actors, shape the importance of education for health. Using two nationally-representative datasets and seven health measures for adults aged 45-89, we show that the size of the educational gradient in health varies markedly across states. The size varies because of variation in the health of lower-educated adults. We use state excise taxes on cigarettes to illustrate one way that states shape educational disparities in health. Our findings underscore the necessity of contextualizing these disparities.

Purpose: We sought to develop and validate automated performance metrics to measure surgeon performance of vesicourethral anastomosis during robotic assisted radical prostatectomy. Furthermore, we sought to methodically develop a standardized training tutorial for robotic vesicourethral anastomosis., Materials and Methods: We captured automated performance metrics for motion tracking and system events data, and synchronized surgical video during robotic assisted radical prostatectomy. Nonautomated performance metrics were manually annotated by video review. Automated and nonautomated performance metrics were compared between experts with 100 or more console cases and novices with fewer than 100 cases. Needle driving gestures were classified and compared. We then applied task deconstruction, cognitive task analysis and Delphi methodology to develop a standardized robotic vesicourethral anastomosis tutorial., Results: We analyzed 70 vesicourethral anastomoses with a total of 1,745 stitches. For automated performance metrics experts outperformed novices in completion time (p <0.01), EndoWrist® articulation (p <0.03), instrument movement efficiency (p <0.02) and camera manipulation (p <0.01). For nonautomated performance metrics experts had more optimal needle to needle driver positioning, fewer needle driving attempts, a more optimal needle entry angle and less tissue trauma (each p <0.01). We identified 14 common robotic needle driving gestures. Random gestures were associated with lower efficiency (p <0.01), more attempts (p <0.04) and more trauma (p <0.01). The finalized tutorial contained 66 statements and figures. Consensus among 8 expert surgeons was achieved after 2 rounds, including among 58 (88%) after round 1 and 8 (12%) after round 2., Conclusions: Automated performance metrics can distinguish surgeon expertise during vesicourethral anastomosis. The expert vesicourethral anastomosis technique was associated with more efficient movement and less tissue trauma. Standardizing robotic vesicourethral anastomosis and using a methodically developed tutorial may help improve robotic surgical training., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Inferior vena cava tumor thrombectomy requires experienced surgical teams due to complex hemodynamic considerations. The teams often use vascular bypass techniques that introduce additional risk. Inferior vena caval control in the pericardium obviates the need for cardiopulmonary bypass. We reviewed our experience with intrapericardial control during inferior vena caval tumor thrombectomy to evaluate perioperative outcomes and determine factors associated with overall survival., Materials and Methods: We retrospectively reviewed the records of 87 patients who underwent nephrectomy with inferior vena caval tumor thrombectomy using intrapericardial inferior vena caval control from 1978 to 2012. This technique was performed in all 43 and 35 cases of intrahepatic and supradiaphragmatic thrombi, respectively, and in 9 select cases of intra-atrial thrombi. Patient demographics, operative variables and postoperative outcomes were examined. Multivariate regression analysis was used to determine associations between clinical variables and overall survival., Results: Mortality 30 days perioperatively was 9.2% and the incidence of high grade complications was 19.5%. Median survival was 3.1 and 2.5 years in patients with pT3bN0 and pT3cN0, respectively. Extended regional lymphadenectomy, which was performed in all cases, revealed nodal metastasis in 38%. On multivariate analysis ECOG greater than 2 and pT3c stage were associated with worse survival. Histological grade, perinephric fat invasion and lymph node involvement were not associated with worse survival., Conclusions: Intrapericardial control of the inferior vena cava enables a single surgical team to safely perform tumor thrombectomy for intrahepatic and supradiaphragmatic thrombi, eliminating the risk and morbidity related to cardiopulmonary bypass. Although supradiaphragmatic extent and ECOG greater than 2 are associated with worse survival, complete resection with lymphadenectomy can allow for long-term survival in patients with locally advanced disease., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate robotic dry laboratory (dry lab) exercises in terms of their face, content, construct and concurrent validities. To evaluate the applicability of the Global Evaluative Assessment of Robotic Skills (GEARS) tool to assess dry lab performance., Materials and Methods: Participants were prospectively categorized into two groups: robotic novice (no cases as primary surgeon) and robotic expert (≥30 cases). Participants completed three virtual reality (VR) exercises using the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA, USA), as well as corresponding dry lab versions of each exercise (Mimic Technologies, Seattle, WA, USA) on the da Vinci Surgical System. Simulator performance was assessed by metrics measured on the simulator. Dry lab performance was blindly video-evaluated by expert review using the six-metric GEARS tool. Participants completed a post-study questionnaire (to evaluate face and content validity). A Wilcoxon non-parametric test was used to compare performance between groups (construct validity) and Spearman's correlation coefficient was used to assess simulation to dry lab performance (concurrent validity)., Results: The mean number of robotic cases experienced for novices was 0 and for experts the mean (range) was 200 (30-2000) cases. Expert surgeons found the dry lab exercises both 'realistic' (median [range] score 8 [4-10] out of 10) and 'very useful' for training of residents (median [range] score 9 [5-10] out of 10). Overall, expert surgeons completed all dry lab tasks more efficiently (P < 0.001) and effectively (GEARS total score P < 0.001) than novices. In addition, experts outperformed novices in each individual GEARS metric (P < 0.001). Finally, in comparing dry lab with simulator performance, there was a moderate correlation overall (r = 0.54, P < 0.001). Most simulator metrics correlated moderately to strongly with corresponding GEARS metrics (r = 0.54, P < 0.001)., Conclusions: The robotic dry lab exercises in the present study have face, content, construct and concurrent validity with the corresponding VR tasks. Until now, the assessment of dry lab exercises has been limited to basic metrics (i.e. time to completion and error avoidance). For the first time, we have shown it is feasibile to apply a global assessment tool (GEARS) to dry lab training., (© 2013 The Authors. BJU International © 2013 BJU International.)

The cellular program responsible for the restoration of adipose tissue mass after weight loss is largely uncharacterized. Leptin mRNA levels are highly correlated with adipose tissue mass, and leptin expression can thus be used as a surrogate for changes in the amount of adipose tissue. To further study the responses of adipocytes to changes in weight, we created a transgenic mouse expressing the luciferase reporter gene under the control of leptin regulatory sequences, which allows noninvasive imaging of the leptin expression of mice in vivo. We used these animals to show that weight loss induced by fasting or leptin treatment results in the retention of lipid-depleted adipocytes in adipose depots. To further study the cellular response to weight regain after leptin treatment, a leptin withdrawal protocol was used to induce a state of acute leptin deficiency in wild type mice. Acute leptin deficiency led to the transient deposition of large amounts of glycogen within pre-existing, lipid-depleted adipocytes. This was followed by rapid reaccumulation of lipid. Transcriptional profiling revealed that this cellular response was associated with induction of mRNAs for the entire pathway of enzymes necessary to convert glucose into acetyl-CoA and glycerol, key substrates for the synthesis of triglycerides.

Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNF alpha protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNF alpha was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNF alpha-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNF alpha-induced death.

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

The muscle of Lawrence (MOL) is a bilaterally symmetrical muscle spanning the tergite of the fifth abdominal segment of adult male Drosophila melanogaster. It is not, however, a general feature of male-specific development within the subfamily Drosophilinae. Of 95 species surveyed within this subfamily, 67 exist with no MOL at all. By drawing comparisons with published cladograms of species relatedness, three conclusions regarding the evolutionary history of the MOL are made: (i) The MOL predates the major radiations of the genus Drosophila, given its presence in earlier-branching Chymomyza and Scaptodrosophila; the MOL has been subsequently excluded in at least one present species of each of these two primitive genera. (ii) Within the genus Drosophila the MOL is present sporadically in the radiation of the subgenus Sophophora, showing repetitive loss even in very close evolutionary lineages. (iii) The MOL may have been entirely excluded from the prolific radiation of the subgenus Drosophila. Thus the MOL shows a uniquely incongruous pattern of presence or absence relative to accepted drosophilid phylogeny.