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Objective: To support long COVID research in National COVID Cohort Collaborative (N3C), the N3C Phenotype and Data Acquisition team created data designs to aid contributing sites in enhancing their data. Enhancements include long COVID specialty clinic indicator; Admission, Discharge, and Transfer transactions; patient-level social determinants of health; and in-hospital use of oxygen supplementation., Materials and Methods: For each enhancement, we defined the scope and wrote guidance on how to prepare and populate the data in a standardized way., Results: As of June 2024, 29 sites have added at least one data enhancement to their N3C pipeline., Discussion: The use of common data models is critical to the success of N3C; however, these data models cannot account for all needs. Project-driven data enhancement is required. This should be done in a standardized way in alignment with common data model specifications. Our approach offers a useful pathway for enhancing data to improve fit for purpose., Conclusion: In this initiative, we rapidly produced project-specific data modeling guidance and documentation in support of long COVID research while maintaining a commitment to terminology standards and harmonized data., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objectives: To understand the early stages if Alport nephropathy, we characterize the structural, functional, and biophysical properties of glomerular capillaries and podocytes in Col4α3 -/- mice, analyze kidney cortex transcriptional profiles at three time points, and investigate the effects of the ER stress mitigation by TUDCA on these parameters. We use human FSGS associated genes to identify molecular pathways rescued by TUDCA., Findings: We define a disease progression timeline in Col4α3 -/- mice. Podocyte injury is evident by 3 months, with glomeruli reaching maximum deformability at 4 months, associated with 40% podocytes loss, followed by progressive capillary stiffening, increasing proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis from months 4 to 7. RNA sequencing at 2, 4, and 7 months reveals increased cytokine and chemokine signaling, matrix and cell injury, and activation of the TNF pathway genes by 7 months, similar to NEPTUNE FSGS cohorts. These features are suppressed by TUDCA., Conclusions: We define two phases of Col4α3 -/- nephropathy. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. Disease suppression by TUDCA treatment identifies potential therapeutic targets for treating Alport and related nephropathies.

Background: A wealth of clinically relevant information is only obtainable within unstructured clinical narratives, leading to great interest in clinical natural language processing (NLP). While a multitude of approaches to NLP exist, current algorithm development approaches have limitations that can slow the development process. These limitations are exacerbated when the task is emergent, as is the case currently for NLP extraction of signs and symptoms of COVID-19 and postacute sequelae of SARS-CoV-2 infection (PASC)., Objective: This study aims to highlight the current limitations of existing NLP algorithm development approaches that are exacerbated by NLP tasks surrounding emergent clinical concepts and to illustrate our approach to addressing these issues through the use case of developing an NLP system for the signs and symptoms of COVID-19 and PASC., Methods: We used 2 preexisting studies on PASC as a baseline to determine a set of concepts that should be extracted by NLP. This concept list was then used in conjunction with the Unified Medical Language System to autonomously generate an expanded lexicon to weakly annotate a training set, which was then reviewed by a human expert to generate a fine-tuned NLP algorithm. The annotations from a fully human-annotated test set were then compared with NLP results from the fine-tuned algorithm. The NLP algorithm was then deployed to 10 additional sites that were also running our NLP infrastructure. Of these 10 sites, 5 were used to conduct a federated evaluation of the NLP algorithm., Results: An NLP algorithm consisting of 12,234 unique normalized text strings corresponding to 2366 unique concepts was developed to extract COVID-19 or PASC signs and symptoms. An unweighted mean dictionary coverage of 77.8% was found for the 5 sites., Conclusions: The evolutionary and time-critical nature of the PASC NLP task significantly complicates existing approaches to NLP algorithm development. In this work, we present a hybrid approach using the Open Health Natural Language Processing Toolkit aimed at addressing these needs with a dictionary-based weak labeling step that minimizes the need for additional expert annotation while still preserving the fine-tuning capabilities of expert involvement., (©Andrew Wen, Liwei Wang, Huan He, Sunyang Fu, Sijia Liu, David A Hanauer, Daniel R Harris, Ramakanth Kavuluru, Rui Zhang, Karthik Natarajan, Nishanth P Pavinkurve, Janos Hajagos, Sritha Rajupet, Veena Lingam, Mary Saltz, Corey Elowsky, Richard A Moffitt, Farrukh M Koraishy, Matvey B Palchuk, Jordan Donovan, Lora Lingrey, Garo Stone-DerHagopian, Robert T Miller, Andrew E Williams, Peter J Leese, Paul I Kovach, Emily R Pfaff, Mikhail Zemmel, Robert D Pates, Nick Guthe, Melissa A Haendel, Christopher G Chute, Hongfang Liu, National COVID Cohort Collaborative, The RECOVER Initiative. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 09.09.2024.)

Objective: Chronic kidney disease (CKD) and end-stage renal disease are traditionally associated with worse outcomes after endovascular aortic repair (EVAR) and open aneurysm repair (OAR) of abdominal aortic aneurysms (AAAs). However, there needs to be more data on complex AAA repair involving the aorta's visceral segment. This study stratifies complex AAA repair outcomes by CKD severity and dialysis dependence., Methods: All patients undergoing elective OAR and fenestrated/branched EVAR (F-BEVAR) for complex AAA with preoperative renal function data captured by the Vascular Quality Initiative between January 2003 and September 2020 were analyzed. Patients were stratified by CKD class as follows: normal/mild (CKD 1 and 2), moderate (CKD class 3a), moderate to severe (CKD 3b), severe (CKD class 4 and 5), and dialysis. Only patients with clamp sites above one of the renal arteries were included for complex OAR. For F-BEVAR, patients with proximal landing zones below zone 5 (above celiac artery) were included, and distal landing zones between zones 1 and 5 were excluded. Primary outcomes were perioperative and 1-year mortality. Predictors of mortality were identified by Cox multivariate regression models., Results: We identified 7849 elective complex AAA repairs: 4230 (54%) complex OARs and 3619 (46%) F-BEVARs. Most patients were White (89%) and male (74%), with an average age of 72 ± 8 years. The patients who underwent F-BEVAR were older and had more comorbidities. Elective F-BEVAR for complex AAA started in 2012 and increased from 1.4% in 2012 to 58% in 2020 (P < .001). The OAR cohort had more perioperative complications, but less 1-year mortality. The normal/mild CKD cohort had the highest 1-year survival compared with other groups after both complex OAR and F-BEVAR. On Cox regression analysis, when compared with CKD 1-2, worsening CKD stage (CKD 3b: hazard ratio [HR], 2.5; 95% confidence interval [CI], 1.82-3.40; P < .001; CKD 4-5: HR, 1.9; 95% CI, 1.16-3.26; P = .011; and dialysis: HR, 4.4; 95% CI, 2.53-7.72; P < .001) were independently associated with 1-year survival after F-BEVAR. After complex OAR, worsening CKD stage but not dialysis was associated with 1-year mortality compared with CKD 1-2 (CKD 3b: HR, 1.6; 95% CI, 1.13-2.35; P = .009; CKD 4-5: HR, 3.4; 95% CI, 2.03-5.79; P < .001)., Conclusions: CKD severity is an essential predictor of perioperative and 1-year mortality after complex AAA repair, irrespective of the treatment modality, which may reflect the natural history of CKD. Consideration should be given to raising the threshold for elective AAA repair in patients with moderate to severe CKD and end-stage renal disease, given the high 1-year mortality rate., Competing Interests: Disclosures C.H.T. has been a consultant for and received research support from Cook Medical Inc., W. L. Gore & Associates, Inc., and Phillips Healthcare. M.L.K. has been a consultant for W. L. Gore & Associates, Inc. This article's other editors and reviewers have no relevant financial relationships to disclose per the JVS policy., (Copyright © 2023 Society for Vascular Surgery. All rights reserved.)

Background: Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking., Methods: In this open-label, cluster-randomized trial, we assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive an intervention that used a personalized algorithm (based on the patient's electronic health record [EHR]) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year. Secondary outcomes included emergency department visits, readmissions, cardiovascular events, dialysis, and death., Results: We assigned 71 practices (enrolling 5690 patients) to the intervention group and 70 practices (enrolling 5492 patients) to the usual-care group. The hospitalization rate at 1 year was 20.7% (95% confidence interval [CI], 19.7 to 21.8) in the intervention group and 21.1% (95% CI, 20.1 to 22.2) in the usual-care group (between-group difference, 0.4 percentage points; P = 0.58). The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death from any cause were similar in the two groups. The risk of adverse events was also similar in the trial groups, except for acute kidney injury, which was observed in more patients in the intervention group (12.7% vs. 11.3%)., Conclusions: In this pragmatic trial involving patients with the triad of chronic kidney disease, type 2 diabetes, and hypertension, the use of an EHR-based algorithm and practice facilitators embedded in primary care clinics did not translate into reduced hospitalization at 1 year. (Funded by the National Institutes of Health and others; ICD-Pieces ClinicalTrials.gov number, NCT02587936.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: Determine the incidence of vestibular disorders in patients with SARS-CoV-2 compared to the control population., Study Design: Retrospective., Setting: Clinical data in the National COVID Cohort Collaborative database (N3C)., Methods: Deidentified patient data from the National COVID Cohort Collaborative database (N3C) were queried based on variant peak prevalence (untyped, alpha, delta, omicron 21K, and omicron 23A) from covariants.org to retrospectively analyze the incidence of vestibular disorders in patients with SARS-CoV-2 compared to control population, consisting of patients without documented evidence of COVID infection during the same period., Results: Patients testing positive for COVID-19 were significantly more likely to have a vestibular disorder compared to the control population. Compared to control patients, the odds ratio of vestibular disorders was significantly elevated in patients with untyped (odds ratio [OR], 2.39; confidence intervals [CI], 2.29-2.50; P < 0.001), alpha (OR, 3.63; CI, 3.48-3.78; P < 0.001), delta (OR, 3.03; CI, 2.94-3.12; P < 0.001), omicron 21K variant (OR, 2.97; CI, 2.90-3.04; P < 0.001), and omicron 23A variant (OR, 8.80; CI, 8.35-9.27; P < 0.001)., Conclusions: The incidence of vestibular disorders differed between COVID-19 variants and was significantly elevated in COVID-19-positive patients compared to the control population. These findings have implications for patient counseling and further research is needed to discern the long-term effects of these findings., Competing Interests: None declared., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

This study aimed to validate the Simple View of Reading (SVR) in L2 English readers with alphabetic and morphosyllabic L1 writing system backgrounds. Forty-five L2 English learners enrolled in American university bridge programs completed a set of tasks that measured real word decoding efficiency, pseudoword decoding efficiency, linguistic (listening) comprehension, passage reading comprehension, and word meaning inferencing. There were two major findings: (1) only pseudoword decoding efficiency predicted passage reading comprehension in learners with a morphosyllabic L1, whereas both pseudoword decoding efficiency and linguistic comprehension were significant predictors in learners with an alphabetic L1; (2) pseudoword decoding efficiency was a significant predictor of word meaning inferencing in learners with a morphosyllabic L1, and moderated the effect of real word decoding efficiency on word meaning inference in learners with an alphabetic L1. The findings indicate the complex relationships among word decoding, linguistic comprehension, and passage reading comprehension in adult L2 English learners., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Risk assessment of hepatobiliary toxicities represents one of the greatest challenges and, more often than not, one of the most rewarding activities in which toxicologic pathologists can partake, and often times lead. This is in part because each liver toxicity picture is a bit different, informed by a broad range and diversity of relevant data, and also in part because the heavily relied upon animal models are imperfect regarding predictivity of hepatic effects in humans. Following identification and characterization of a hepatotoxicity hazard, typically in nonclinical toxicology studies, a holistic and integrated assessment of liver-relevant endpoints is conducted that typically incorporates ADME (absorption, distribution, metabolism, and excretion) information (ideally, including extensive transporter data, exposure margins, and possibly concentration of parent/metabolite at region of injury), target expression/function, in silico prediction data, in vitro hepatocyte data, liver/circulating biomarkers, and importantly, species specificity of any of these data. Of course, a thorough understanding, developed in close partnership with clinical colleagues, of the anticipated liver disease status of intended patient populations is paramount to hepatic risk assessment. This is particularly important since the likelihood of translatable determinant hepatic events observed in nonclinical models to occur in humans has been reasonably well established., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale & Objective: Limited data exist on patient perspectives of the implications of kidney biopsies. We explored patients' perspectives alongside those of clinicians to better understand how kidney biopsies affect patients' viewpoints and the clinical utility of biopsies., Study Design: Prospective Cohort Study., Setting & Participants: Patient participants and clinicians in the Kidney Precision Medicine Project, a prospective cohort study of patients who undergo a research protocol biopsy, at 9 recruitment sites across the United States. Surveys were completed at enrollment before biopsy and additional timepoints after biopsy (participants: 28 days, 6 months; clinicians: 2 weeks)., Analytical Approach: Kappa statistics assessed prebiopsy etiology concordance between clinicians and participants. Participant perspectives after biopsy were analyzed using a thematic approach. Clinician ratings of clinical management value were compared to prebiopsy ratings with Wilcoxon matched-pairs signed-rank tests and paired t tests., Results: A total of 167 participants undergoing biopsy (124 participants with chronic kidney disease [CKD], 43 participants with acute kidney injury [AKI]) and 58 clinicians were included in this study. CKD participants and clinicians had low etiology concordance for the 2 leading causes of CKD: diabetes (k = 0.358) and hypertension (k = 0.081). At 28 days postbiopsy, 46 (84%) participants reported that the biopsy affected their understanding of their diagnosis, and 21 (38%) participants reported that the results of the biopsy affected their medications. Participants also shared biopsy impressions in free-text responses, including impacts on lifestyle and concurrent condition management. The biopsy positively shifted clinician perceptions of the procedure's clinical management benefits, while perceptions of prognostic value decreased and diagnostic ratings remained unchanged., Limitations: Our study did not have demographic data of clinicians and could not provide insight into postbiopsy experiences for participants who did not respond to follow-up surveys., Conclusions: Participant perspectives of the personal implications of kidney biopsy can be integrated into shared decision-making between clinicians and patients. Enhanced biopsy reports and interactions between nephrologists and pathologists could augment the management and prognostic value of kidney biopsies., Plain-Language Summary: The utility of kidney biopsy is debated among clinicians, and patients' perspectives are even less explored. To address these gaps, we synthesized perspectives from clinicians and patient participants of the Kidney Precision Medicine Project (KPMP). Both before and after biopsy, clinicians were surveyed on how the procedure affected their clinical management, diagnosis, and prognosis. After biopsy, participants shared how the procedure affected their diagnosis, medication, and lifestyle changes. Clinicians and patients shared an appreciation for the biopsy's impact on medical management but diverged in their takeaways on diagnosis and prognosis. These findings highlight the need for greater collaboration between patients and clinicians, particularly as they navigate shared decision-making when considering kidney biopsy., (© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Objective: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions Trial found no benefit of renal artery stenting (RAS) over medical therapy, although it was underpowered to detect a benefit among patients with chronic kidney disease (CKD). A post hoc analysis demonstrated improved event-free survival after RAS for patients whose renal function improved by 20% or more. A significant obstacle to achieving this benefit is the inability to predict which patients' renal function will improve from RAS. The objectives of the current study were to identify predictors of renal function response to RAS., Methods: The Veteran Affairs Corporate Data Warehouse was queried for patients who underwent RAS between 2000 and 2021. The primary outcome was improvement in renal function (estimated glomerular filtration rate [eGFR]) after stenting. Patients were categorized as responders if the eGFR at 30 days or greater after stenting increased by 20% or more compared with before stenting. All others were nonresponders., Results: The study cohort included 695 patients with a median follow-up of 7.1 years (interquartile range, 3.7-11.6 years). Based on postoperative change in eGFR, 202 stented patients (29.1%) were responders, and the remainder (n = 493 [70.9%]) were nonresponders. Before RAS, responders had a significantly higher mean serum creatinine, lower mean eGFR, and higher rate of decline of preoperative GFR in the months before stenting. After stenting, responders had a 26.1% increase in eGFR, compared with before stenting (P < .0001), which remained stable during follow-up. In contrast, nonresponders had a progressive 5.5% decrease in eGFR after stenting. Logistic regression analysis identified three predictors of renal function response to stenting: (1) diabetes (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.44-0.91; P = .013), (2) CKD stages 3b or 4 (OR, 1.80; 95% CI, 1.26-2.57; P = .001), and (3) rate of decline in preoperative eGFR per week before stenting (OR, 1.21; 95% CI, 1.05-1.39; P = .008). CKD stages 3b and 4 and the rate of decline in preoperative eGFR are positive predictors of renal function response to stenting, whereas diabetes is a negative predictor., Conclusions: Based on our data, patients in CKD stages 3b and 4 (eGFR 15-44 mL/min/1.73 m 2 ) are the only subgroups with a significant probability of improved renal function after RAS. The rate of decline of preoperative eGFR over the months before stenting is a powerful discriminator of patients who are most likely to benefit from RAS. Specifically, patients with a more rapid decrease in eGFR before stenting have a significantly greater probability of improved renal function with RAS. In contrast, diabetes is a negative predictor of improved renal function, so interventionalists should be circumspect about RAS in diabetic patients., (Published by Elsevier Inc.)

Objective: Chronic kidney disease (CKD) and end-stage renal disease are traditionally associated with worse outcomes after endovascular and open repair of abdominal aortic aneurysm (AAA). This study stratifies outcomes of AAA repair by approach, CKD severity, and dialysis dependence., Methods: All patients undergoing elective infrarenal open aneurysm repair (OAR) and endovascular aortic repair (EVAR) with preoperative renal function data captured by the Vascular Quality Initiative between January 2003 and September 2020 were analyzed. Patients were stratified by CKD class as follows: CKD stages 1 and 2, CKD stage 3a, CKD stage 3b, CKD stages 4 and 5, and dialysis. Primary outcomes were perioperative and 1-year mortality. Predictors of survival were identified by Cox multivariate regression models., Results: In total, 53,867 elective AAA repairs were identified: 5396 (10%) OARs and 48,471 (90%) EVARs. Most patients were White (90%) and male (81%), with a mean age of 73 ± 9 years. Patients who underwent EVAR were older and had more comorbidities. The use of elective EVAR for AAA increased from 52% in 2003 to 91% in 2020 (P < .001). The OAR cohort had more perioperative complications and short-term mortality. The CKD 1 and 2 group had the highest 1-year survival compared with the other groups after both OAR and EVAR. On Cox regression analysis, after EVAR, compared with CKD 1 and 2, worsening CKD stage (CKD 3a: hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.93-1.68; P = .13; CKD 3b: HR, 1.74; 95% CI, 1.23-2.45; P < .050; CKD 4-5: HR, 3.23; 95% CI, 2.13-4.88; P < .001), and dialysis (HR, 4.48; 95% CI, 1.90-10.6; P < .001) were independently associated with worse 1-year survival rates. After OAR, compared with CKD 1 and 2, worsening CKD stage (CKD 3a: HR, 1.08; 95% CI, 0.96-1.20; P = .20; CKD 3b: HR, 1.60; 95% CI, 1.41-1.81; P < .001; CKD 4-5: HR, 2.85; 95% CI, 2.39-3.41; P < .001), and dialysis (HR, 3.79; 95% CI, 3.01-4.76; P < .001) were independently associated with worse 1-year survival rates., Conclusions: Regardless of the treatment approach, CKD severity is an important predictor of perioperative and 1-year mortality rates after infrarenal AAA repair and may reflect the natural history of CKD. Open repair is associated with high perioperative mortality risk in patients with CKD stages 4 and 5, as well as end-stage renal disease. Individualization of patient decision-making is especially important in patients with a glomerular filtration rate of less than 45 and perhaps consideration should be given to raising the threshold for elective AAA repair in these patients. Further studies focusing on appropriate size threshold for repair in these patients may be warranted., (Published by Elsevier Inc.)

Background: The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multiorgan failure phenotype in Klotho-hypomorphic mice ( kl/kl mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown., Methods: We measured sKlotho in WT and tubule-specific CaSR -/- (TS-CaSR -/- ) mice treated with calcimimetics, alkali, or acid, and Klotho shed from minced mouse kidneys, and from HEK-293 cells expressing the CaSR and Klotho, in response to calcimimetics, calcilytics, alkalotic and acidic pH, and ADAM protease inhibitors. The CaSR, Klotho, and ADAM10 were imaged in mouse kidneys and cell expression systems using confocal microscopy., Results: The CaSR, Klotho, and ADAM10 colocalize on the basolateral membrane of the DCT. Calcimimetics and HCO 3 increase serum sKlotho levels in WT but not in CaSR -/- mice, and acidic pH suppresses sKlotho levels in WT mice. In minced kidneys and cultured cells, CaSR activation with high Ca, calcimimetics, or alkali increase shed Klotho levels via ADAM10, as demonstrated using the ADAM10 inhibitor GI254023X and siRNA. In cultured cells, the CaSR, Klotho, and ADAM10 form cell surface aggregates that disperse after CaSR activation., Conclusions: We identify a novel physiologic mechanism for regulation of sKlotho levels by the renal CaSR-ADAM10-Klotho pathway. We show that CaSR activators, including alkali, increase renal CaSR-stimulated Klotho shedding and predict that this mechanism is relevant to the effects of acidosis and alkali therapy on CKD progression., (Copyright © 2021 by the American Society of Nephrology.)

The Kidney Precision Medicine Project (KPMP) is a multisite study designed to improve understanding of CKD attributed to diabetes or hypertension and AKI by performing protocol-driven kidney biopsies. Study participants and their kidney tissue samples undergo state-of-the-art deep phenotyping using advanced molecular, imaging, and data analytical methods. Few patients participate in research design or concepts for discovery science. A major goal of the KPMP is to include patients as equal partners to inform the research for clinically relevant benefit. The purpose of this report is to describe patient and community engagement and the value they bring to the KPMP. Patients with CKD and AKI and clinicians from the study sites are members of the Community Engagement Committee, with representation on other KPMP committees. They participate in KPMP deliberations to address scientific, clinical, logistic, analytic, ethical, and community engagement issues. The Community Engagement Committee guides KPMP research priorities from perspectives of patients and clinicians. Patients led development of essential study components, including the informed consent process, no-fault harm insurance coverage, the ethics statement, return of results plan, a "Patient Primer" for scientists and the public, and Community Advisory Boards. As members across other KPMP committees, the Community Engagement Committee assures that the science is developed and conducted in a manner relevant to study participants and the clinical community. Patients have guided the KPMP to produce research aligned with their priorities. The Community Engagement Committee partnership has set new benchmarks for patient leadership in precision medicine research., (Copyright © 2021 by the American Society of Nephrology.)

Objective: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers., Materials and Methods: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics., Results: Organized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access., Conclusions: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Cytoskeletal structure and its regulation are essential for maintenance of the differentiated state of specific types of cells and their adaptation to physiologic and pathophysiologic conditions. Renal glomerular capillaries, composed of podocytes, endothelial cells, and the glomerular basement membrane, have distinct structural and biophysical properties and are the site of injury in many glomerular diseases. Calcineurin inhibitors, immunosuppressant drugs used for organ transplantation and auto-immune diseases, can protect podocytes and glomerular capillaries from injury by preserving podocyte cytoskeletal structure. These drugs cause complications including hypertension and hyperkalemia which are mediated by WNK (With No Lysine) kinases as well as vasculopathy with glomerulopathy. WNK kinases and their target kinases oxidative stress-responsive kinase 1 (OSR1) and SPS1-related proline/alanine-rich kinase (SPAK) have fundamental roles in angiogenesis and are activated by calcineurin inhibitors, but the actions of these agents on kidney vasculature, and glomerular capillaries are not fully understood. We investigated WNK1 expression in cultured podocytes and isolated mouse glomerular capillaries to determine if WNK1 contributes to calcineurin inhibitor-induced preservation of podocyte and glomerular structure. WNK1 and OSR1/SPAK are expressed in podocytes, and in a pattern similar to podocyte synaptopodin in glomerular capillaries. Calcineurin inhibitors increased active OSR1/SPAK in glomerular capillaries, the Young's modulus (E) of glomeruli, and the F/G actin ratio, effects all blocked by WNK inhibition. In glomeruli, WNK inhibition caused reduced and irregular synaptopodin-staining, abnormal capillary and foot process structures, and increased deformability. In cultured podocytes, FK506 activated OSR1/SPAK, increased lamellipodia, accelerated cell migration, and promoted traction force. These actions of FK506 were reduced by depletion of WNK1. Collectively, these results demonstrate the importance of WNK1 in regulation of the podocyte actin cytoskeleton, biophysical properties of glomerular capillaries, and slit diaphragm structure, all of which are essential to normal kidney function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Yoon, Wichaidit, Jaykumar, Dbouk, Embry, Liu, Henderson, Chang, Cobb and Miller.)

Due to multiple compensating mechanisms, the serum bicarbonate concentration is a relatively insensitive marker of acid-base status; especially in chronic kidney disease (CKD). This is a major drawback that impairs the ability to diagnose acid excess or monitor alkali therapy. We postulated that it is more logical to measure the compensatory defense mechanism(s) rather than the defended parameter, which remains normal if the compensation is successful. Therefore, a retrospective cross-sectional study was performed in 1733 stone formers along with a prospective cross-sectional study of 22 individuals with normal kidney function and 50 patients in different stages of CKD. While serum bicarbonate was flat and did not fall below the reference range until near CKD stage 5, citrate excretion (24-hour urinary citrate excretion rate; urinary citrate-to-creatinine ratio, in the retrospective analysis, and spot urinary citrate-to-creatinine ratio in the prospective study) progressively and significantly declined starting from CKD stage 2. Following an acute acid load in 25 participants with a wide range of estimated glomerular filtration rates, the urinary citrate-to-creatinine ratio inversely and significantly associated with acid accumulation, whereas serum bicarbonate did not. We compared changes in serum bicarbonate and urinary citrate-to-creatinine ratio in response to alkali therapy in patients with CKD stage 3 or 4 started on potassium citrate in our kidney stone database. With alkali therapy, there was no change in serum bicarbonate, but the urinary citrate-to-creatinine ratio rose consistently in all patients adherent to potassium citrate therapy. Thus, the urinary citrate-to-creatinine ratio (the defense mechanism) is a potential easily implementable, pragmatic, and a superior parameter to serum bicarbonate (the defended entity) to assess acid-base status, and monitor alkali therapy. Additional studies are needed before a clinical test can be devised., (Copyright © 2020 International Society of Nephrology. All rights reserved.)

Objective: The purpose of this study is to review CDK 4/6 inhibitors used to treat metastatic breast cancer for patient safety, cost and utilization. By evaluating patient outcomes and payer influence, this study will provide critical information to aid prescribers in therapeutic decisions., Methods: This retrospective cohort study included patients from a national specialty pharmacy with a diagnosis of breast cancer and received either palbociclib, abemaciclib, or ribociclib for treatment. Patients were stratified into four subgroups based on their total oncolytic regimen at the time of their first eligible study medication dispense. Pharmacy claims data were reviewed to determine cost and therapy adherence., Results: The mean proportion of days covered was highest in patients on combination therapy with a hormone agent, 81.0%. While secondary insurances largely affected final patient out-of-pocket costs, final copays were significantly lower than the average wholesale price (AWP) of each CDK 4/6 inhibitor. When analyzing patient reported side effects, over 60% of the study population did not experience an adverse drug event (ADE) during the study time period. Ribociclib had the fewest number of reported side effects with abemaciclib patients reporting the most. Although reported ADE profiles were similar across all three study medications, difference in frequency should be evaluated when considering medication choice with specific comorbidities., Conclusion: CDK 4/6 inhibitors have demonstrated safety and tolerability in HR-positive/HER2-negative breast cancer patients. Real world safety data and out-of-pocket patient costs in addition patient specific comorbidities should be considered when developing a treatment plan that includes a CDK 4/6 inhibitor selection., (© 2020 AllianceRx Walgreens Prime. Published by Informa UK Limited, trading as Taylor & Francis Group.)

Ectopic hamartomatous thymoma is a rare neck lesion originally thought to represent a non-neoplastic hamartoma, even though thymic origin has been questioned, and there is uncertainty about whether the lesion is a neoplasm. We investigated the genetics by performing targeted next generation sequencing (NGS). Three cases were identified from the authors' consultation files. A custom, targeted NGS panel including 1385 pan-cancer-related genes was performed on all cases. Three patients included 2 males and 1 female, aged 50, 58 and 70 years, respectively (mean 59.3 years), with tumors arising in the low anterior neck. All cases showed classical histologic features of EHT, with one case showing intraductal carcinoma in association with the EHT. By targeted NGS, one case harbored a hotspot HRAS mutation (p.Gln61Lys), while the other two cases only showed non oncogenic variants. Dual mesoderm and endoderm derivation/differentiation (biphenotypic) has been previously recognized, with epithelial and myoepithelial components, and arising from the apparatus contributing to neck development (branchial apparatus). Thus, EHT has been shown to have genetic alterations in HRAS. These findings, without evidence of thymic derivation or an ectopic tissue location, strongly support that EHT is a true neoplasm. The name biphenotyic branchioma more correctly reflects the true nature of this dual mesoderm and endoderm derived tumor occurring in the lower neck.

Introduction: While numerous studies have found emergency department (ED) lactate levels to be associated with increased in-hospital mortality, little information is available on the role age plays in this association. This study investigates whether age is a necessary variable to consider when using lactate levels as a marker of prognosis and a guide for management decisions in the ED., Methods: This was a retrospective cohort study in an urban, tertiary-care teaching hospital. A total of 13,506 lactate levels were obtained over a 4.5-year period. All adult patients who had a lactate level obtained by the treating provider in the ED were screened for inclusion. The main outcome measure was in-hospital mortality using age-adjusted cohorts and expanded lactate thresholds with secondary outcomes comparing mortality based on the primary clinical impression., Results: Of the 8796 patients in this analysis, there were 474 (5.4%) deaths. Mortality rates increased with both increasing lactate levels and increasing age. For all ages, mortality rates increased from 2.8% in the less than 2.0 millimoles per liter (mmol/L) lactate level, to 5.6% in the 2.0-2.9 mmol/L lactate level, to 8.0% in the 3.0-3.9 mmol/L lactate level, to 13.9% in the 4.0-4.9 mmol/L lactate level, to 13.7% in the 5.0-5.9 mmol/L lactate level, and to 39.1% in the 6.0 mmol/L or greater lactate level (p <0.0001). Survivors, regardless of age, had a mean lactate level <2.0 whereas non-survivors had mean lactate levels of 6.5, 4.5, and 3.7 mmol/L for age cohorts 18-39, 40-64, and ≥ 65 years, respectively., Conclusion: Our findings suggest that although lactate levels can be used as a prognostic tool to risk stratify ED patients, the traditional lactate level thresholds may need to be adjusted to account for varying risk based on age and clinical impressions.

Objective: Compare rates of lactic acidosis (LA) among metformin-exposed and unexposed patients with type 2 diabetes mellitus and varying degrees of chronic kidney disease (CKD)., Research Design and Methods: Retrospective, nested case-control study using data from national VA Corporate Data Warehouse. All adult patients with type 2 diabetes and CKD newly dispensed any antihyperglycaemic medication during FY 2003-13 were included. The outcome was LA hospitalization or serum lactate >5 mEq/L. Exposure to metformin was evaluated in the three months prior to event. Estimates were adjusted for 31 covariates, including demographics, comorbidities and medications., Results: Overall, 320 882 patients were included, contributing a total of 1 331 784 person-years of follow-up. LA occurred in 2 665 patients, generating an overall incidence rate of 2.00 (95% CI 1.93-2.08) per 1000 person-years. Metformin exposure in the prior 3 months was associated with an elevated adjusted hazard of LA (HR 1.97, 95% CI 1.69-2.29). No association was evident in patients with CKD stage 1 or 2 (HR 1.05, 95% CI 0.71-1.57), but associations were present and progressively greater in patients with CKD stage 3a through 5: HR 3.09, 95% CI 2.19-4.35 in CKD 3a, HR 3.34, 95% CI 1.95-5.72 in CKD 3b, HR 7.87, 95% CI 3.51-17.61 in CKD stage 4&5., Conclusion: Metformin was not associated with an elevated risk of LA in persons with stage 1-2 CKD, but was associated with a progressively higher risk at more advanced stages of CKD., Competing Interests: All investigators report no conflicts of interest., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Purpose: A national specialty pharmacy implemented a split-fill option within an oral oncology patient management program to reduce pharmacy costs and medication wastage resulting from early discontinuations. Payers covered dispensed medications at half-quantity intervals for each dispense up to 3 months. Proactive outreach to patients before they had used up the initial dispensed medication quantity helped assess the patient's tolerance to the new medication and adverse effects. This study compared costs for patients with a split-fill option to similar costs for patients without this option taking into account patient discontinuation rates, patient-reported adverse effects rates, estimated pharmacy costs, and potential wastage., Methods: This retrospective cohort study included patients who were new to therapy on a split-fill medication between September 2015 and August 2017. A 1:1 greedy match algorithm was conducted using propensity variables to match patients from each cohort. Per-month discontinuation rates were determined for both split-fill and non-split-fill groups. The non-split-fill potential wastage was calculated as monthly costs for discontinuations in the following month and weighted by split-fill discontinuation rates., Results: Of the 2,363 program patients who met selection criteria for the 11 medications, 671 patients from each group were matched. Payers with a split-fill program had significant medication savings per covered month ($2,147.60 at 1 month) and at a cumulative 6 months. Modeled wastage indicated that payers without a split-fill program could expect to save $2,646.74 monthly by using this option. Both cohorts had similar rates of adverse effects and time until first reported adverse effect., Conclusion: In the first 6 months, the split-fill patient managed program had lower discontinuation rates, significantly reduced pharmacy costs, and reduced potential wastage.

This review focuses on technical aspects of diagnostic immunohistochemistry (IHC), with an emphasis on aspects of methodology and interpretation that may be problematic for practicing pathologists. Pitfalls in IHC are reviewed, and the importance of good controls and the the use of multi-tissue controls is discussed. Also covered is the optimal use of IHC in cytologic specimens and specimens where no paraffin block is available. Artifacts encountered in IHC are discussed and illustrated, and a number of useful techniques are described in detail, including preparation of multi-tissue control material, tissue and cell transfer techniques, and tissue protection techniques., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease which results in thickening and scarring of the interstitial tissue. As the only 2 Food and Drug Administration (FDA)-approved medications on the market, it is valuable to compare the impact of nintedanib and pirfenidone on clinical outcomes. Records of patients who started nintedanib or pirfenidone between calendar years 2015 and 2016 at a national specialty pharmacy were retrospectively reviewed. Data collection was derived from patient management applications and statistical data analysis was completed in SAS (SAS Institute Inc ® ). The nintedanib population contained 2605 patients and of the population completing clinical assessment surveys (n = 1343), 46% of respondents (n = 612) reported no adverse events, with the remaining 54% reporting at least 1 adverse event. Average proportion of days covered (PDC) was 84.2% (SD = 17.0). Average final monthly copay for this group was $235. The pirfenidone population had 1322 patients, and of the surveyed population (n = 764), 58% of respondents (n = 445) reported no adverse events, with the remaining 42% reporting at least 1 adverse event. Average PDC was 83.4% (SD = 17.3). Average final monthly copay for this group was $339. Outcomes in the studied IPF population were similar for nintedanib and pirfenidone., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background FSGS is a pattern of podocyte injury that leads to loss of glomerular function. Podocytes support other podocytes and glomerular capillary structure, oppose hemodynamic forces, form the slit diaphragm, and have mechanical properties that permit these functions. However, the biophysical characteristics of glomeruli and podocytes in disease remain unclear. Methods Using microindentation, atomic force microscopy, immunofluorescence microscopy, quantitative RT-PCR, and a three-dimensional collagen gel contraction assay, we studied the biophysical and structural properties of glomeruli and podocytes in chronic (Tg26 mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury. Results Compared with wild-type glomeruli, Tg26 glomeruli became progressively more deformable with disease progression, despite increased collagen content. Tg26 podocytes had disordered cytoskeletons, markedly abnormal focal adhesions, and weaker adhesion; they failed to respond to mechanical signals and exerted minimal traction force in three-dimensional collagen gels. Protamine treatment had similar but milder effects on glomeruli and podocytes. Conclusions Reduced structural integrity of Tg26 podocytes causes increased deformability of glomerular capillaries and limits the ability of capillaries to counter hemodynamic force, possibly leading to further podocyte injury. Loss of normal podocyte mechanical integrity could injure neighboring podocytes due to the absence of normal biophysical signals required for podocyte maintenance. The severe defects in podocyte mechanical behavior in the Tg26 model may explain why Tg26 glomeruli soften progressively, despite increased collagen deposition, and may be the basis for the rapid course of glomerular diseases associated with severe podocyte injury. In milder injury (protamine), similar processes occur but over a longer time., (Copyright © 2018 by the American Society of Nephrology.)

Background: Trauma systems currently rely on imperfect and subjective tools to prioritize responses and resources, thus there is a critical need to develop a more accurate trauma severity score. Our objective was to modify the Rapid Emergency Medicine (REMS) Score for the trauma population and test its accuracy as a predictor of in-hospital mortality when compared to other currently used scores, including the Revised Trauma Score (RTS), the Injury Severity Score (ISS), the "Mechanism, Glasgow Coma Scale, Age and Arterial Pressure" (MGAP) score, and the Shock Index (SI) score., Methods: The two-part study design involved both a modification step and a validation step. The first step incorporated a retrospective analysis of a local trauma database (3680 patients) where three components of REMS were modified to more accurately represent the trauma population. Using clinical judgment and goodness-of-fit tests, systolic blood pressure was substituted for mean arterial pressure, the weighting of age was reduced, and the weighting of Glasgow Coma Scale was increased. The second part comprised validating the new modified REMS (mREMS) score retrospectively on a U.S. National Trauma Databank (NTDB) that included 429,711 patients admitted with trauma in 2012. The discriminate power of mREMS was compared to other trauma scores using the area under the receiver operating characteristic (AUC) curve., Results: Overall the mREMS score with an AUC of 0.967 (95% CI: 0.963-0.971) was demonstrated to be higher than RTS (AUC 0.959 [95% CI: 0.955-0.964]), ISS (AUC 0.780 [95% CI 0.770-0.791]), MGAP (AUC 0.964 [95% CI: 0.959-0.968]), and SI (AUC 0.670 [95% CI: 0.650-0.690]) in predicting in-hospital mortality on the NTDB., Conclusion: In the trauma population, mREMS is an accurate predictor of in-hospital mortality, outperforming other used scores. Simple and objective, mREMS may hold value in the pre-hospital and emergency department setting in order to guide trauma team responses., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with autoantibodies against the calcium-sensing receptor (anti-CaSR) are rare and poorly understood conditions. Here, we describe a patient with acquired parathyroid hormone (PTH)-dependent hypercalcemia with associated hypocalciuria, found to have true lymphocytic parathyroiditis on histopathology, and circulating anti-CaSR antibodies in serum., Design and Methods: A 64-year-old woman was referred to our clinic for persistent hypercalcemia after a subtotal parathyroidectomy. She was normocalcemic until the age of 63 years when she was diagnosed with primary hyperparathyroidism. She underwent subtotal parathyroidectomy with appropriate intraoperative PTH decline. Two weeks post-parathyroidectomy, she presented with persistent hypercalcemia and hyperparathyroidism. Urine studies revealed an inappropriately low 24-h urine calcium (Ca)/creatinine clearance ratio. Surgical pathology was consistent with true lymphocytic parathyroiditis with lymphoid follicles. The presence of circulating anti-CaSR antibodies was detected by immunoprecipitation of CaSR by the patient's serum. After a 4-week course of prednisone, serum Ca and PTH normalized, and her anti-CaSR titers declined. She remains normocalcemic 10 months after the discontinuation of glucocorticoid therapy. We present this patient in the context of the relevant published literature on lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia related to anti-CaSR antibodies., Conclusions: Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with anti-CaSR antibodies is a very rare yet important condition to be considered in a patient with acquired PTH-dependent hypercalcemia with inappropriate hypocalciuria. Although subtotal parathyroidectomy is unlikely to correct the hypercalcemia, this entity may respond to a short course of prednisone therapy., (© 2017 European Society of Endocrinology.)

Background: The hepatitis C virus (HCV) is the most common chronic blood-borne infection and the leading cause of liver transplantation in the United States. There are approximately 3.2 million people currently infected with HCV in the United States. In late 2013, the introduction of sofosbuvir and simeprevir represented a critical advancement in the treatment of HCV by improving sustained virologic response (SVR) rates., Purpose: The purpose of this study was to evaluate medication utilization and clinical outcomes of patients with HCV who were treated with any Food and Drug Administration-approved combination of ribavirin, peginterferon products, simeprevir, and sofosbuvir., Methods: Prescription records and clinical assessment forms of patients who started HCV therapy and were eligible for SVR between January 1, 2014, and December 31, 2014, were retrospectively reviewed. Data collection included patient demographics, genotype, SVR, patient-reported adverse events, discontinuations, and adherence markers., Results: A total of 367 eligible patients were identified who had initiated treatment during the study period. Genotype 1 was the most common genotype, and an overall SVR rate of 86.9% was observed. Results were similar to those seen in phase III clinical trials. In addition, adverse events of these medications were more tolerable, and discontinuation rates were lower than with previous therapies.

The destruction and degradation of forest habitats are major threats to the sustainability of lemur populations in Madagascar. Madagascan landscapes often contain forest fragments that represent refuges for native fauna, while also being used for firewood and timber by local human populations. As undisturbed forest becomes increasingly scarce, understanding resource competition between humans and wildlife in disturbed habitats will be increasingly important. We tested the hypothesis that Malagasy and aye-ayes (Daubentonia madagascariensis) compete for the limited number of dead trees in rainforest fragments at Tsinjoarivo, Madagascar. We surveyed 2.16 ha within five fragments (range 5-228 ha) surrounding human settlements to quantify the density of dead trees and traces of both human and aye-aye activity. Neither aye-aye nor human traces were distributed according to the availability of particular trees species, and aye-ayes and Malagasy apparently preferred several different species. Although overlap was recorded in tree species used, human use tended to be positively correlated with a species' desirability as firewood, while a negative relationship was seen for aye-ayes. Both consumers used trees of similar diameter at breast height, but those used by aye-ayes tended to be older, suggesting that human use might precede usefulness for aye-ayes. Finally, the density of dead trees and aye-aye traces were highest in smaller fragments, but human traces did not vary across fragment size. Although further study is needed to better quantify the aye-aye diet in this region, these data suggest that aye-ayes and local people compete for dead trees, and this competition could constitute a pressure on aye-aye populations.

Ca2+, a ubiquitous cellular signal, and filamin A, an actin-binding protein, play an important role in the regulation of cell adhesion, shape and motility. Using transwell filters to analyze cell migration, we found that extracellular Ca2+ (Cao2+) promotes the migration of androgen receptor (AR)-deficient and highly metastatic prostate cancer cell lines (DU145 and PC-3) compared to AR-positive and relatively less metastatic prostate cancer cells (LNCaP). Furthermore, we found that expression of filamin A is up-regulated in DU145 and PC-3 cells, and that Cao2+ significantly induces the cleavage of filamin A. Silencing expression of Ca2+-sensing receptor (CaR) and p115RhoGEF, and treating with leupeptin, a protease inhibitor, and ALLM, a calpain specific inhibitor, we further demonstrate that Cao2+-induced filamin A cleavage occurs via a CaR- p115RhoGEF-calpain dependent pathway. Our data show that Cao2+ via CaR- mediated signaling induces filamin A cleavage and promotes the migration in AR-deficient and highly metastatic prostate cancer cells.

Physical properties are differentiated characteristics of tissues that are essential to their function. For example, the function of bone depends on its rigidity, and the function of skin depends on its elasticity. The aggregate physical properties of tissues are determined by a collaborative relationship between their cells and matrix and are the product of genetic programs, circulating chemical signals, physical signals, and age. The mechanical properties of matrix and basement membranes in biologic systems are difficult to understand in detail because of their complexity and technical limitations of measurements. Matrix may contain fibrillary collagens, network collagens, other fibrillar proteins such as elastin, fibronectin, and laminins, proteoglycans, and can be a reservoir for growth factors. In each tissue and in different regions of the same tissue, matrix composition can vary. The goal of measuring the mechanical properties of matrix is to understand the physical environment experienced by specific cell types to be able to control cell behavior in vivo and for tissue engineering. At this time, such precise analysis is not possible. The general elastic properties of tissues are now better characterized, and model systems using limited numbers of matrix constituents permit improved understanding of the physical behavior of matrix and its effects on cells. This review will describe model systems for understanding problems of matrix elasticity, focus on a relatively new aspect of matrix mechanics, strain-stiffening, and the interactions of cells with matrix to produce overall tissue mechanical properties., (Copyright © 2016. Published by Elsevier B.V.)

The elastic properties of renal glomeruli and their capillaries permit them to maintain structural integrity in the presence of variable hemodynamic forces. Measured by micro-indentation, glomeruli have an elastic modulus (E, Young's modulus) of 2.1 kPa, and estimates from glomerular perfusion studies suggest that the E of glomeruli is between 2 and 4 kPa. F-actin depolymerization by latrunculin, inhibition of acto-myosin contractility by blebbistatin, reduction in ATP synthesis, and reduction of the affinity of adhesion proteins by EDTA reduced the glomerular E to 1.26, 1.7, 1.5, and 1.43 kPa, respectively. Actin filament stabilization with jasplakinolide and increasing integrin affinity with Mg2+ increased E to 2.65 and 2.87 kPa, respectively. Alterations in glomerular E are reflected in commensurate changes in F/G actin ratios. Disruption of vimentin intermediate filaments by withaferin A reduced E to 0.92 kPa. The E of decellularized glomeruli was 0.74 kPa, indicating that cellular components of glomeruli have dominant effects on their elasticity. The E of glomerular basement membranes measured by magnetic bead displacement was 2.4 kPa. Podocytes and mesangial cells grown on substrates with E values between 3 and 5 kPa had actin fibers and focal adhesions resembling those of podocytes in vivo. Renal ischemia and ischemia-reperfusion reduced the E of glomeruli to 1.58 kPa. These results show that the E of glomeruli is between 2 and 4 kPa. E of the GBM, 2.4 kPa, is consistent with this value, and is supported by the behavior of podocytes and mesangial cells grown on variable stiffness matrices. The podocyte cytoskeleton contributes the major component to the overall E of glomeruli, and a normal E requires ATP synthesis. The reduction in glomerular E following ischemia and in other diseases indicates that reduced glomerular E is a common feature of many forms of glomerular injury and indicative of an abnormal podocyte cytoskeleton., Competing Interests: The authors have declared that no competing interests exist.

Objective: To describe the health conditions treated by a health services center at a Boy Scout summer camp and make recommendations for appropriate resources and supplies., Methods: We conducted a retrospective review of health center utilization at a Boy Scout camp in central Missouri during the summers of 2012 and 2013. Health logbook data were compiled and analyzed using descriptive and comparative statistics., Results: During the study period 19,771 camp participants made 1586 visits to the health care center. The overall incidence rate of health center visits was 6.20 visits per 1000 camp days. Two-thirds of visits were for illness and the remainder for injury. Over 90% of patients were returned to camp, 7.3% were transferred to another health facility, and 1.6% were advised to leave camp and return home. The most common treatments were rehydration (17.8 %) and administration of analgesics (13.4%) and topical creams (12.3%)., Conclusions: Summer camps need to be prepared for a wide range of conditions and injuries in youth campers, leaders, and staff members. Over 90% of presenting complaints were managed on site, and the majority of conditions were easily treatable minor injuries and illnesses. We provide recommendations for appropriate medical supplies and suggest opportunities for improvement to aid health centers in planning and treatment., (Copyright © 2016 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Differences in the responses of conventional and germfree male Sprague-Dawley rats to acute injury induced by alpha-naphthylisothiocyanate (ANIT), a well-characterized biliary epithelial toxicant, were evaluated. Conventional and germfree rats were dosed once orally with 50 mg/kg of ANIT or corn oil alone and serially sacrificed daily for the next 3 days. Germfree rats treated with ANIT tended to have greater increases in virtually all liver and biliary-related analytes compared with conventional rats treated with ANIT; however, significant differences were found only in a few of these analytes including increased bile acids on day 3, total bilirubin on day 4, glutamate dehydrogenase (GLDH) on day 3, and reduced paraoxonase 1 (PON1) on days 2 and 3. Histologic differences between the conventional and germfree rats were modest, but most pronounced on day 2 (24-hr post dosing). Based on subjective scoring, biliary necrosis, neutrophilic cholangitis, and portal tract edema were more severe in germfree rats at 24 hr post dosing compared with conventional rats. Biliary epithelial replication did not differ between treated groups, however. Overall, germfree rats had a modestly greater level of biliary tract injury based on subjective histologic scoring and clinical chemistry measurements following an acute exposure to the well-characterized biliary toxin, ANIT; however, the difference between the ANIT-treated germfree and conventional groups was modest and most evident only within the first day following exposure. These findings suggest that the microbiome did not significantly affect ANIT-induced acute biliary tract injury in the conditions of this study., (© The Author(s) 2016.)

Increased focus on sports concussion means you're likely to see greater numbers of children and adolescents with mild brain trauma. Here's what to keep in mind.

Background: The cycle management program (CMP) was implemented in 2008 at a national specialty pharmacy with a focus on providing specialized counseling and monitoring for patients on select oral oncology medications. The program now includes nine medications: bexarotene, dasatinib, erlotinib, everolimus, nilotinib, pazopanib, sorafenib, sunitinib, and vorinostat. Patients receive frequent assessments to encourage adherence, identify adverse events, and track discontinuations through a pharmacist outreach at the initiation of therapy, day 10 and 20 of the first month, then monthly thereafter. The use of oral agents is increasing in cancer patients, shifting away from regimens exclusively involving intravenous chemotherapy. This offers advantages for patients in terms of convenience, but introduces risk as patients become more responsible for the administration and monitoring of the medications., Purpose: To evaluate utilization patterns of the oral oncology medications in the CMP including adverse event occurrence, medication discontinuations, and adherence markers., Methods: This study is a retrospective review of patient-reported data from the CMP assessments completed in 2013. Data collected include adverse events and grades, adherence markers, and discontinuation rates. A total of 1163 assessments were reviewed from 557 patients. The assessments included in the analysis were the initial assessment, 10-day assessment, 20-day assessment, and the first monthly follow-up assessment, which encompasses the first two months of therapy., Results: A total of 1453 adverse events were reported. Adverse events were cited as the reason for 39% of discontinuations and 28% of missed/held doses. A total of 101 discontinuations were reported across the nine CMP medications based on the first two months of data. Missed or held doses were reported in 130 assessments., Conclusions: Patient engagement and pharmacist interventions, through programs such as the CMP, are important to help patients manage these complex, high-risk medications., (© The Author(s) 2014.)

Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVP-induced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C., (© The Author(s) 2016.)

To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established., (© The Author(s) 2015.)

Polypharmacy is common, and may modify mechanisms of drug-induced liver injury. We examined the effect of these drug-drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for acetaminophen, isoniazid, valproic acid, and amoxicillin/clavulanic acid. Then, we evaluated the liver event reporting frequency of these 4 drugs in the presence of co-reported medications. Each of the 4 primary drugs was reported as having more than 2000 liver events, and co-reported with more than 600 different medications. Overall, the effect of 2275 co-reported drugs (316 drug classes) on the reporting frequency was analyzed. Decreased liver event reporting frequency was associated with 245 drugs/122 drug classes, including anti-TNFα, opioids, and folic acid. Increased liver event reporting frequency was associated with 170 drugs/82 drug classes; in particular, halogenated hydrocarbons, carboxamides, and bile acid sequestrants. After adjusting for age, gender, and other co-reported drug classes, multiple co-reported drug classes were significantly associated with decreased/increased liver event reporting frequency in a drug-specific/unspecific manner. In conclusion, co-reported medications were associated with changes in the liver event reporting frequency of drugs commonly associated with hepatotoxicity, suggesting that comedications may modify drug hepatic safety., (Copyright © 2015 Elsevier Inc. All rights reserved.)