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Background ERAS® Society guidelines are holistic, multidisciplinary tools designed to improve outcomes after surgery. The enhanced recovery after surgery (ERAS) approach was initially developed for colorectal surgery and has been implemented successfully across a large number of settings, resulting in improved patient outcomes. As the ERAS approach is increasingly being adopted worldwide and new guidelines are being generated for new populations, there is a need to define an ERAS® Society guideline and the methodology that should be followed in its development. Methods The ERAS® Society recommended approach for developing new guidelines is based on the creation of multidisciplinary guideline development groups responsible for defining topics, planning the literature search, and assessing the quality of the evidence. Results Clear definitions for the elements of an ERAS guideline involve multimodal and multidisciplinary approaches impacting on multiple patient outcomes. Recommended methodology for guideline development follows a rigorous approach with systematic identification and evaluation of evidence, and consensus‐based development of recommendations. Guidelines should then be evaluated and reviewed regularly to ensure that the best and most up‐to‐date evidence is used consistently to support surgical patients. Conclusion There is a need for a standardized, evidence‐informed approach to both the development of new ERAS® Society guidelines, and the adaptation and revision of existing guidelines.

Abstract How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing’s impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017–2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan–Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment (n = 158) showed a trend toward improved overall survival vs. afternoon (n = 79); the median survival was 158 vs. 79 days (p = 0.20, HR = 0.84, CI95% 0.84–0.91). Subgroup benefits for morning treatment in females (p = 0.04) and trends in controlled primary disease (p = 0.11) and breast cancer metastases (p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors’ relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Rationale & Objective: Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. Study Design: In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439). Setting & Participants: CRIC is a multicenter prospective cohort of adults with CKD. Exposure: MMP-2 measured in plasma at baseline and at year 2. Outcomes: A composite kidney endpoint (KRT/eGFR halving) Analytical Approach: Weighted Cox proportional hazards models for case-cohort participants. Results: Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein

BackgroundMusculoskeletal injuries (MSKIs) are endemic in military populations. Thus, it is essential to identify and mitigate MSKI risks. Time-to-event machine learning models utilizing self-reported questionnaires or existing data (e.g., electronic health records) may aid in creating efficient risk screening tools.MethodsA total of 4,222 U.S. Army Service members completed a self-report MSKI risk screen as part of their unit's standard in-processing. Additionally, participants' MSKI and demographic data were abstracted from electronic health record data. Survival machine learning models (Cox proportional hazard regression (COX), COX with splines, conditional inference trees, and random forest) were deployed to develop a predictive model on the training data (75%; n = 2,963) for MSKI risk over varying time horizons (30, 90, 180, and 365 days) and were evaluated on the testing data (25%; n = 987). Probability of predicted risk (0.00–1.00) from the final model stratified Service members into quartiles based on MSKI risk.ResultsThe COX model demonstrated the best model performance over the time horizons. The time-dependent area under the curve ranged from 0.73 to 0.70 at 30 and 180 days. The index prediction accuracy (IPA) was 12% better at 180 days than the IPA of the null model (0 variables). Within the COX model, “other” race, more self-reported pain items during the movement screens, female gender, and prior MSKI demonstrated the largest hazard ratios. When predicted probability was binned into quartiles, at 180 days, the highest risk bin had an MSKI incidence rate of 2,130.82 ± 171.15 per 1,000 person-years and incidence rate ratio of 4.74 (95% confidence interval: 3.44, 6.54) compared to the lowest risk bin.ConclusionSelf-reported questionnaires and existing data can be used to create a machine learning algorithm to identify Service members' MSKI risk profiles. Further research should develop more granular Service member-specific MSKI screening tools and create MSKI risk mitigation strategies based on these screenings.

Introduction The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45–76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial’s secondary outcome of kidney disease.Research design and methods We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to 60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR

Soil-based emissions from land conversions are often overlooked in climate planning. The objectives of this study were to use quantitative data on soil-based greenhouse gas (GHG) emissions for the state of Georgia (GA) (USA) to examine context-specific (temporal, biophysical, economic, and social) climate planning and legal options to deal with these emissions. Currently, 30% of the land in GA has experienced anthropogenic land degradation (LD) primarily due to agriculture (64%). All seven soil orders were subject to various degrees of anthropogenic LD. Increases in overall LD between 2001 and 2021 indicate a lack of land degradation neutrality (LDN) in GA. Besides agricultural LD, there was also LD caused by increased development through urbanization, with 15,197.1 km2 developed, causing midpoint losses of 1.2 × 1011 kg of total soil carbon (TSC) with a corresponding midpoint social cost from carbon dioxide (CO2) emissions (SC-CO2) of USD $20.4B (where B = billion = 109, $ = U.S. dollars (USD)). Most developments occurred in the Metro Atlanta and Coastal Economic Development Regions, which indicates reverse climate change adaptation (RCCA). Soil consumption from developments is an important issue because it limits future soil or forest carbon (C) sequestration potential in these areas. Soil-based emissions should be included in GA’s carbon footprint. Understanding the geospatial and temporal context of land conversion decisions, as well as the social and economic costs, could be used to create incentives for land management that limit soil-based GHG emissions in a local context with implications for relevant United Nations (UN) initiatives.

Abstract Inundation of coastal stormwater networks by tides is widespread due to sea‐level rise (SLR). The water quality risks posed by tidal water rising up through stormwater infrastructure (pipes and catch basins), out onto roadways, and back out to receiving water bodies is poorly understood but may be substantial given that stormwater networks are a known source of fecal contamination. In this study, we (a) documented temporal variation in concentrations of Enterococcus spp. (ENT), the fecal indicator bacteria standard for marine waters, in a coastal waterway over a 2‐month period and more intensively during two perigean spring tide periods, (b) measured ENT concentrations in roadway floodwaters during tidal floods, and (c) explained variation in ENT concentrations as a function of tidal inundation, antecedent rainfall, and stormwater infrastructure using a pipe network inundation model and robust linear mixed effect models. We find that ENT concentrations in the receiving waterway vary as a function of tidal stage and antecedent rainfall, but also site‐specific characteristics of the stormwater network that drains to the waterway. Tidal variables significantly explain measured ENT variance in the waterway, however, runoff drove higher ENT concentrations in the receiving waterway. Samples of floodwaters on roadways during both perigean spring tide events were limited, but all samples exceeded the threshold for safe public use of recreational waters. These results indicate that inundation of stormwater networks by tides could pose public health hazards in receiving water bodies and on roadways, which will likely be exacerbated in the future due to continued SLR.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD. Study Design: Observational cohort study. Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI

Rationale & Objective: This study aimed to assess the effect of exposure to organic pollutants in adults with chronic kidney disease (CKD). Study Design: This was a cross-sectional and longitudinal analysis. Setting and Participants: Forty adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC). Exposures: Exposure at baseline and longitudinally to various organic chemical pollutants. Outcomes: The outcomes were as follows: death; composite of congestive heart failure, myocardial infarction, and stroke; event-free survival from kidney failure or ≥50% decline in estimated glomerular filtration rate (eGFR); and longitudinal trajectory of eGFR. Analytical Approach: We used high-performance liquid chromatography with tandem mass spectrometry to measure urinary concentrations of bisphenols, phthalates, organophosphate pesticides, polycyclic aromatic hydrocarbons, melamine, and cyanuric acid at years 1, 3, and 5 after enrollment in the CRIC. Univariate and multivariable logistic regression were used to examine the association of individual compounds and classes of pollutants with the outcomes. The Cox proportional hazards model and Kaplan-Meier method were used to calculate hazard ratios and 95% CIs for each class of pollutants. Results: Median baseline eGFR and urinary protein-to-creatinine ratio were 33 mL/min/1.73 m2 and 0.58 mg/g, respectively. Of 52 compounds assayed, 30 were detectable in ≥50% of participants. Urinary chemical concentrations were comparable in patients with CKD and healthy individuals from contemporaneous National Health and Nutrition Examination Survey cohorts. Phthalates were the only class with a trend toward higher exposure in patients with CKD. There was an inverse relationship between exposure and the eGFR slopes for bisphenol F, mono-(3-carboxypropyl) phthalate, mono-benzyl phthalate, mono-[2-(carboxymethyl)hexyl] phthalate, and melamine. There were no associations between organic pollutant exposure and cardiovascular outcomes. Limitations: Small sample size, evaluation of single rather than combined exposures. Conclusions: Simultaneous measurement of multiple organic pollutants in adults with CKD is feasible. Exposure levels are comparable with healthy individuals. Select contaminants, especially in the phthalate class, may be associated with more rapid deterioration in kidney function. Plain-Language Summary: The effect of exposure to organic pollutants has not been studied in adults with chronic kidney disease. (CKD). To fill this gap, we measured the exposure to a wide range of chemicals that are found in plastics, personal care products, and food preparation. Overall, the exposure was similar to that noted in the healthy population living in the United States. Only select compounds, mainly phthalates, demonstrated a trend with a more rapid decline in kidney function. These findings provide a useful reference for future studies that aim to evaluate organic pollutant exposure in patients with CKD. This is significant because these exposures represent a modifiable risk factor for disease progression through alterations in diet or lifestyle.

Abstract Objective The serum lipidomic profile associated with neuropathy in type 2 diabetes is not well understood. Obesity and dyslipidemia are known neuropathy risk factors, suggesting lipid profiles early during type 2 diabetes may identify individuals who develop neuropathy later in the disease course. This retrospective cohort study examined lipidomic profiles 10 years prior to type 2 diabetic neuropathy assessment. Methods Participants comprised members of the Gila River Indian community with type 2 diabetes (n = 69) with available stored serum samples and neuropathy assessment 10 years later using the combined Michigan Neuropathy Screening Instrument (MNSI) examination and questionnaire scores. A combined MNSI index was calculated from examination and questionnaire scores. Serum lipids (435 species from 18 classes) were quantified by mass spectrometry. Results The cohort included 17 males and 52 females with a mean age of 45 years (SD = 9 years). Participants were stratified as with (high MNSI index score > 2.5407) versus without neuropathy (low MNSI index score ≤ 2.5407). Significantly decreased medium‐chain acylcarnitines and increased total free fatty acids, independent of chain length and saturation, in serum at baseline associated with incident peripheral neuropathy at follow‐up, that is, participants had high MNSI index scores, independent of covariates. Participants with neuropathy also had decreased phosphatidylcholines and increased lysophosphatidylcholines at baseline, independent of chain length and saturation. The abundance of other lipid classes did not differ significantly by neuropathy status. Interpretation Abundance differences in circulating acylcarnitines, free fatty acids, phosphatidylcholines, and lysophosphatidylcholines 10 years prior to neuropathy assessment are associated with neuropathy status in type 2 diabetes.

The United Nations (UN) Sustainable Development Goals (SDGs) offer an opportunity to improve soil science education on sustainability because they provide specific context to educate faculty and students from various disciplines, including Science, Technology, Engineering, and Mathematics (STEM) about SDGs. Soil science is a STEM discipline with a wide range of applications in the SDGs. The objectives of this study were to use a matrix approach (framework for presenting options for discussion and implementation) to integrate SDGs into an existing introductory soil science course taught to undergraduate students from different STEM fields (environmental and natural resources; wildlife biology; and forestry). The course was enriched with a lecture on SDGs and students were asked to link soil properties and class activities to specific SDGs. A post-assessment survey revealed an increase in students’ familiarity with SDGs, and their relevance to soil properties and course activities. Students acknowledged the importance of soils and individual actions for achieving the SDGs. There was an overall increase in student familiarity (+59.4%) with SDGs. Most students agreed (46.7%) and strongly agreed (23.3%) that the course activities were an effective way to learn about SDGs with examples from soil science. Identified learning gaps in subject matter found through the surveys on SDGs were clarified during later classroom discussions. The advantage of this teaching approach is that it seamlessly integrates SDGs with existing course materials while relying on students’ critical thinking skills to effectively analyze soil science information and form a judgement on how it relates to SDGs.

Abstract Changes in climate and land‐use and land‐cover (LULC) are expected to influence surface water runoff and nutrient characteristics of estuarine watersheds, but the extent to which estuaries are vulnerable to altered nutrient loading under future conditions is poorly understood. The present work aims to address this gap through the development of a new vulnerability assessment framework that accounts for (a) estuarine exposure to projected changes in total nitrogen (TN) and total phosphorus (TP) loads as a function of LULC and climate change under several scenarios, (b) sensitivity, and (c) adaptive capacity. The framework was applied to 112 estuaries and their contributing watersheds across the contiguous U.S., specifically to look at regional variability in estuarine vulnerability to nutrient loading. Study findings revealed that the largest increases in estuarine nutrient loads are expected in the North and South Atlantic regions and eastern Gulf of Mexico, while the lowest increases are expected in the North and South Pacific regions and the western Gulf of Mexico. However, the North Atlantic and the South Pacific had the highest adaptive capacity, which could potentially counteract the effects of LULC and climate change on nutrient loads. Strong variation in predicted estuarine nutrient loads was observed as a function of climate model projections, while projected LULC changes were more consistently associated with elevated loads. Our findings illustrate the benefits of integrating natural and socio‐ecological factors to identify opportunities to develop adaptation plans and policies to mitigate ecological degradation in vitally important estuaries.

Abstract In the USA, historical data on the period over which industrial swine farms have operated are usually only available at the county scale and released every 5 years via the USDA Census of Agriculture, leaving the history of the swine industry and its potential legacy effects on the environment poorly understood. We developed a changepoint-based workflow that recreates the construction timelines of swine farms, specifically by identifying the construction years of swine manure lagoons from historical Landsat 5 imagery for the period of 1984 to 2012. The study focused on the Coastal Plain of North Carolina, a major pork-producing state in the USA. The algorithm successfully predicted the year of swine waste lagoon construction (+ /− 1 year) with an accuracy of approximately 94% when applied to the study area. By estimating the year of construction of 3405 swine waste lagoons in NC, we increased the resolution of available information on the expansion of swine production from the county scale to spatially-explicit locations. We further analyzed how the locations of swine waste lagoons changed in proximity to water resources over time, and found a significant increase in swine waste lagoon distances to the nearest water feature across the period of record.

Rationale and Objective: Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Study Design: Prospective observational cohort. Setting & Participants: 3,664 Chronic Renal Insufficiency Cohort participants. Exposure: Aspirin use in patients with and without preexisting CVD. Outcomes: Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Analytical Approach: Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use. Results: The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. Limitations: This is not a randomized controlled trial, and therefore, causality cannot be determined. Conclusions: Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.

In the United States (U.S.), state agencies in charge of mariculture regulation are mandated under the U.S. Food and Drug Administration’s (FDA) National Shellfish Sanitation Program (NSSP) to monitor fecal indicator bacteria (FIB) concentrations, commonly of fecal coliforms, to determine the safety of coastal waters for supporting harvestable shellfish for human consumption. Many states have monitored bacteriological water quality for decades, creating impressive long-term records with the potential to advance foundational understanding of coastal systems and contribute to other complementary monitoring efforts. However, state shellfish sanitation programs differ in how they collect, manage, and share bacteriological monitoring data, resulting in their data typically being available in disparate state-level repositories with non-standardized database structures. Here, we outline three key recommendations as to how shellfish sanitation programs could implement practices to make their data more Findable, Accessible, Interoperable, and Reusable (FAIR), in turn creating new opportunities for the full potential of the data to be realized. We also offer sample materials of a standardized database, ShellBase, to provide an example of how diverse shellfish sanitation data may be integrated with a common data structure.

Mucosal-Associated Invariant T (MAIT) cells are associated with established functions during bacterial infection. Here the authors show inoculation with Francisella tularensis results in induction of MAIT cells associated with prototypic Th1 immunity and confer protection to systemic and local infection.

Rationale & Objective: Having a usual source of care increases use of preventive services and is associated with improved survival in the general population. We evaluated this association in adults with chronic kidney disease (CKD). Study Design: Prospective, observational cohort study. Setting & Participants: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor: Usual source of care was self-reported as: 1) clinic, 2) emergency department (ED)/urgent care, 3) other. Outcomes: Primary outcomes included incident end-stage kidney disease (ESKD), atherosclerotic events (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, hospitalization events, and all-cause death. Analytical Approach: Multivariable regression analyses to evaluate the association between usual source of care (ED/urgent care vs clinic) and primary outcomes. Results: Among 3,140 participants, mean age was 65 years, 44% female, 45% non-Hispanic White, 43% non-Hispanic Black, and 9% Hispanic, mean estimated glomerular filtration rate 50 mL/min/1.73 m2. Approximately 90% identified clinic as usual source of care, 9% ED/urgent care, and 1% other. ED/urgent care reflected a more vulnerable population given lower baseline socioeconomic status, higher comorbid condition burden, and poorer blood pressure and glycemic control. Over a median follow-up time of 3.6 years, there were 181 incident end-stage kidney disease events, 264 atherosclerotic events, 263 incident heart failure events, 288 deaths, and 7,957 hospitalizations. Compared to clinic as usual source of care, ED/urgent care was associated with higher risk for all-cause death (HR, 1.53; 95% CI, 1.05-2.23) and hospitalizations (RR, 1.41; 95% CI, 1.32-1.51). Limitations: Cannot be generalized to all patients with CKD. Causal relationships cannot be established. Conclusions: In this large, diverse cohort of adults with moderate-to-severe CKD, those identifying ED/urgent care as usual source of care were at increased risk for death and hospitalizations. These findings highlight the need to develop strategies to improve health care access for this high-risk population.

Objective: Preference for dietary fat vs. carbohydrate varies markedly across free-living individuals. It is recognized that food choice is under genetic and physiological regulation, and that the central melanocortin system is involved. However, how genetic and dietary factors interact to regulate relative macronutrient intake is not well understood. Methods: We investigated how the choice for food rich in carbohydrate vs. fat is influenced by dietary cholesterol availability and agouti-related protein (AGRP), the orexigenic component of the central melanocortin system. We assessed how macronutrient intake and different metabolic parameters correlate with plasma AGRP in a cohort of obese humans. We also examined how both dietary cholesterol levels and inhibiting de novo cholesterol synthesis affect carbohydrate and fat intake in mice, and how dietary cholesterol deficiency during the postnatal period impacts macronutrient intake patterns in adulthood. Results: In obese human subjects, plasma levels of AGRP correlated inversely with consumption of carbohydrates over fats. Moreover, AgRP-deficient mice preferred to consume more calories from carbohydrates than fats, more so when each diet lacked cholesterol. Intriguingly, inhibiting cholesterol biosynthesis (simvastatin) promoted carbohydrate intake at the expense of fat without altering total caloric consumption, an effect that was remarkably absent in AgRP-deficient mice. Finally, feeding lactating C57BL/6 dams and pups a cholesterol-free diet prior to weaning led the offspring to prefer fats over carbohydrates as adults, indicating that altered cholesterol metabolism early in life programs adaptive changes to macronutrient intake. Conclusions: Together, our study illustrates a specific gene–diet interaction in modulating food choice.

Abstract Background Chronic kidney disease (CKD) is an increasing epidemic globally that is associated with adverse health outcomes including end stage kidney disease (ESKD), cardiovascular disease (CVD), and death. American Indians (AIs) have a higher prevalence of CKD than most other racial/ethnic groups, due in part to a high prevalence of type 2 diabetes. Other genetic and environmental factors not yet identified may also contribute to the disproportionate burden of CKD in AIs. Method We will establish 3 clinical centers to recruit AIs from the Southwest United States (US) to expand the Chronic Renal Insufficiency Cohort (CRIC) study. We will follow the current CRIC protocol for kidney and cardiovascular measures and outcomes, which include ambulatory monitoring of kidney function and the use of mobile health technologies for CVD sub-phenotyping, and compare the outcomes in AIs with those in other racial/ethnic groups in CRIC. Discussion AI-CRIC will identify the role of various risk factors for rapid loss of kidney function among AIs of the Southwest US. In addition, to better understand the natural history of CKD and CVD in this high-risk population, we will identify unique risk factors for CKD and CVD progression in AIs. We will also compare event rates and risk factors for kidney and cardiovascular events in AIs with the other populations represented in CRIC.

Antibodies are employed ubiquitously in biomedical sciences, including for diagnostics and therapeutics. One of the most important uses is for immunohistochemical (IHC) staining, a process that has been improving and evolving over decades. IHC is useful when properly employed, yet misuse of the method is widespread and contributes to the “reproducibility crisis” in science. We report some of the common problems encountered with IHC assays, and direct readers to a wealth of literature documenting and providing some solutions to this problem. We also describe a series of vignettes that include our approach to analytical validation of antibodies and IHC assays that have facilitated a number of biological insights into prostate cancer and the refutation of a controversial association of a viral etiology in gliomas. We postulate that a great deal of the problem with lack of accuracy in IHC assays stems from the lack of awareness by researchers for the critical necessity for end-users to validate IHC antibodies and assays in their laboratories, regardless of manufacturer claims or past publications. We suggest that one reason for the pervasive lack of end-user validation for research antibodies is that researchers fail to realize that there are two general classes of antibodies employed in IHC. First, there are antibodies that are “clinical grade” reagents used by pathologists to help render diagnoses that influence patient treatment. Such diagnostic antibodies, which tend to be highly validated prior to clinical implementation, are in the vast minority (e.g. 3 800 000), which are often not extensively validated prior to commercialization. Given increased awareness of the problem, both the United States, National Institutes of Health and some journals are requiring investigators to provide evidence of specificity of their antibody-based assays. Keywords: Prostate cancer, Antibodies, Immunohistochemistry

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P

Extant protein-coding sequences span a huge range of ages, from those that emerged only recently to those present in the last universal common ancestor. Because evolution has had less time to act on young sequences, there might be ‘phylostratigraphy’ trends in any properties that evolve slowly with age. A long-term reduction in hydrophobicity and hydrophobic clustering was found in previous, taxonomically restricted studies. Here we perform integrated phylostratigraphy across 435 fully sequenced species, using sensitive HMM methods to detect protein domain homology. We find that the reduction in hydrophobic clustering is universal across lineages. However, only young animal domains have a tendency to have higher structural disorder. Among ancient domains, trends in amino acid composition reflect the order of recruitment into the genetic code, suggesting that the composition of the contemporary descendants of ancient sequences reflects amino acid availability during the earliest stages of life, when these sequences first emerged.

The top genetic association signal for type 2 diabetes (T2D) in Southwestern American Indians maps to intron 15 of KCNQ1, an imprinted gene. We aim to understand the biology whereby variation at this locus affects T2D specifically in this genomic background. To do so, we obtained human induced pluripotent stem cells (hiPSC) derived from American Indians. Using these iPSCs, we show that imprinting of KCNQ1 and CDKN1C during pancreatic islet-like cell generation from iPSCs is consistent with known imprinting patterns in fetal pancreas and adult islets and therefore is an ideal model system to study this locus. In this report, we detail the use of allele-specific guide RNAs and CRISPR to generate isogenic hiPSCs that differ only at multiple T2D associated intronic SNPs at this locus which can be used to elucidate their functional effects. Characterization of these isogenic hiPSCs identified a few aberrant cell lines; namely cell lines with large hemizygous deletions in the putative functional region of KCNQ1 and cell lines hypomethylated at the KCNQ1OT1 promoter. Comparison of an isogenic cell line with a hemizygous deletion to the parental cell line identified CDKN1C and H19 as differentially expressed during the endocrine progenitor stage of pancreatic-islet development.

Emergency physicians supervise residents performing rare clinical procedures, but they infrequently perform those procedures independently. Simulation offers a forum to practice procedural skills, but simulation labs often target resident learners, and barriers exist to faculty as learners in simulation-based training. Simulation-based curricula focused on improving emergency medicine (EM) faculty’s rare procedure skills were not discovered on review of published literature. Our objective was to create a sustainable, simulation-based faculty education curriculum for rare procedural skills in EM. Between 2012 and 2019, most EM teaching faculty at a single, urban, Level 1 trauma center completed an annual two-hour simulation-based rare procedure lab with small-group learning and guided hands-on instruction, covering 30 different procedural education sessions for faculty learners. A questionnaire administered before and after each session assessed EM faculty physicians’ self-perceived ability to perform these rare procedures. Participants’ self-reported confidence in their performance improved for all procedures, regardless of prior procedural experience. Faculty participation was initially mandatory, but is now voluntary. Diverse strategies were used to address barriers in this learner group including eliciting learner feedback, offering continuing medical education credits, gradual roll-out of checklist assessments, and welcoming expertise of faculty leaders from EM and other specialties and professions. Participants perceived training to be most helpful for the most rarely-encountered clinical procedures. Similar curricula could be implemented with minimal risk at other institutions.

Abstract Background Multiple guidelines seek to alter rates of prostate-specific antigen (PSA)-based prostate cancer screening. The costs borne by payers associated with PSA-based screening for men of different age groups—including the costs of screening and subsequent diagnosis, treatment, and adverse events—remain uncertain. We sought to develop a model of PSA costs that could be used by payers and health care systems to inform cost considerations under a range of different scenarios. Methods We determined the prevalence of PSA screening among men aged 50 and higher using 2013-2014 data from a large, multispecialty group, obtained reimbursed costs associated with screening, diagnosis, and treatment from a commercial health plan, and identified transition probabilities for biopsy, diagnosis, treatment, and complications from the literature to generate a cost model. We estimated annual total costs for groups of men ages 50-54, 55-69, and 70+ years, and varied annual prostate cancer screening prevalence in each group from 5 to 50% and tested hypothetical examples of different test characteristics (e.g., true/false positive rate). Results Under the baseline screening patterns, costs of the PSA screening represented 10.1% of the total costs; costs of biopsies and associated complications were 23.3% of total costs; and, although only 0.3% of all screen eligible patients were treated, they accounted for 66.7% of total costs. For each 5-percentage point decrease in PSA screening among men aged 70 and older for a single calendar year, total costs associated with prostate cancer screening decreased by 13.8%. For each 5-percentage point decrease in PSA screening among men 50-54 and 55-69 years old, costs were 2.3% and 7.3% lower respectively. Conclusions With constrained financial resources and with national pressure to decrease use of clinically unnecessary PSA-based prostate cancer screening, there is an opportunity for cost savings, especially by focusing on the downstream costs disproportionately associated with screening men 70 and older.

Patients with diabetic nephropathy suffer from impaired albumin reabsorption by proximal tubular epithelial cells. Here authors use diabetic and transgenic mouse models and in vitro models to show the cause for this lies in the down regulation and internalization of the ion channels, ORAI1-3.