CD1a on Langerhans cells controls inflammatory skin disease.

CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4(+) helper T cells that produced the cytokines IL-17 and IL-22 (TH17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.

An integrated approach to uncover drivers of cancer.

Systematic characterization of cancer genomes has revealed a staggering number of diverse aberrations that differ among individuals, such that the functional importance and physiological impact of most tumor genetic alterations remain poorly defined. We developed a computational framework that integrates chromosomal copy number and gene expression data for detecting aberrations that promote cancer progression. We demonstrate the utility of this framework using a melanoma data set. Our analysis correctly identified known drivers of melanoma and predicted multiple tumor dependencies. Two dependencies, TBC1D16 and RAB27A, confirmed empirically, suggest that abnormal regulation of protein trafficking contributes to proliferation in melanoma. Together, these results demonstrate the ability of integrative Bayesian approaches to identify candidate drivers with biological, and possibly therapeutic, importance in cancer.

The RNA helicase DDX6 controls early mouse embryogenesis by repressing aberrant inhibition of BMP signaling through miRNA-mediated gene silencing.

The evolutionarily conserved RNA helicase DDX6 is a central player in post-transcriptional regulation, but its role during embryogenesis remains elusive. We here show that DDX6 enables proper cell lineage specification from pluripotent cells by analyzing Ddx6 knockout (KO) mouse embryos and employing an in vitro epiblast-like cell (EpiLC) induction system. Our study unveils that DDX6 is an important BMP signaling regulator. Deletion of Ddx6 causes the aberrant upregulation of the negative regulators of BMP signaling, which is accompanied by enhanced expression of Nodal and related genes. Ddx6 KO pluripotent cells acquire higher pluripotency with a strong inclination toward neural lineage commitment. During gastrulation, abnormally expanded Nodal and Eomes expression in the primitive streak likely promotes endoderm cell fate specification while inhibiting mesoderm differentiation. We also genetically dissected major DDX6 pathways by generating Dgcr8, Dcp2, and Eif4enif1 KO models in addition to Ddx6 KO. We found that the miRNA pathway mutant Dgcr8 KO phenocopies Ddx6 KO, indicating that DDX6 mostly works along with the miRNA pathway during early development, whereas its P-body-related functions are dispensable. Therefore, we conclude that DDX6 prevents aberrant upregulation of BMP signaling inhibitors by participating in miRNA-mediated gene silencing processes. Overall, this study delineates how DDX6 affects the development of the three primary germ layers during early mouse embryogenesis and the underlying mechanism of DDX6 function.

CONTRIBUTION FACTORS OF EFFECTIVE LENS POSITION, TILT, AND DECENTRATION DURING FLANGED SCLERAL FIXATION OF INTRAOCULAR LENS: A Model Eye Study.

PURPOSE: The authors aimed to elucidate the factors related to effective lens position, tilt, and decentration of scleral fixed intraocular lenses (IOLs) with a flanged haptic technique in an artificial eye model using anterior segment optical coherence tomography. METHODS: Two bent 27-gauge needles were passed through a 1.0- or 2.0-mm scleral tunnel, 2.0 mm posterior to the limbus and 180° apart. Both haptics of a three-piece IOL were docked with guide needles and externalized. Factors related to the IOL position were analyzed using anterior segment optical coherence tomography and a stereomicroscope. RESULTS: The 1.0-mm scleral tunnel induced a significantly longer effective lens position than the 2.0-mm tunnel and suture fixation ( P < 0.05 and P < 0.01, respectively). Discrepancy in scleral tunnel length induced higher decentration of the optic to the opposite side of the haptic-embedded shorter tunnel and tilt perpendicular to the fixed axis than that in the scleral tunnel of the same length ( P < 0.001 and P < 0.05, respectively). If the scleral fixation points of both haptics are not exactly 180° apart, the IOL may become decentered and tilted ( P < 0.01 and P < 0.05, respectively). CONCLUSION: In the flanged haptic technique, the length, balance, and position of both scleral tunnels determine IOL effective lens position, tilt, and decentration.

Clustering plasma concentration-time curves: applications of unsupervised learning in pharmacogenomics.

Pharmaceutical researchers are continually searching for techniques to improve both drug development processes and patient outcomes. An area of recent interest is the potential for machine learning (ML) applications within pharmacology. One such application not yet given close study is the unsupervised clustering of plasma concentration-time curves, hereafter, pharmacokinetic (PK) curves. In this paper, we present our findings on how to cluster PK curves by their similarity. Specifically, we find clustering to be effective at identifying similar-shaped PK curves and informative for understanding patterns within each cluster of PK curves. Because PK curves are time series data objects, our approach utilizes the extensive body of research related to the clustering of time series data as a starting point. As such, we examine many dissimilarity measures between time series data objects to find those most suitable for PK curves. We identify Euclidean distance as generally most appropriate for clustering PK curves, and we further show that dynamic time warping, Fréchet, and structure-based measures of dissimilarity like correlation may produce unexpected results. As an illustration, we apply these methods in a case study with 250 PK curves used in a previous pharmacogenomic study. Our case study finds that an unsupervised ML clustering with Euclidean distance, without any subject genetic information, is able to independently validate the same conclusions as the reference pharmacogenomic results. To our knowledge, this is the first such demonstration. Further, the case study demonstrates how the clustering of PK curves may generate insights that could be difficult to perceive solely with population level summary statistics of PK metrics.

GARP on hepatic stellate cells is essential for the development of liver fibrosis.

BACKGROUND & AIMS: Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-ß docking molecule. While the immune regulatory properties of GARP on blood cells have been studied, the function of GARP on tissue stromal cells remains unclear. Here, we investigate the role of GARP expressed on hepatic stellate cells (HSCs) in the development of liver fibrosis. METHODS: The function of GARP on HSCs was explored in toxin-induced and metabolic liver fibrosis models, using conditional GARP-deficient mice or a newly generated inducible system for HSC-specific gene ablation. Primary mouse and human HSCs were isolated to evaluate the contribution of GARP to the activation of latent TGF-ß. Moreover, cell contraction of HSCs in the context of TGF-ß activation was tested in a GARP-dependent fashion. RESULTS: Mice lacking GARP in HSCs were protected from developing liver fibrosis. Therapeutically deleting GARP on HSCs alleviated the fibrotic process in established disease. Furthermore, natural killer T cells exacerbated hepatic fibrosis by inducing GARP expression on HSCs through IL-4 production. Mechanistically, GARP facilitated fibrogenesis by activating TGF-ß and enhancing endothelin-1-mediated HSC contraction. Functional GARP was expressed on human HSCs and significantly upregulated in the livers of patients with fibrosis. Lastly, deletion of GARP on HSCs did not augment inflammation or liver damage. CONCLUSIONS: GARP expressed on HSCs drives the development of liver fibrosis via cell contraction-mediated activation of latent TGF-ß. Considering that systemic blockade of TGF-ß has major side effects, we highlight a therapeutic niche provided by GARP and surface-mediated TGF-ß activation. Thus, our findings suggest an important role of GARP on HSCs as a promising target for the treatment of liver fibrosis. IMPACT AND IMPLICATIONS: Liver fibrosis represents a substantial and increasing public health burden globally, for which specific treatments are not available. Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-ß docking molecule. Here, we show that GARP expressed on hepatic stellate cells drives the development of liver fibrosis. Our findings suggest GARP as a novel target for the treatment of fibrotic disease.

Thinking inside the box: endogenous α-anomeric lipid antigens.

The most powerful iNKT cell antigen is α-galactosylceramide (α-GalCer), derived from the marine sponge. However, α-anomeric glycolipids are thought to be absent in mammals. In this issue of Immunity, Kain et al., (2014) demonstrate the presence of mammalian α-linked glycosylceramides, such as α-GalCer.

Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine.

BACKGROUND: Oliceridine (Olinvyk) is a µ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. METHODS: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. RESULTS: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. CONCLUSIONS: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Comparing the Outcomes and Complication Rates of Biologic vs Synthetic Meshes in Implant-Based Breast Reconstruction: A Systematic Review.

OBJECTIVE: This systematic review evaluates all published studies comparing biologic and synthetic meshes in implant-based breast reconstruction (IBBR), to determine which category of mesh produces the most favorable outcomes. SUMMARY BACKGROUND DATA: Breast cancer is the most common cancer in women globally. Implant-based breast reconstruction is currently the most popular method of postmastectomy reconstruction, and recently, the use of surgical mesh in IBBR has become commonplace. Although there is a long-standing belief among surgeons that biologic mesh is superior to synthetic mesh in terms of surgical complications and patient outcomes, few studies exist to support this claim. METHODS: A systematic search of the EMBASE, PubMed, and Cochrane databases was performed in January 2022. Primary literature studies comparing biologic and synthetic meshes within the same experimental framework were included. Study quality and bias were assessed using the validated Methodological Index for Non-Randomized Studies criteria. RESULTS: After duplicate removal, 109 publications were reviewed, with 12 meeting the predetermined inclusion criteria. Outcomes included common surgical complications, histological analysis, interactions with oncologic therapies, quality of life measures, and esthetic outcomes. Across all 12 studies, synthetic meshes were rated as at least equivalent to biologic meshes for every reported outcome. On average, the studies in this review tended to have moderate Methodological Index for Non-Randomized Studies scores. CONCLUSION: This systematic review offers the first comprehensive evaluation of all publications comparing biologic and synthetic meshes in IBBR. The consistent finding that synthetic meshes are at least equivalent to biologic meshes across a range of clinical outcomes offers a compelling argument in favor of prioritizing the use of synthetic meshes in IBBR.

Adaptive designs for IVPT data with mixed scaled average bioequivalence.

In vitro permeation tests (IVPT) offer accurate and cost-effective development pathways for locally acting drugs, such as topical dermatological products. For assessment of bioequivalence, the FDA draft guidance on generic acyclovir 5% cream introduces a new experimental design, namely the single-dose, multiple-replicate per treatment group design, as IVPT pivotal study design. We examine the statistical properties of its hypothesis testing method-namely the mixed scaled average bioequivalence (MSABE). Meanwhile, some adaptive design features in clinical trials can help researchers make a decision earlier with fewer subjects or boost power, saving resources, while controlling the impact on family-wise error rate. Therefore, we incorporate MSABE in an adaptive design combining the group sequential design and sample size re-estimation. Simulation studies are conducted to study the passing rates of the proposed methods-both within and outside the average bioequivalence limits. We further consider modifications to the adaptive designs applied for IVPT BE trials, such as Bonferroni's adjustment and conditional power function. Finally, a case study with real data demonstrates the advantages of such adaptive methods.

Rethinking Disparities in Minimally Invasive Myomectomy: Identifying Drivers of Disparate Surgical Approach to Myomectomy Between African American and White Women.

STUDY OBJECTIVE: To identify drivers of disparities among patients undergoing surgical management of myomas when stratified by self-identified patient race. DESIGN: This is a retrospective institutional review board-approved chart review of all patients who underwent a myomectomy at a large academic center. Surgical approach to myomectomy was classified as abdominal, laparoscopic, or robotic-assisted laparoscopic. Myoma burden was quantified preoperatively using uterine volume, intraoperatively by number of myomas listed on operative report, and postoperatively by myoma weight from pathology reports. SETTING: A large tertiary care hospital containing a comprehensive myoma treatment center. PATIENTS: A total of 265 white patients and 121 African American patients who underwent a myomectomy between January 2012 and October 2018 were included in the study population. INTERVENTIONS: Abdominal, laparoscopic, and robotic-assisted myomectomy. Laparoscopic and robotic-assisted myomectomy were classified as minimally invasive myomectomy. Multivariable logistic regression models and a propensity score matching algorithm were used to match African American (AA) women and white women for myoma burden. MEASUREMENTS AND MAIN RESULTS: A total of 386 women were included in the study. AA women (31%; n = 121) had higher myoma burden than white women by preoperative imaging (AA: 36% with 3 or more myomas; white: 19% with 3 or more myomas; p <.01) and operative report (>8 AA: 31% vs white 13%; p <.01). Despite this, AA women underwent minimally invasive myomectomy at similar rates as compared with white women when adjusted for myoma burden, body mass index, preoperative hematocrit, hypertension, and surgical indication (adjusted odds ratio 1.3; 95% confidence interval, 0.8-2.2 myomas; p <.01). Sensitivity analysis using propensity score matching found similar results. CONCLUSION: In this population, AA women had a higher myoma burden than white women. When matched for myoma burden, however, there was no statistically significant difference between rates of minimally invasive myomectomy and abdominal myomectomy. This finding was consistent when controlling for myoma burden measured by preoperative, intraoperative, or postoperative methods of measurement. Further studies are needed to better characterize this disparity at other hospitals and to investigate ways to increase access and equity among patients undergoing minimally invasive myomectomy.

Rates of Cesarean Conversion and Associated Predictors and Outcomes in Planned Vaginal Twin Deliveries.

OBJECTIVE: Twin vaginal deliveries (VDs) are often performed in the operating room (OR) given the risk of conversion to cesarean delivery (CD) for the aftercoming twin. We aim to investigate the rates of conversion to CD for planned twin VDs and identify predictors and outcomes of conversion. STUDY DESIGN: A retrospective cohort study of all women who underwent a planned twin VD at two large academic medical centers over 4 years. Demographic and outcome data were chart abstracted. Various statistical tests were used to evaluate the influence of perinatal variables on mode of delivery and identify possible predictors of conversion. RESULTS: Eight hundred and eighty-five twin deliveries were identified, of which 725 (81.9%) were possible candidates for VD. Of those, 237 (32.7%) underwent successful VD of twin A. Ninety-five (40.1%) had a nonvertex second twin at time of delivery. Conversion to CD occurred in 10 planned VDs (4.2%). Conversions were higher with spontaneous labor (relative risk [RR]: 2.1; 95% confidence interval [CI] 1.6-2.7; p = 0.003), and having an intertwin delivery interval greater than 60 minutes (RR: 5.1; 95% CI: 2.5-10.8; p < 0.001). Nonvertex presentation of twin B, type of delivery provider, or years out in practice of delivery provider were not significantly different between groups. There were no significant differences in neonatal outcomes between VD and conversion groups. There was a significant association between use of forceps for twin B and successful VD (p = 0.02), with 84.6% in the setting of a nonvertex twin B. CONCLUSION: Successful VD was achieved in planned VD of twins in 95.8% of cases, and there were no significant differences in maternal and fetal outcomes between successful VD and conversion to CD for twin B. With the optimal clinical scenario and shared decision-making, performing vaginal twin deliveries in labor and delivery rooms should be discussed. KEY POINTS: · There is a propensity to perform twin vaginal deliveries in the operating room.. · Rates of conversion to cesarean section are very low.. · There are no significant differences in perinatal outcomes with conversion..

O-Heterocycle Synthesis via Intramolecular C-H Alkoxylation Catalyzed by Iron Acetylacetonate.

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared α-diazo-ß-ketoesters using commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

Endogenous T1ρ cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients. METHODS: HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15-20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE --); otherwise, the image was labeled equivocal (LGE + -). RESULTS: In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman's rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman's rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman's rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE -- slices had lower ECV than LGE + + (p = 0.01). CONCLUSIONS: Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients.

Prevalence of depression in women with low income living in developed countries.

OBJECTIVE: To conduct a systematic review of studies reporting prevalence rates of depression in women living in low-income circumstances in developed countries. METHODS: The published and unpublished literature was searched for studies reporting prevalence of depression in women with low income in developed countries. Searches, data extraction, and methodological appraisal were conducted twice independently. To perform the analysis, the meta and metafor packages in R, a random effect model to account for both between and within studies' variances, and the restricted maximum likelihood method for estimation were used. RESULTS: One-hundred sixty-four studies, involving 218,035 participants, were located through the search process. The point prevalence of depression among women in low-income circumstances using self-report instruments in 134 studies was 37.4% (95% CI, 34.0%-40.7%). Additionally, the point prevalence according to depression diagnosis in 25 studies was 22.9% (95% CI, 17.8%-28.5%). CONCLUSIONS: The high rate of depression among women living in low-income circumstances is of serious public health concern. POLICY IMPLICATIONS: Women living in low-income circumstances should receive screening and referral/treatment in not only medical service settings, but also in social service settings serving women receiving welfare benefits.

A Two-Stage Decision Making Approach for Safety Studies.

For safety studies, two types of hypothesis testing are often considered: detecting a safety signal and ruling out a safety concern. Under the detecting framework, statistical non-significance is often confused with the conclusion that there is no safety concern. Such a conclusion, in the presence of low study power or large variability, is problematic. To overcome the interpretation issue with non-significant results from a detecting hypothesis, we propose a Two-Stage Decision-Making (TSDM) approach for safety studies. It is basically a ruling-out design allowing an interim analysis that applies both detecting and ruling-out criteria at the interim and final stages with a pre-specified alpha spending function. The proposed TSDM approach incorporates both detecting a safety signal and ruling out safety concerns into a single study design to increase the probability of making a definite decision. It is based on the ruling-out framework that utilizes both directions of the confidence interval to make a decision for ruling out unacceptable risk or detecting safety signal at each analysis stage. We assess the proposed TSDM approach by investigating properties such as operational type I error rate, overall study power based on analytical approximations, overall probability of making a decision, and required sample sizes. We conduct Monte Carlo simulations to evaluate such properties regarding various outcome types of confidence intervals and summarize the statistical interpretations and the implications on study design.

Family history in patients who would have been candidates for active surveillance.

INTRODUCTION It is unknown whether a family history of prostate cancer confers additional risk among men who are candidates for active surveillance (AS). MATERIALS AND METHODS: Using a prospectively maintained database of men who underwent radical prostatectomy (RP) (2010- 2018), candidates for AS were identified according to the expanded criteria. Pathological upgrading was defined as a pathologic Gleason score (pGS) of 3+4 or higher for patients with a biopsy GS of 3+3 and a pGS of 4+3 or higher for patients with a biopsy GS of 3+4. Major upgrading was defined as a pGS of 4+4 or higher. The ₓ2 test was used for comparisons. RESULTS: Of 1,320 men who were candidates for AS, 288 (21.8%) had a family history of prostate cancer. There were no differences in terms of the age, number of positive cores, or number of patients with a GS of 7 between the two groups. Pathological upgrading was observed in 61.1% of the total cohort, with no difference observed between the two groups (60.7% versus 62.5%; p = 0.5). CONCLUSION: In men who are eligible for AS according to the expanded criteria, a family history of prostate cancer does not appear to be associated with adverse pathology at RP.

Influence of mid-life cognitive activity on cognitive function among men aged 68 years or older.

BACKGROUND: Cognitive activity in early and late life has been associated with increased cognitive function among older adults. There is less evidence on the effects of midlife cognitive activity. AIMS: We examined the association of midlife cognitive activity with cognitive function after age 65. METHODS: We studied 78 men 68 years old or older. We asked participants to assess their current and midlife cognitive activity using adaptations of a measure created by Wilson et al., which includes reading, writing letters, visiting museums and other leisure activities. Our outcomes were validated measures of cognitive and overall function. We compared midlife cognitive activity to our outcome measures in simple bivariable analyses, then adjusted for demographic characteristics using linear regression. RESULTS: Our study population of older (mean age 74.8 years) men was primarily white (87%) and well-educated; 65% had at least some post high school education. Although 67% were retired, household income was high (24% < $30 k and 44% > $50 k). More midlife cognitive activity was related to more current cognitive activity (p = < .0001, r2 = 0.55339). However, midlife activity was not associated with measures of cognitive or overall function, adjusted analyses gave similar results. DISCUSSION: We did not find an association between midlife cognitive activity and later life function. However, the Wilson measure of cognitive activity that we used excludes instrumental cognitive activities such as dealing with finances or healthcare, likely underestimating cognitive activity for many participants. CONCLUSION: Midlife cognitive activity was associated with late-life cognitive activity, suggesting efforts to increase late-life cognitive activity may need to start earlier in life. However, more robust measures of everyday cognitive activity might detect such an association.

DNA sequencing of anatomy lab cadavers to provide hands-on precision medicine introduction to medical students.

BACKGROUND: Medical treatment informed by Precision Medicine is becoming a standard practice for many diseases, and patients are curious about the consequences of genomic variants in their genome. However, most medical students' understanding of Precision Medicine derives from classroom lectures. This format does little to foster an understanding for the potential and limitations of Precision Medicine. To close this gap, we implemented a hands-on Precision Medicine training program utilizing exome sequencing to prepare a clinical genetic report of cadavers studied in the anatomy lab. The program reinforces Precision Medicine related learning objectives for the Genetics curriculum. METHODS: Pre-embalmed blood samples and embalmed tissue were obtained from cadavers (donors) used in the anatomy lab. DNA was isolated and sequenced and illustrative genetic reports provided to the students. The reports were used to facilitate discussion with students on the implications of pathogenic genomic variants and the potential correlation of these variants in each "donor" with any anatomical anomalies identified during cadaver dissection. RESULTS: In 75% of cases, analysis of whole exome sequencing data identified a variant associated with increased risk for a disease/abnormal condition noted in the donor's cause of death or in the students' anatomical findings. This provided students with real-world examples of the potential relationship between genomic variants and disease risk. Our students also noted that diseases associated with 92% of the pathogenic variants identified were not related to the anatomical findings, demonstrating the limitations of Precision Medicine. CONCLUSION: With this study, we have established protocols and classroom procedures incorporating hands-on Precision Medicine training in the medical student curriculum and a template for other medical educators interested in enhancing their Precision Medicine training program. The program engaged students in discovering variants that were associated with the pathophysiology of the cadaver they were studying, which led to more exposure and understanding of the potential risks and benefits of genomic medicine.

Use of propensity score and disease risk score for multiple treatments with time-to-event outcome: a simulation study.

Propensity score (PS) and disease risk score (DRS) are often used in pharmacoepidemiologic safety studies. Methods of applying these two balancing scores are extensively studied in binary treatment settings. However, the use of PS and DRS is not well understood in the case of non-ordinal multiple treatments. Some PS methods of multiple treatments have been implemented since the theoretical establishment. Nevertheless, most of the work applies to continuous or binary outcomes. Little work has been done for time-to-event outcomes. In this study, we extend the application of the PS and DRS methods to time-to-event outcomes in multiple treatment settings. The analytical approaches include weighing, matching, stratification, and regression. Simulation studies with rare event rates are conducted to evaluate the performances of different methods. Different treatment-covariates and outcome-covariates strength of associations are considered. Additionally, the impacts of imbalanced designs and large or limited PS overlaps are investigated on various analytical approaches. We found that the inverse probability treatment weighting with bootstrap variance estimator, the generalized PS matching, and the Cox regression estimated DRS in full cohort generally performed well in multiple treatment settings. This study aims to provide additional guidance for researchers on PS and DRS analyses in pharmacoepidemiologic observational studies.