Gradient-flow adaptive importance sampling for Bayesian leave one out cross-validation for sigmoidal classification models.

We introduce a set of gradient-flow-guided adaptive importance sampling (IS) transformations to stabilize Monte-Carlo approximations of point-wise leave one out cross-validated (LOO) predictions for Bayesian classification models. One can leverage this methodology for assessing model generalizability by for instance computing a LOO analogue to the AIC or computing LOO ROC/PRC curves and derived metrics like the AUROC and AUPRC. By the calculus of variations and gradient flow, we derive two simple nonlinear single-step transformations that utilize gradient information to shift a model's pre-trained full-data posterior closer to the target LOO posterior predictive distributions. In doing so, the transformations stabilize importance weights. Because the transformations involve the gradient of the likelihood function, the resulting Monte Carlo integral depends on Jacobian determinants with respect to the model Hessian. We derive closed-form exact formulae for these Jacobian determinants in the cases of logistic regression and shallow ReLU-activated artificial neural networks, and provide a simple approximation that sidesteps the need to compute full Hessian matrices and their spectra. We test the methodology on an n≪p dataset that is known to produce unstable LOO IS weights.

Interpretable (not just posthoc-explainable) medical claims modeling for discharge placement to reduce preventable all-cause readmissions or death.

We developed an inherently interpretable multilevel Bayesian framework for representing variation in regression coefficients that mimics the piecewise linearity of ReLU-activated deep neural networks. We used the framework to formulate a survival model for using medical claims to predict hospital readmission and death that focuses on discharge placement, adjusting for confounding in estimating causal local average treatment effects. We trained the model on a 5% sample of Medicare beneficiaries from 2008 and 2011, based on their 2009-2011 inpatient episodes (approximately 1.2 million), and then tested the model on 2012 episodes (approximately 400 thousand). The model scored an out-of-sample AUROC of approximately 0.75 on predicting all-cause readmissions-defined using official Centers for Medicare and Medicaid Services (CMS) methodology-or death within 30-days of discharge, being competitive against XGBoost and a Bayesian deep neural network, demonstrating that one need-not sacrifice interpretability for accuracy. Crucially, as a regression model, it provides what blackboxes cannot-its exact gold-standard global interpretation, explicitly defining how the model performs its internal "reasoning" for mapping the input data features to predictions. In doing so, we identify relative risk factors and quantify the effect of discharge placement. We also show that the posthoc explainer SHAP provides explanations that are inconsistent with the ground truth model reasoning that our model readily admits.

A Novel Use of a Schanz Pin-Rectal Foreign Body Extraction: A Case Report.

Introduction: Retained rectal foreign bodies (RFBs) can be difficult to extract, forcing the surgeon to get creative. This is the first case report utilizing orthopedic drilling and joystick manipulation techniques for foreign body extraction. Case Report: A 63-year-old male presented to the emergency department with a pool ball in his rectum for two days. Extraction attempts under anesthesia both transanally and through a low midline laparotomy were unsuccessful due to the patient's pelvic anatomy. Orthopedic surgery was consulted to see if any manipulation or resection of the pelvis might aid in extraction. Ultimately, a Schanz pin was drilled retrogradely from the rectum into the pool ball and successfully manipulated the pool ball out of the patient. Conclusion: Techniques such as drilling and joystick manipulation are common in orthopedic surgery but rarely used in other surgical fields. This case presented a novel use of a Schanz pin in RFB extraction. Application of orthopedic surgical technique in a colorectal surgery in this case saved the patient from more invasive interventions such as pubic symphysiotomy or ischial tuberosity resection.

Pole balancing on the fingertip: model-motivated machine learning forecasting of falls.

Introduction: There is increasing interest in developing mathematical and computational models to forecast adverse events in physiological systems. Examples include falls, the onset of fatal cardiac arrhythmias, and adverse surgical outcomes. However, the dynamics of physiological systems are known to be exceedingly complex and perhaps even chaotic. Since no model can be perfect, it becomes important to understand how forecasting can be improved, especially when training data is limited. An adverse event that can be readily studied in the laboratory is the occurrence of stick falls when humans attempt to balance a stick on their fingertips. Over the last 20 years, this task has been extensively investigated experimentally, and presently detailed mathematical models are available. Methods: Here we use a long short-term memory (LTSM) deep learning network to forecast stick falls. We train this model to forecast stick falls in three ways: 1) using only data generated by the mathematical model (synthetic data), 2) using only stick balancing recordings of stick falls measured using high-speed motion capture measurements (human data), and 3) using transfer learning which combines a model trained using synthetic data plus a small amount of human balancing data. Results: We observe that the LTSM model is much more successful in forecasting a fall using synthetic data than it is in forecasting falls for models trained with limited available human data. However, with transfer learning, i.e., the LTSM model pre-trained with synthetic data and re-trained with a small amount of real human balancing data, the ability to forecast impending falls in human data is vastly improved. Indeed, it becomes possible to correctly forecast 60%-70% of real human stick falls up to 2.35 s in advance. Conclusion: These observations support the use of model-generated data and transfer learning techniques to improve the ability of computational models to forecast adverse physiological events.

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a ß-adrenoceptor blocker (propranolol) to determine the role of ß-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min-1 , P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min-1 , P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min-1 , P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min-1  mmHg-1 , P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on ß-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by ß-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by ß-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

Tranexamic Acid and Holding Venous Thromboembolism Prophylaxis Morning of Surgery Do Not Decrease Transfusion Requirements in Patients Undergoing Anterior Intrapelvic Approach for Acetabular Open Reduction and Internal Fixation.

INTRODUCTION: The objective of this study was to determine factors that may affect transfusion rates for patients requiring an anterior intrapelvic (AIP) approach for an acetabulum fracture. METHODS: This was a multicenter retrospective comparison study (3 trauma centers at two urban academic centers). Patients who had an AIP approach for an acetabulum fracture without other notable same-day procedures (irrigation and débridement and/or external fixation were only other allowed procedures) were included. One hundred ninety-five adult (18 and older) patients had adequate records to complete analysis with no preexisting coagulopathy. The main outcome evaluated was the number of units transfused at the time of surgery and up to 7 days after surgery. RESULTS: Factors that were found to affect intraoperative transfusion rates were older age, lower preoperative hematocrit, longer surgery duration, and requiring increased intraoperative intravenous fluids. Factors that did not affect transfusion rate included sex, body mass index, hip dislocation at the time of injury, fracture pattern, AIP approach alone or with lateral window ± distal extension, Injury Severity Score, preoperative platelet count, use of tranexamic acid, and venous thromboembolism prophylaxis received morning of surgery. When followed out through the remainder of a week after surgery, the results for any factor did not change. DISCUSSION: In this large multicenter retrospective study of patients requiring an AIP approach, tranexamic acid and use of venous thromboembolism prophylaxis (or holding it the morning of surgery) did not affect transfusion rates either during surgery or up to a week after surgery. Older age, lower preoperative hematocrit level, longer surgery time, and increased intraoperative intravenous fluids were associated with higher transfusion rates. DATA AVAILABILITY AND TRIAL REGISTRATION NUMBERS: Data are available on request. LEVEL OF EVIDENCE: Level 3, retrospective case-control study.

Early Treatment of Acetabular Fractures Using an Anterior Approach Increases Blood Loss but not Packed Red Blood Cell Transfusion.

OBJECTIVE: The objective of this study was to determine whether time from hospital admission to surgery for acetabular fractures using an anterior intrapelvic (AIP) approach affected blood loss. DESIGN: Retrospective review. SETTING: Three level 1 trauma centers at 2 academic institutions. PATIENT SELECTION CRITERIA: Adult (18 years or older) patients with no pre-existing coagulopathy treated for an acetabular fracture via an AIP approach. Excluded were those with other significant same day procedures (irrigation and debridement and external fixation were the only other allowed procedures). OUTCOME MEASURES AND COMPARISONS: Multiple methods for evaluating blood loss were investigated, including estimated blood loss (EBL), calculated blood loss (CBL) by Gross and Hgb balance methods, and packed red blood cell (PRBC) transfusion requirement. Outcomes were evaluated based on time to surgery. RESULTS: 195 patients were studied. On continuous linear analysis, increasing time from admission to surgery was significantly associated with decreasing CBL at 24 hours (-1.45 mL per hour by Gross method, P = 0.003; -0.440 g of Hgb per hour by Hgb balance method, P = 0.003) and 3 days (-1.69 mL per hour by Gross method, P = 0.013; -0.497 g of Hgb per hour by Hgb balance method, P = 0.010) postoperative, but not EBL or PRBC transfusion. Using 48 hours from admission to surgery to define early versus delayed surgery, CBL was significantly greater in the early group compared to the delayed group (453 [IQR 277-733] mL early versus 364 [IQR 160-661] delayed by Gross method, P = 0.017; 165 [IQR 99-249] g of Hgb early versus 143 [IQR 55-238] g Hgb delayed by Hgb balance method, P = 0.035), but not EBL or PRBC transfusion. In addition, in multivariate linear regression, neither giving tranexamic acid nor administering prophylactic anticoagulation for venous thromboembolism on the morning of surgery affected blood loss at 24 hours or 3 days postoperative ( P > 0.05). CONCLUSION: There was higher blood loss with early surgery using an AIP approach, but early surgery did not affect PRBC transfusion and may not be clinically relevant. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Use of external control arms in immune-mediated inflammatory diseases: a systematic review.

OBJECTIVES: External control arms (ECAs) provide useful comparisons in clinical trials when randomised control arms are limited or not feasible. We conducted a systematic review to summarise applications of ECAs in trials of immune-mediated inflammatory diseases (IMIDs). DESIGN: Systematic review with an appraisal of ECA source quality rated across five domains (data collection, study populations, outcome definitions, reliability and comprehensiveness of the dataset, and other potential limitations) as high, low or unclear quality. DATA SOURCES: Embase, Medline and Cochrane Central Register of Controlled Trial were searched through to 12 September 2023. ELIGIBILITY CRITERIA: Eligible studies were single-arm or randomised controlled trials (RCTs) of inflammatory bowel disease, pouchitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and atopic dermatitis in which an ECA was used as the comparator. DATA EXTRACTION AND SYNTHESIS: Two authors independently screened the search results in duplicate. The characteristics of included studies, external data source(s), outcomes and statistical methods were recorded, and the quality of the ECA data source was assessed by two independent authors. RESULTS: Forty-three studies met the inclusion criteria (inflammatory bowel disease: 16, pouchitis: 1, rheumatoid arthritis: 12, juvenile idiopathic arthritis: 1, ankylosing spondylitis: 5, psoriasis: 3, multiple indications: 4). The majority of these trials were single-arm (33/43) and enrolled adult patients (34/43). All included studies used a historical control rather than a contemporaneous ECA. In RCTs, ECAs were most often derived from the placebo arm of another RCT (6/10). In single-arm trials, historical case series were the most common ECA source (19/33). Most studies (31/43) did not employ a statistical approach to generate the ECA from historical data. CONCLUSIONS: Standardised ECA methodology and reporting conventions are lacking for IMIDs trials. The establishment of ECA reporting guidelines may enhance the rigour and transparency of future research.

Effects of endothelial nitric oxide synthase on mouse arteriovenous fistula hemodynamics.

Newly created arteriovenous fistulas (AVFs) often fail to mature for dialysis use due to disturbed blood flow at and near the AVF anastomosis. The disturbed flow inhibits the endothelial nitric oxide synthase (NOS3) pathway, thus decreasing the production of nitric oxide, a vasodilator. Previously, our group reported that NOS3 expression levels affect AVF lumen size in a mouse model. In this study, we performed MRI-based computational fluid dynamics simulations to investigate the hemodynamical parameters (velocity, wall shear stress (WSS), and vorticity) in a mouse AVF model at day 7 and day 21 post-AVF creation using three NOS3 strains: overexpression (OE), knockout (KO), and wild-type (WT) control. This study is the first to reveal hemodynamics over time in mouse AVFs, consider spatial heterogeneity along the vein, and reveal the effect of NOS3 on the natural history of mouse AVF hemodynamics. From day 7 to day 21, OE has smoother streamlines and had significantly lower vorticity and WSS than WT and KO, suggesting that WSS was attempting to return to pre-surgery baseline, respectively. Our results conclude that the overexpression of NOS3 leads to desired optimal hemodynamics during AVF remodeling. Future studies can investigate enhancing the NOS3 pathway to improve AVF development.

Accuracy of Medical Student Measurements of CT Right-to-Left Ventricular Diameter in Patients with Acute Pulmonary Embolism.

Objectives: Acute pulmonary embolism (PE) is a common disease, necessitating risk stratification to determine management. A right ventricle (RV) to left ventricle (LV) diameter ratio ≥1.0 on computed tomography pulmonary angiography (CTPA) suggests RV strain, which may indicate a worse prognosis. Two prior studies showed that residents with brief training by a radiologist could accurately measure RV/LV ratio. We assessed whether medical students could accurately measure RV dilatation. Methods: We conducted a post hoc analysis of a retrospective cohort study of adults undergoing management for acute PE at 21 community emergency departments across Kaiser Permanente Northern California from 2013 to 2015. We created a sample, stratified to contain an equal number of patients from each of the 5 PE Severity Index classes. Four medical students measured RV and LV diameter on CTPA after training from an emergency medicine physician and an interventional radiologist. We used Cohen's kappa statistics, Bland-Altman plots, and Pearson correlation coefficients to assess interrater reliability. Results: Of the 108 CTPAs reviewed, 79 (73%) showed RV dilatation and 29 (27%) did not. The kappa statistic for the presence of RV dilatation of the medical students compared to the radiologist showed moderate agreement for 3 medical students (kappa (95% CI): 0.46 (0.21-0.70), 0.49 (0.31-0.68), 0.50 (0.32-0.68)) and fair agreement for 1 medical student (kappa (95% CI): 0.29 (0.10-0.47)). The average interrater differences in RV/LV ratio between a radiologist and each of the 4 medical students were -0.04, -0.05, 0.04, and 0.24. Pearson correlation coefficients were 0.87, 0.80, 0.74, and 0.78, respectively, indicating moderate correlation (P < .001 for all). Conclusion: Medical students were able to identify RV dilatation on CTPA in moderate agreement with that of a radiologist. Further study is needed to determine whether medical student accuracy could improve with additional training.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Population genetics analysis of SLC3A1 and SLC7A9 revealed the etiology of cystine stone may be more than what our current genetic knowledge can explain.

BACKGROUND: Cystine stone is a Mendelian genetic disease caused by SLC3A1 or SLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology. METHODS: We analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract all SLC3A1 and SLC7A9 pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium. RESULTS: We found that 9 unique SLC3A1 pathogenic variants were carried by 26 people and 5 unique SLC7A9 pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compoun d heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585. CONCLUSION: The clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.

Multiple models for outbreak decision support in the face of uncertainty.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Progression and flaring of focal dermal hypoplasia during an acute illness.

Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare genodermatosis affecting tissues of mesodermal and ectodermal origin. The characteristic skin changes have been reported to symptomatically flare in response to certain triggers as well as to progress over time in some cases. We present the case of a 5-year-old girl with cutaneous flaring and progression of FDH in the setting of septic shock. This case adds to the growing body of literature on both flaring and progression of the cutaneous manifestations of FDH.

Increasing aggressive prostate cancer.

INTRODUCTION: To compare prostate biopsy (Pbx) characteristics, before and after the 2012 United States Preventive Services Task Force (USPSTF) prostate cancer screening guidelines in our practice. MATERIALS AND METHODS: We completed a retrospective comparative analysis of 1703 sequential patients that had a Pbx in 2010 to 2012 (3 years) with 1006 patients biopsied in 2018, 2019 and 2021 (3 years). Data from a total of 2709 Pbx was collected on patient age, race, prostate-specific antigen (PSA), digital rectal examination (DRE) and Gleason sum score (GSS). The data was analyzed to determine whether the 2012 USPSTF screening recommendations against prostate cancer screening may have affected prostate cancer characteristics. Two study groups were defined as Group A and Group B. Group A represents Pbx prior to the 2012 USPSTF screening guidelines (2010-2012) and Group B represents Pbx in 2018-19 and 2021. The patient population consisted of 76% Black, 14% White and 11% other. RESULTS: The number of patients that had a Pbx in Groups A vs. B: 567 patients/year vs. 335 patients/year. The annual positive Pbx rate for Group A vs. B: 134/year vs. 175/year. High grade prostate cancer (GSS 7-10) in Groups A vs. B: 51.5% vs. 59%. The proportion of patients with a PSA 10 ng/mL or greater in Groups A vs. B: 25.4% vs. 31%. The PSA 10 ng/mL and over and GSS 7-10 was higher in Group B for all age groups. In 2021, GSS 7-10 was present in 64% of 70-80 year olds. In Group B, GSS 6 decreased by 7.5% while GSS 7-10 increased by 7.5% compared with Group A. CONCLUSIONS: Our data through the year 2021 shows that after the 2012 USPSTF recommendations against prostate cancer screening, Pbx decreased and prostate cancer diagnosis and high grade (GSS 7-10) prostate cancer increased. As our patient population consists of 76% Black patients and 33% of men age 70-80 years old, our results support annual prostate cancer screening for US men 50-80 years old and especially high-risk patients that include Black men, men with a family history of prostate cancer and healthy men age 70-80 years old. Annual DRE- and PSA- based prostate cancer screening will likely markedly decrease prostate cancer morbidity, mortality and the cost of prostate cancer management.

Role of the angiotensin type 1 receptor in modulating the carotid chemoreflex in an ovine model of renovascular hypertension.

OBJECTIVE: The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear. METHODS: Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. RESULTS: In both hypertensive and sham animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure but a reduction in renal vascular conductance. These responses were not different between groups. Infusion of angiotensin II led to an increase in arterial pressure and reduction in renal blood flow. The sensitivity of the renal vasculature to angiotensin II was significantly attenuated in hypertension compared with the sham animals. Systemic inhibition of the AT1R did not alter blood pressure in either group. Interestingly carotid body-evoked arterial pressure responses were attenuated by AT1R blockade in renovascular hypertension but not in shams. CONCLUSION: Taken together, our findings indicate a decrease in vascular reactivity of the non-clipped kidney to angiotensin II in hypertension. The CB-evoked increase in blood pressure in hypertension is mediated in part, by the AT1R. These findings indicate a differential role of the AT1R in the carotid body versus the renal vasculature.

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by deficiency of the mitochondrial protein frataxin. Lack of frataxin causes neuronal loss in various areas of the CNS and PNS. In particular, cerebellar neuropathology in FRDA patients includes loss of large principal neurons and synaptic terminals in the dentate nucleus (DN), and previous studies have demonstrated early synaptic deficits in the Knockin-Knockout mouse model of FRDA. However, the exact correlation of frataxin deficiency with cerebellar neuropathology remains unclear. Here we report that doxycycline-induced frataxin knockdown in a mouse model of FRDA (FRDAkd) leads to synaptic cerebellar degeneration that can be partially reversed by AAV8-mediated frataxin restoration. Loss of cerebellar Purkinje neurons and large DN principal neurons are observed in the FRDAkd mouse cerebellum. Levels of the climbing fiber-specific glutamatergic synaptic marker VGLUT2 decline starting at 4 weeks after dox induction, whereas levels of the parallel fiber-specific synaptic marker VGLUT1 are reduced by 18-weeks. These findings suggest initial selective degeneration of climbing fiber synapses followed by loss of parallel fiber synapses. The GABAergic synaptic marker GAD65 progressively declined during dox induction in FRDAkd mice, while GAD67 levels remained unaltered, suggesting specific roles for frataxin in maintaining cerebellar synaptic integrity and function during adulthood. Expression of frataxin following AAV8-mediated gene transfer partially restored VGLUT1/2 levels. Taken together, our findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function.

Regularized Bayesian calibration and scoring of the WD-FAB IRT model improves predictive performance over marginal maximum likelihood.

Item response theory (IRT) is the statistical paradigm underlying a dominant family of generative probabilistic models for test responses, used to quantify traits in individuals relative to target populations. The graded response model (GRM) is a particular IRT model that is used for ordered polytomous test responses. Both the development and the application of the GRM and other IRT models require statistical decisions. For formulating these models (calibration), one needs to decide on methodologies for item selection, inference, and regularization. For applying these models (test scoring), one needs to make similar decisions, often prioritizing computational tractability and/or interpretability. In many applications, such as in the Work Disability Functional Assessment Battery (WD-FAB), tractability implies approximating an individual's score distribution using estimates of mean and variance, and obtaining that score conditional on only point estimates of the calibrated model. In this manuscript, we evaluate the calibration and scoring of models under this common use-case using Bayesian cross-validation. Applied to the WD-FAB responses collected for the National Institutes of Health, we assess the predictive power of implementations of the GRM based on their ability to yield, on validation sets of respondents, ability estimates that are most predictive of patterns of item responses. Our main finding indicates that regularized Bayesian calibration of the GRM outperforms the regularization-free empirical Bayesian procedure of marginal maximum likelihood. We also motivate the use of compactly supported priors in test scoring.