Search

Background and Aims: Endoscopic retrograde cholangiopancreatography (ERCP) carries potential for serious adverse events and there is risk for unplanned health encounters following the procedure. The primary objective of this study was to identify the rate of 30-day hospital admission following outpatient ERCP in patients at elevated risk for post-ERCP pancreatitis based on patient- and procedure-related risk factors. We also explored whether pancreatitis rates and length of hospital stay differ with delayed hospitalization (vs admission immediately after ERCP) and identified factors associated with 30-day hospital admission., Methods: High-risk patients in the SVI trial who underwent outpatient ERCP were identified. The primary outcome was hospital admission within 30 days following outpatient ERCP. Patient and procedural factors associated with 30-day hospital admission were explored by univariable analysis followed by multivariable analysis, controlling for potential known confounders., Results: Among 768 patients at high risk for post-ERCP pancreatitis who underwent outpatient ERCP and were discharged home, 21.9% required hospitalization within 30 days. Compared to patients who underwent outpatient ERCP but were admitted immediately to the hospital post-procedure, patients who were discharged after ERCP and admitted later had a higher incidence of post-ERCP pancreatitis (40.5% vs 30.9%, P=0.04), moderate-severe post-ERCP pancreatitis (24.4% vs 13.8 %, P <0.01), and longer length of hospital stay (6.2 days vs 3.7 days, P<0.001). Factors associated with 30-day hospitalization included patient age (OR 0.98, 95% CI 0.97, 0.99), biliary stent placement (OR 1.62, 95% CI 1.05, 2.48), and attempt at pancreatic duct cannulation (OR 1.64, 95% CI 1.02, 2.64)., Conclusions: High-risk patients who undergo outpatient ERCP and are discharged home are at considerable risk for hospital admission within 30 days and have increased rate of pancreatitis and longer length of hospital stay compared to outpatients admitted to the hospital immediately following ERCP, and some factors may predict this outcome. These findings should influence decision making and informed consent when electing to proceed with high-risk ERCP, recognizing that patients with sphincter of Oddi dysfunction were over-represented in this cohort, which may limit generalizability to a typical ERCP practice., (Copyright © 2025 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular autonomic neuropathy (CAN) and inflammation predict more severe outcomes in type 1 diabetes (T1D). However, the link between CAN and inflammation in T1D remains unclear. We examined associations between CAN measures and inflammatory biomarkers in individuals with T1D., Methods and Results: In a cross-sectional study, we measured cardiovascular autonomic reflex tests and heart rate variability (established CAN measures) and a panel of 39 inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), in T1D participants of the TINSAL-T1DN (Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy) trial (n=57, discovery), and the PERL (Preventing Early Renal Loss in Diabetes) trial (n=468, validation). Amongst 39 inflammatory biomarkers measured in TINSAL-T1DN, suPAR levels had the strongest negative correlations with CAN measures: expiration/inspiration ( r =-0.48), Valsalva ( r =-0.28), 30:15 ( r =-0.37), SD of the normal RR interval ( r =-0.37), and root mean square of differences of successive RR intervals ( r =-0.31) (all P <0.05). Findings were validated in PERL. In unadjusted analyses, median suPAR levels significantly differed between the lowest and highest SD of the normal RR interval tertiles (3.79 versus 3.12 ng/mL, P <0.001) and root mean square of differences of successive RR intervals (3.76 versus 3.17 ng/mL, P <0.001). After adjusting for covariates (age, sex, hemoglobin A1c, and estimated glomerular filtration rate), median suPAR values remained significantly elevated in the lowest tertiles of SD of the normal RR interval ( P =0.004) and root mean square of differences of successive RR intervals ( P =0.006)., Conclusions: Amongst several inflammatory biomarkers, suPAR, an immune-mediated glycoprotein, has a singular association with CAN measures. The potential of targeting suPAR as a disease-modifying approach for CAN in T1D warrants further exploration., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02936843, NCT02017171.

Rationale: The impact of COPD screening on US primary care clinician behavior and patient outcomes is unclear. Objectives: Assess the impact of receiving CAPTURE (COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening scores on clinical and patient outcomes. Methods: Cluster randomized trial included 49 usual care (COPD education only) and 51 intervention (COPD and CAPTURE education plus screening scores) primary care practices. Twelve-month medical record and patient survey outcome data were collected in patients with elevated screening scores or study spirometric abnormalities. Measurements and Main Results: Among 387 CAPTURE+ patients, no significant difference was noted between usual care and intervention practices in the primary composite outcome of: 1) spirometry referral/completion, 2) new COPD diagnosis, 3) newly prescribed inhaled long-acting respiratory medication, 4) referral to a respiratory specialist, or 5) pulmonary rehabilitation referral/completion, 45.9% versus 41.9% (+4.0%, 95% CI -6.9, +15.0, p=0.47). Only spirometry referral/completion was higher in the intervention group (+10.4%, 95% CI +0.1, +20.7, p = 0.0465). No differences were noted for secondary outcomes, composite components, change in COPD Assessment Test scores, rates of respiratory illnesses, or hospitalizations. For the 1,028 screen-negative (CAPTURE-) patients, composite primary and all secondary outcomes were similar in the two arms. In secondary and post hoc analyses evaluating the potential impact of the pandemic, intervention group differences in clinician and patient outcomes were noted for CAPTURE+ and CAPTURE- patients in the pre-pandemic period that diminished during the pandemic. Conclusions: Within these US primary care practices, COPD and CAPTURE education plus receipt of CAPTURE screening scores did not change clinician COPD assessment or care or patient outcomes for CAPTURE+ patients. However, in the pre-pandemic period CAPTURE+ patients were more likely to undergo spirometry referral completion while for CAPTURE- patients clinicians were significantly less likely to assess for COPD suggesting that the intervention resulted in a more appropriate use of healthcare resources.

Background: Ureteral stents are placed by urologists to ensure ureteral patency in the postoperative period following ureteroscopy to treat kidney stones, with the goal to reduce complications. However, ureteral stents themselves cause pain and urinary symptoms in many patients that can lead to morbidity. Professional society guidelines support stent omission after uncomplicated ureteroscopy, which represents most cases. Despite this, ureteral stents are utilized in more than 80% of all ureteroscopy procedures. One reason for guideline discordance is the low level of evidence supporting stent omission recommendations. Studies are inconclusive on whether stents increase pain and complications. A recent Cochrane review concluded higher quality and large trials are needed to inform decision-making. Furthermore, there is a lack of studies evaluating health-related quality of life (HRQOL), patient-reported outcomes (PROs), and unplanned healthcare utilization. Another factor is that prospective clinical trials are hindered by patient reluctance to be randomized to either stent placement or omission. The outcomes of patients who decline randomization have been ignored in trials, limiting the generalizability of the evidence., Methods: Through collaboration with patient partners, we developed a pragmatic multi-center combined randomized and observational cohort study in a quality improvement collaborative. Patients will be prospectively enrolled into a randomized cohort in which assignment to ureteral stent omission (vs. placement) is determined in the operating room using a web-based randomization platform. Patients who decline randomization are invited to take part in an observational (real-world) cohort in which the determination of stent use is at the discretion of the urologist. Patients in both cohorts will complete preoperative and postoperative assessments of PROs including pain, urinary symptoms, interference with usual activities, time taken off work or school, and treatment satisfaction. Unplanned healthcare utilization within 30 days postoperatively will be assessed by review of the electronic health record. Severe adverse events will be recorded. A subgroup of patients and urologists will also participate in qualitative semi-structured interviews focusing on knowledge, preferences, and practice patterns regarding ureteral stenting. Interview transcripts will be thematically analyzed., Discussion: This study is designed to evaluate the HRQOL and 30-day healthcare utilization of patients undergoing ureteral stent omission compared to stent placement following uncomplicated ureteroscopic treatment of upper urinary tract stones. Additionally, patient and urologist opinions and preferences related to ureteral stenting will be explored through qualitative interviews, with the aim of identifying key barriers and facilitators of practice change related to stenting practices., Trial Registration: ClinicalTrials.gov, NCT05866081. Registered on 19 May 2023., Competing Interests: Declarations. Ethics approval and consent to participate {24}: The SOUL study has received IRB approval by WCG (24 May 2023, protocol #20232054), which will serve as the central IRB for all participating performance sites. Written, informed consent to participate will be obtained from all participants. Consent for publication {32}: This manuscript does not contain individual personal data from patients. Competing interests {28}: KRG is a consultant to medical device companies in the field of stone disease: Olympus, Boston Scientific, Ambu, Coloplast. KRG has investigator funding for a clinical trial funded by Coloplast. CAD is a consultant to medical device companies in the field of stone disease: Boston Scientific, Cook Medical. The remaining authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: To explore associations between maternal characteristics and recall of obstetric provider actions in promoting antepartum tetanus-diphtheria-acellular-pertussis (Tdap) vaccination. Methods: A convenience sample of 1,682 postpartum women was surveyed in this cross-sectional study. Maternal characteristics and recall of four obstetric provider actions (recommending antepartum Tdap vaccine, offering it in clinic, providing written information, and referring patients elsewhere for vaccination) were collected. Univariate and multivariable logistic regression analyses were performed to characterize the association between maternal characteristics and each provider action. Results: Among 1,604 surveys (95% of total collected), maternal recall of an obstetric provider recommending Tdap vaccination, offering it in clinic, providing written information, or referring patients elsewhere was 68%, 59%, 53%, and 15%, respectively. Multivariable analysis revealed specific maternal characteristics that increased odds of recalling at least one obstetric provider action promoting Tdap vaccination, including receipt of first trimester prenatal care (adjusted odds ratio [aOR] 1.77, 95% confidence interval [CI] = 1.06-2.97), primiparity (aOR 1.35, 95% CI = 1.05-1.75), private health insurance (aOR 1.56, 95% CI = 1.16-2.04), higher household income (aOR ranging from 1.71 to 2.10 for ≥$150,000 for two actions), and non-White, non-Hispanic race/ethnicity (aOR ranging from 1.49 to 1.74 for Asian non-Hispanic for two actions and aOR 1.71 for Black non-Hispanic). Conclusion: Prenatal care, parity, insurance type, household income, and race/ethnicity are associated with recall of obstetric provider activities that impact antepartum Tdap vaccine promotion. Obstetric providers should recommend this potentially life-saving vaccine with each pregnancy, irrespective of differences in maternal characteristics, and policymakers should work to combat systemic factors that may cause disparities in uptake.

Background and Aims: Difficult biliary cannulation (DBC) is a known risk factor for developing post-ERCP pancreatitis (PEP). To better understand how DBC increases PEP risk, we examined the interplay between technical aspects of DBC and known PEP risk factors., Methods: This was a secondary analysis of a multicenter, randomized controlled trial comparing rectal indomethacin alone with the combination of rectal indomethacin and prophylactic pancreatic duct (PD) stent placement for PEP prophylaxis in high-risk patients. Participants were categorized into 3 groups: DBC with high preprocedure risk for PEP, DBC without high preprocedure risk for PEP, and non-DBC at high preprocedure risk for PEP., Results: In all, 1601 participants (84.1%) experienced DBC, which required a mean of 12 cannulation attempts (standard deviation, 10) and mean duration of 14.7 minutes (standard deviation, 14.9). PEP rate was highest (20.7%) in DBC with a high preprocedure risk, followed by non-DBC with a high preprocedure risk (13.5%), and then DBC without a high preprocedure risk (8.8%). Increasing number of PD wire passages (adjusted odds ratio [aOR], 1.97; 95% confidence interval [CI], 1.25-3.1) was associated with PEP in DBC, but PD injection, pancreatic sphincterotomy, and number of cannulation attempts were not associated with PEP. Combining indomethacin with PD stent placement lowered the risk of PEP (aOR, .61; 95% CI, .44-.84) in DBCs. This protective effect was evident in up to at least 4 PD wire passages., Conclusions: DBC confers higher PEP risk in an additive fashion to preprocedural risk factors. PD wire passages appear to add the greatest PEP risk in DBCs, but combining indomethacin with PD stent placement reduces this risk, even with increasing PD wire passages., Competing Interests: Disclosure Dr. Andrew Y. Wang discloses owning publicly traded stock in Pfizer and GE HealthCare Technologies. Dr. Mouen Khashab is a consultant for Boston Scientific and Olympus and he receives royalties from Elsevier and UpToDate. Dr. Andy Ross is a consultant for Boston Scientific and Olympus. Dr. Samuel Han is a consultant for Boston Scientific. Dr. Ji Young Bang is a consultant for Boston Scientific and Olympus. Dr. Shyam Varadarajulu is a consultant for Boston Scientific and Olympus. Dr. Field F. Willingham is a consultant for Boston Scientific and Cook Medical. Dr. Somashekar G. Krishna receives honoraria and grant support from Taewoong. Dr. Rajesh Keswani is a consultant for Boston Scientific. Dr. Steven A. Edmundowivcz is a consultant for Olympus and receives honoraria from Boston Scientific. Dr. Raj J. Shah is a consultant for Boston Scientific and Cook Medical. Dr. Nauzer Forbes is a consultant for Boston Scientific and Pentax. Dr. Yen-I Chen is a consultant for Boston Scientific. Dr. Alan Barkun is a Research support, consultation, Advisory board in Medtronic; Research support in Cook; Consultant, Payment or honoraria for lectures and trave in Takeda Canada Inc.; Consultant, Payment or honoraria for lectures and travel fees in Olympus Inc.; Payment or honoraria for lectures and travel fees in AstraZeneca Inc.; Advisory board in Pendopharm Canada Inc. The other authors disclosed no financial relationships. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award number: U01DK104833. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Introduction: Prophylactic pancreatic stent placement (PSP) is effective for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk cases, but the optimal technical approach to this intervention remains uncertain., Methods: In this secondary analysis of 787 clinical trial patients who underwent successful stent placement, we studied the impact of (i) whether pancreatic wire access was achieved for the sole purpose of PSP or naturally during the conduct of the case, (ii) the amount of effort expended on PSP, (iii) stent length, (iv) stent diameter, and (v) guidewire caliber. We used logistic regression models to examine the adjusted association between each technical factor and post-ERCP pancreatitis (PEP)., Results: Ninety-one of the 787 patients experienced PEP. There was no clear association between PEP and whether pancreatic wire access was achieved for the sole purpose of PSP (vs occurring naturally; odds ratio [OR] 0.82, 95% confidence interval [CI] 0.37-1.84), whether substantial effort expended on stent placement (vs nonsubstantial effort; OR 1.58, 95% CI 0.73-3.45), stent length (>5 vs ≤5 cm; OR 1.01, 95% CI 0.63-1.61), stent diameter (≥5 vs <5 Fr; OR 1.13, 95% CI 0.65-1.96), or guidewire caliber (0.035 vs 0.025 in; 0.83, 95% CI 0.49-1.41)., Discussion: The 5 modifiable technical factors studied in this secondary analysis of large-scale randomized trial data did not appear to have a strong impact on the benefit of prophylactic PSP in preventing PEP after high-risk ERCP. Within the limitations of post hoc subgroup analysis, these findings may have important implications in procedural decision making and suggest that the benefit of PSP is robust to variations in technical approach., (Copyright © 2024 by The American College of Gastroenterology.)

Introduction: Fluid overload is a source of substantial morbidity for adults and children with nephrotic syndrome (NS). Preparation and Rationale for a Fluid Overload in Nephrotic Syndrome Clinical Outcomes Assessment Set for Drug Development (Prepare-NS, 5UG3FD007308) was funded by the US Food and Drug Administration to develop a core set of patient-reported and observer-reported (for young children) outcome measures of fluid overload for use in pharmaceutical trials across the lifespan., Methods: The Prepare-NS study team developed the proposed context of use with input from stakeholders. We conducted a scoping review to assess the available literature on relevant patient- and observer-reported measures and performed secondary analyses of existing qualitative and quantitative data., Results: The outcome set will aim to serve individuals 2 years of age and older with primary NS conditions (specifically focal segmental glomerulosclerosis, minimal change disease, IgM nephropathy, membranous nephropathy, and childhood-onset NS not biopsied). The existing literature describing patient-reported outcomes in NS largely relies on nonspecific measures of health-related quality of life; fluid overload has been associated with lower scores on these measures., Conclusion: To address the gap in measure availability and fluid overload content, the Prepare-NS team has launched a set of qualitative studies for concept elicitation from the population of interest to inform development of new measures. The resulting measures subsequently will undergo psychometric evaluation and validation in a survey study., Competing Interests: Eloise Salmon, Noelle E. Carlozzi, Jin-Shei Lai, Catherine Spino, Yujie Wang, Emily Capellari, Rebecca Scherr, Kayla Sifre, Shawn Sullivan, Courtney Hurt, Tina Creguer, Kelly Helm, Richard Lafayette, Patrick H. Nachman, David T. Selewski, and John Devin Peipert report no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: There are two main schools of thought about statistical inference: frequentist and Bayesian. The frequentist approach relies solely on available data for predictions, while the Bayesian approach incorporates both data and prior knowledge about the event of interest. Bayesian methods were developed hundreds of years ago; however, they were rarely used due to computational challenges and conflicts between the two schools of thought. Recent advances in computational capabilities and a shift toward leveraging prior knowledge for inferences have led to increased use of Bayesian methods., Methods: Many biostatisticians with expertise in frequentist approaches lack the skills to apply Bayesian techniques. To address this gap, four faculty experts in Bayesian modeling at the University of Michigan developed a practical, customized workshop series. The training, tailored to accommodate the schedules of full-time staff, focused on immersive, project-based learning rather than traditional lecture-based methods. Surveys were conducted to assess the impact of the program., Results: All 20 participants completed the program and when surveyed reported an increased understanding of Bayesian theory and greater confidence in using these techniques. Capstone projects demonstrated participants' ability to apply Bayesian methodology. The workshop not only enhanced the participants' skills but also positioned them to readily apply Bayesian techniques in their work., Conclusions: Accommodating the schedules of full-time biostatistical staff enabled full participation. The immersive project-based learning approach resulted in building skills and increasing confidence among staff statisticians who were unfamiliar with Bayesian methods and their practical applications., Competing Interests: None., (© The Author(s) 2024.)

Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes., (© 2024 by the American Diabetes Association.)

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1 ) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2 ) early disease risk factors and methods to improve diagnosis, and 3 ) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Background: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention., Methods: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete., Findings: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups., Interpretation: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines., Funding: US National Institutes of Health., Competing Interests: Declaration of interests The following authors have received honoraria, consulting fees, or research support from companies that manufacture prophylactic pancreatic stents or indomethacin within the last 2 years: SAE (consulting fees from Olympus, honoraria from Boston Scientific), NF (consulting fees and payment or honoraria for lectures or receipt of equipment or materials from Boston Scientific and Pentax), FFW (consulting fees from Cook/Boston Scientific), SV (consulting fees from Boston Scientific/Olympus), JYB (consulting fees from Boston Scientific/Olympus), MK (consulting fees from Boston Scientific), RK (consulting fees from Boston Scientific), Y-IC (consulting fees, honoraria, research grants, and travel payments from Boston Scientific), AB (financial interest in Olympus), ARo (payment or honoraria for lectures or presentations and travel from Boston Scientific), and study group members SGK (honoraria and grant support from Taewoong Medical) and SG (consulting fees and honoraria from Boston Scientific). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Background: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood., Methods: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119)., Results: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not., Conclusions: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Competing Interests: Debbie Gipson received research funding through the University of Michigan from Reata, Travere, Novartis, Boehringer Ingelheim, and Goldfinch Bio and past consulting through the University of Michigan from Novartis, Vertex, and Genentech/Roche. Chia-shi Wang, Eloise Salmon, Rasheed Gbadegesin, Abhijit Naik, and Simone Sanna-Cherchi have no disclosures. Alessia Fornoni is one of the inventors on pending (PCT/US2019/032215; US 17/057,247; PCT/US2019/041730; PCT/US2013/036484; US 17/259,883; US17/259,883; JP501309/2021 and EU19834217.2; CN-201980060078.3; CA2,930,119; CA3,012,773; and CA2,852,904) or issued patents (US10,183,038 and US10,052,345) aimed at preventing and treating renal disease. She stands to gain royalties from their future commercialization. AF is vice president of L&F Health LLC and is a consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc., has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney disease from L&F Research, which was partially funded by L&F Health LLC. She also holds equities in Renal 3 River Corporation. Matthias Kretzler has received research support on behalf of the University of Michigan from Boehringer Ingelheim, Novo Nordisk, Certa, Poxel, Astellas, and Janssen, has received research funding from NIH, JDRF, Chan Zuckerburg Initiative, amfAR, AstraZeneca, Boehringer Ingelheim, Elpidera, Gilead, Goldfinch Bio, Eli Lilly, Angion Biomedica, Certa, Novo Nordisk, Janssen, Chinook, RenalytixAI, Regeneron Pharmaceuticals, Travere Therapeutics, and Ionis Pharmaceuticals, is on the editorial boards for J Am Soc Nephrology, Kidney Int, and Kidney Dis, and is on an advisory board for NephCure Kidney International. Sandra Merscher is an inventor on pending and issued patents aimed to diagnose or treat proteinuric renal diseases. She stands to gain royalties from their future commercialization. She holds equity interest in L&F Research and is a shareholder of ZyVersa Pharmaceuticals, Inc., who has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney diseases from L&F Research. Paul Hoover, Kelley Kidwell, Moin Saleem, Leonard Riella, Lawrence Holzman, Annette Jackson, and Opeyemi Olabisi have no disclosures. Paolo Cravedi is a consultant for Chinook therapeutics, Repertoire Immune Medicines, and Calliditas Therapeutics. Benjamin Freedman is an inventor on a patent and patent applications related to human kidney organoid differentiation and modeling of FSGS in this system (e.g., “three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human micro-physiology, toxicology, and morphogenesis” [Japan, USA, and Australia], licensed to STEMCELL Technologies). He has ownership interest in Plurexa LLC. Hailey Desmond received research funding through the University of Michigan from Boehringer Ingelheim, Travere, Roche, Novartis, and Reata. Howard Trachtman is a consultant to Travere Therapeutics Inc., Walden, Boehringer Ingelheim (pending), Natera, Otsuka, and Aclipse. He is the board of the Kidney Health Initiative and the editorial board of Pediatric Nephrology and Kidney360.

Background: Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes., Methods: Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed., Results: eSMM was calculated in 127 participants (5-18 y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd., Conclusion: Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

An exceptional level of control over the direction of the (2,3)-sigmatropic rearrangement between N-oxides and alkoxylamine is achieved by simply changing the solvent in which they are dissolved. Protic solvents like water, methanol and hexafluoroisopropanol favour the N-oxide form, while other solvents like acetone, acetonitrile and benzene favour the alkoxylamine. The reaction temperature and nature of the substituents on the alkene affect the rate of rearrangement. A N-oxide fragment was attached to two fluorescent molecules and acted as an on/off switch for their fluorescence. The conversion of alkoxylamines into the corresponding N-oxides has not previously been described and is here termed the 'Reverse Meisenheimer Rearrangement'., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Trimming of host glycans is a mechanism that is broadly employed by both commensal and pathogenic microflora to enable colonization. Host glycan trimming by the opportunistic Gram-positive bacterium Streptococcus pneumoniae has been demonstrated to be an important mechanism of virulence. While S. pneumoniae employs a multitude of glycan processing enzymes, the exo -mannosidase SpGH92 has been shown to be an important virulence factor. Accordingly, SpGH92 is hypothesized to be a target for much-needed new treatments of S. pneumoniae infection. Here we report the synthesis of 4-methylumbelliferyl α-d-mannopyranosyl-(1→2)-β-d-mannopyranoside (Manα1,2Manβ-4MU) as a fluorogenic disaccharide substrate and development of an assay for SpGH92 that overcomes its requirement for +1 binding site occupancy. We miniaturize our in vitro assay and apply it to a high-throughput screen of >65 000 compounds, identifying a single inhibitory chemotype, LIPS-343. We further show that Manα1,2Manβ-4MU is also a substrate of the human Golgi-localized α-mannosidase MAN1A1, suggesting that this substrate should be useful for assessing the activity of this and other mammalian α-mannosidases.

Translational research is a data-driven process that involves transforming scientific laboratory- and clinic-based discoveries into products and activities with real-world impact to improve individual and population health. Successful execution of translational research requires collaboration between clinical and translational science researchers, who have expertise in a wide variety of domains across the field of medicine, and qualitative and quantitative scientists, who have specialized methodologic expertise across diverse methodologic domains. While many institutions are working to build networks of these specialists, a formalized process is needed to help researchers navigate the network to find the best match and to track the navigation process to evaluate an institution's unmet collaborative needs. In 2018, a novel analytic resource navigation process was developed at Duke University to connect potential collaborators, leverage resources, and foster a community of researchers and scientists. This analytic resource navigation process can be readily adopted by other academic medical centers. The process relies on navigators with broad qualitative and quantitative methodologic knowledge, strong communication and leadership skills, and extensive collaborative experience. The essential elements of the analytic resource navigation process are as follows: (1) strong institutional knowledge of methodologic expertise and access to analytic resources, (2) deep understanding of research needs and methodologic expertise, (3) education of researchers on the role of qualitative and quantitative scientists in the research project, and (4) ongoing evaluation of the analytic resource navigation process to inform improvements. Navigators help researchers determine the type of expertise needed, search the institution to find potential collaborators with that expertise, and document the process to evaluate unmet needs. Although the navigation process can create a basis for an effective solution, some challenges remain, such as having resources to train navigators, comprehensively identifying all potential collaborators, and keeping updated information about resources as methodologists join and leave the institution., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)

Introduction: Millions of patients receive general anaesthesia for surgery annually. Crucial gaps in evidence exist regarding which technique, propofol total intravenous anaesthesia (TIVA) or inhaled volatile anaesthesia (INVA), yields superior patient experience, safety and outcomes. The aim of this pilot study is to assess the feasibility of conducting a large comparative effectiveness trial assessing patient experiences and outcomes after receiving propofol TIVA or INVA., Methods and Analysis: This protocol was cocreated by a diverse team, including patient partners with personal experience of TIVA or INVA. The design is a 300-patient, two-centre, randomised, feasibility pilot trial. Patients 18 years of age or older, undergoing elective non-cardiac surgery requiring general anaesthesia with a tracheal tube or laryngeal mask airway will be eligible. Patients will be randomised 1:1 to propofol TIVA or INVA, stratified by centre and procedural complexity. The feasibility endpoints include: (1) proportion of patients approached who agree to participate; (2) proportion of patients who receive their assigned randomised treatment; (3) completeness of outcomes data collection and (4) feasibility of data management procedures. Proportions and 95% CIs will be calculated to assess whether prespecified thresholds are met for the feasibility parameters. If the lower bounds of the 95% CI are above the thresholds of 10% for the proportion of patients agreeing to participate among those approached and 80% for compliance with treatment allocation for each randomised treatment group, this will suggest that our planned pragmatic 12 500-patient comparative effectiveness trial can likely be conducted successfully. Other feasibility outcomes and adverse events will be described., Ethics and Dissemination: This study is approved by the ethics board at Washington University (IRB# 202205053), serving as the single Institutional Review Board for both participating sites. Recruitment began in September 2022. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media., Trial Registration Number: NCT05346588., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Clinical trials in early diffuse SSc have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design., Methods: We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse systemic sclerosis (ASSET) trial outcome data., Results: We identified 403 patients with <18 months, and 514 with <36 months disease duration. The median number of mRSS follow-up scores was 14 (interquartile range 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up, and thereby as potential enrichment variables. When applied to the ASSET data, adjustment for both RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR Composite Response Index in Systemic Sclerosis (CRISS) score was found with adjustment by RNAP3 at 6 months, and TFR or RNAP3 at 12 months., Conclusion: Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The association of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status before delivery with breastfeeding is unknown. This study compares breastfeeding initiation, exclusivity, and duration between SARS-CoV-2-positive (+) and SARS-CoV-2-negative (-) mothers during the first 2 months of their newborns' lives., Methods: A single center, retrospective cohort study of pediatric contacts during the first 2 months in a diverse mother-infant population (n = 285) compared breastfeeding outcomes by maternal SARS-CoV-2 status during a pandemic surge. Infants of SARS-CoV-2 positive mothers were also tested before discharge. Comparison of maternal demographics (age, race, ethnicity), maternal/infant characteristics (parity, insurance, delivery mode, infant sex, hospital length of stay), and pediatric contacts by maternal SARS-CoV-2 status included Fisher's exact and Wilcoxon tests and Poisson regression for count outcomes. Logistic regression compared breastfeeding outcomes between the 2 groups, adjusting for potential confounders and effect modifiers., Results: Maternal demographics and maternal/infant characteristics were similar. While 19% of mothers tested positive for SARS-CoV-2 (n = 54), their infants were all negative. SARS-CoV-2 positive mothers had fewer in-person, but more virtual pediatric contacts. After controlling for the above variables, SARS-CoV-2 positive mothers had lower odds of breastfeeding initiation within 1 to 7 days of life (78% vs 88%; adjusted odds ratio [aOR] = 0.40, 95% confidence interval [CI]: 0.17, 0.96) and of any breastfeeding during month 2 (54% vs 76%; aOR = 0.37, 95% CI: 0.16, 0.86) compared with SARS-CoV-2 negative mothers., Conclusions: Maternal SARS-CoV-2 positivity at delivery was independently associated with less initiation and shorter duration of any breastfeeding during month 2. SARS-CoV-2 positive women would likely benefit from additional breastfeeding support during pandemic surges., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care., Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD., Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice-based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected., Exposure: Undiagnosed COPD., Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months., Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85)., Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes.

Background and Aims: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis., Approach and Results: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS., Conclusions: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD)., Methods: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871., Findings: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths., Interpretation: Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials., Funding: Genentech., Competing Interests: Declaration of interests SKD reports grants and salary support from Brigham and Women's Hospital, during the study; grants, personal fees, and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Galaplagos; personal fees from Galecto, and Lupin Pharma; grants from Bristol Meyers Squibb; salary support from the Pulmonary Fibrosis Foundation, and Royalties for Topics on systemic erythematous pneumonia- interstitial lung disease and myositis- interstitial lung disease from UpToDate, outside the submitted work. IG reports personal fees from Boehringer Ingelheim and personal fees from Ad Alta, Amplia, Accendatech, and Lassen, outside the submitted work. PFD served on an unpaid advisory committee at Boehringer Ingleheim, and reports receiving non-financial support for serving as a site-principal investigator for Bristol Myers and Genentech, outside the submitted work. RV reports grants from Bristol Myers Squibb, Pfizer, and Sun Pharma, outside the submitted work. PGC reports grants from InterMune, outside the submitted work. KRF reports grants and personal fees from Boehringer Ingelheim; personal fees from Roche/Genentech, Bellerophon, Respivant, Shionogi, DevPro, AstraZeneca, Pure Health, Horizon, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, Pure Tech, Trevi Pharmaceuticals, CSL Behring, Daewong, DevPro, Dispersol, Immumet, and NeRRe Therapeutics, outside the submitted work. LT reports personal fees from Boehringer Ingelheim outside the submitted work. MBS reports grants from Boehringer Ingelheim, Veracyte, and Genentech; financial support from Genentech, United Therapeutics, Veracyte; honoraria from Boehringer Ingelheim, United Therapeutics, and Veracyte, and meeting and travel support from Genentech and the American College of Chest Physicians. NC reports personal fees from Boehringer Ingelheim, Redex, Novartis, Liminal Biosciences, Vicor Pharma, Bridge Biotherapeutics, and Roche, outside the submitted work. DAL reports grants from Boehringer Ingelheim and grants and personal fees from Calyx, outside the submitted work; DAL has a patent issued on systems and methods for automatic detection and quantification of pathology using dynamic feature classification (US10706533B2). DCC reports that Roche/Genentech provided the investigational medicinal product free of charge during the study; and that he served as principal investigator for a trial site in a Roche sponsored study outside the submitted work, in which per patient fees were paid to the site. MK reports grants from Genentech, during the study; grants from Canadian Pulmonary Fibrosis Foundation and Canadian Institute for Health Research; an allowance as chief editor from European Respiratory Journal; grants and personal fees from Boehringer Ingelheim and Roche Canada; and personal fees from Horizon, Algernon, CSL Behring, and DevPro; and served as a site principal investigator for industry sponsored clinical trials (Roche and Boehringer Ingelheim); outside the submitted work. GR served as a consultant/steering committee member for IPF and PPF studies for Roche/Genentech and served on a data safety monitoring board for an IPF study (Avalyn), outside the submitted work. HJG reports receiving support to participate as a member of the Clinical Coordinating Center and coprincipal investigator, from Genentech, during the study. FAW is currently an employee at Avalyn. IOR reports grants from Genentech/Roche, during the conduct of the study and personal fees from Genentech/Roche, Boehringer Ingelheim, and Immunomet, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Four intrinsic molecular subsets (inflammatory, fibroproliferative, limited, normal-like) have previously been identified in SSc and are characterized by unique gene expression signatures and pathways. The intrinsic subsets have been linked to improvement with specific therapies. Here, we investigated associations between baseline demographics and intrinsic molecular subsets in a meta-analysis of published datasets., Methods: Publicly available gene expression data from skin biopsies of 311 SSc patients measured by DNA microarray were classified into the intrinsic molecular subsets. RNA-sequencing data from 84 participants from the ASSET trial were used as a validation cohort. Baseline clinical demographics and intrinsic molecular subsets were tested for statistically significant associations., Results: Males were more likely to be classified in the fibroproliferative subset (P = 0.0046). SSc patients who identified as African American/Black were 2.5 times more likely to be classified as fibroproliferative compared with White/Caucasian patients (P = 0.0378). ASSET participants sera positive for anti-RNA pol I and RNA pol III autoantibodies were enriched in the inflammatory subset (P = 5.8 × 10-5, P = 9.3 × 10-5, respectively), while anti-Scl-70 was enriched in the fibroproliferative subset. Mean modified Rodnan Skin Score (mRSS) was statistically higher in the inflammatory and fibroproliferative subsets compared with normal-like (P = 0.0027). The average disease duration for inflammatory subset was less than fibroproliferative and normal-like intrinsic subsets (P = 8.8 × 10-4)., Conclusions: We identified multiple statistically significant differences in baseline demographics between the intrinsic subsets that may represent underlying features of disease pathogenesis (e.g. chronological stages of fibrosis) and have implications for treatments that are more likely to work in certain SSc populations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Here, the efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic subset would show the most significant clinical improvement. Eighty-four participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-Seq was performed on 233 skin paired biopsies at baseline and at 3 and 6 months. Improvement was defined as a 5-point or more than 20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subsets (inflammatory, fibroproliferative, or normal-like subsets). In the abatacept arm, change in mRSS was most pronounced for the inflammatory and normal-like subsets relative to the placebo subset. Gene expression for participants on placebo remained in the original molecular subset, whereas inflammatory participants treated with abatacept had gene expression that moved toward the normal-like subset. The Costimulation of the CD28 Family Reactome Pathway decreased in patients who improved on abatacept and was specific to the inflammatory subset. Patients in the inflammatory subset had elevation of the Costimulation of the CD28 Family pathway at baseline relative to that of participants in the fibroproliferative and normal-like subsets. There was a correlation between improved ΔmRSS and baseline expression of the Costimulation of the CD28 Family pathway. This study provides an example of precision medicine in systemic sclerosis clinical trials.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial., Methods: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC., Discussion: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920., (© 2022. The Author(s).)

Introduction: Antepartum Tdap remains low despite national recommendations. This prospective observational study aims to identify factors associated with lower antepartum Tdap rates., Methods: Maternal demographics, personal health beliefs, Tdap vaccination status, and recall of in-office obstetric provider actions were collected from a convenience sample of postpartum women in a New York metropolitan hospital. Bivariate and multivariable logistic regression were used to identify significant factors and adjusted odds ratios (OR) for recorded Tdap; OR > 1 reflects elements with increased odds of not receiving antepartum Tdap, while OR < 1 demonstrates increased odds of receipt., Results: Surveys were collected (n = 1682) from a study population demographically similar to New York City and more diverse in race/ethnicity than the national population. Demographic analysis showed Hispanic women less likely than white, non-Hispanic women to vaccinate (OR 2.44, CI 1.54-3.88). Health beliefs associated with non-receipt of antepartum Tdap included "It is dangerous for pregnant women to get vaccines" (OR 1.68, CI 1.01-2.77), and "I worry about the safety of the Tdap vaccine" (OR 1.59, CI 1.12-2.24). Obstetric provider actions associated with vaccination included receiving an OB recommendation (OR 0.39, CI 0.23-0.65), getting written information about Tdap (OR 0.44, CI 0.30-0.64), and having Tdap offered in office (OR 0.24, CI 0.15-0.37). Health beliefs associated with antepartum Tdap included "I generally do what my OB/GYN provider recommends" (OR 0.49, CI 0.30-0.80), and "Pregnant women should get the Tdap (pertussis) vaccine" (OR 0.17, CI 0.09-0.33)., Discussion: Maternal race/ethnicity, personal health beliefs, and obstetric provider actions predict antepartum Tdap., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Podocytes are insulin-sensitive cells, and their loss is critical in diabetic nephropathy (DN) progression that could lead to end-stage kidney disease. We have previously shown that decreased DUSP4 expression caused elevated JNK phosphorylation in the diabetic kidney and worsened DN characteristics. Yet, the role of DUSP4 in diabetic podocyte insulin resistance and the progression of DN remains unclear. Here, we report that HG-exposed podocytes exhibited reduced DUSP4 expression, increased phosphorylation of JNK and serine 307 of IRS1 as well as Nox4 expression, while decreasing insulin signaling actions. DUSP4 overexpression, JNK and Nox1/4 inhibition prevented HG-induced serine 307 phosphorylation of IRS1 and restored insulin actions. Diabetic mice showed renal dysfunction and insulin resistance, characteristics that were exacerbated in diabetic DUSP4 deficient mice due to Nox1/4 upregulation. Thus, our results demonstrated that diabetes-induced reduction of DUSP4 leads to JNK activation and elevated Nox4 expression, which contributes to podocyte dysfunction, insulin resistance and progression of DN., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the absence of a full spectrum of evidence-based guidelines for the appropriate use of antimicrobial agents, dentists, including periodontists, remain a highly frequent antibiotic prescribing group. With the goal of understanding antibiotic prescribing practices, the authors surveyed a convenience sample of dental practitioners and periodontists to identify differences between the 2 cohorts and assess the factors that affect prescribing practices., Methods: An institutional review board-approved 15-item survey was developed to capture antibiotic prescribing practices addressing the main research question, factors affecting systemic antibiotic prescription patterns, and prescription timing. The authors collaborated with the American Dental Association (ADA) and the American Academy of Periodontology (AAP) for survey dissemination. Responses were summarized using descriptive statistics. Multivariable models were developed to identify antibiotic prescription predictors., Results: Overall, 32.4% of the participants prescribed systemic antibiotics with scaling and root planing. When comparing the 2 groups, the authors found that 46.4% and 18.7% of the AAP and ADA members, respectively, prescribed systemic antibiotics with scaling and root planing (P = .0001). The authors found a significant difference between the AAP and ADA groups in prescription timing (P = .01). The multivariable model revealed that practitioner sex (P = .03), AAP membership (P = .0001), and years of practitioner experience (P = .04) predicted antibiotic prescription practices. The geographic location, practice setting, and occupation type did not predict antibiotic prescription patterns., Conclusion: The authors found a lack of clarity related to prescription timing, factors determining prescription patterns, and selection of patient population who would benefit more from antibiotics., Practical Implications: This study confirmed a lack of clarity related to antibiotic prescription patterns in combination with nonsurgical periodontal treatment., (Copyright © 2022 American Dental Association. Published by Elsevier Inc. All rights reserved.)

The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials., Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS., Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022., Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy., Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria., Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50)., Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Apoptotic exosome-like vesicles (ApoExos) are a novel type of extracellular vesicle that contribute to the propagation of inflammation at sites of vascular injury when released by dying cells. ApoExos are characterized by the presence of the C-terminal perlecan LG3 fragment and 20S proteasome, and they are produced downstream of caspase-3 activation. In the present study, we assessed the relative roles of autophagy and caspase-3-mediated pathways in controlling the biogenesis and secretion of immunogenic ApoExos. Using electron microscopy and confocal immunofluorescence microscopy in serum-starved endothelial cells, we identified large autolysosomes resulting from the fusion of lysosomes, multivesicular bodies, and autophagosomes as a site of ApoExo biogenesis. Inhibition of autophagy with ATG7 siRNA or biochemical inhibitors (wortmannin and bafilomycin) coupled with proteomics analysis showed that autophagy regulated the processing of perlecan into LG3 and its loading onto ApoExos but was dispensable for ApoExo biogenesis. Caspase-3 activation was identified using caspase-3-deficient endothelial cells or caspase inhibitors as a pivotal regulator of fusion events between autolysosomes and the cell membrane, therefore regulating the release of immunogenic ApoExos. Collectively, these findings identified autolysosomes as a site of ApoExo biogenesis and caspase-3 as a crucial regulator of autolysosome cell membrane interactions involved in the secretion of immunogenic ApoExos., (© 2022. The Author(s).)

Rigorous scientific review of research protocols is critical to making funding decisions, and to the protection of both human and non-human research participants. Given the increasing complexity of research designs and data analysis methods, quantitative experts, such as biostatisticians, play an essential role in evaluating the rigor and reproducibility of proposed methods. However, there is a common misconception that a statistician's input is relevant only to sample size/power and statistical analysis sections of a protocol. The comprehensive nature of a biostatistical review coupled with limited guidance on key components of protocol review motived this work. Members of the Biostatistics, Epidemiology, and Research Design Special Interest Group of the Association for Clinical and Translational Science used a consensus approach to identify the elements of research protocols that a biostatistician should consider in a review, and provide specific guidance on how each element should be reviewed. We present the resulting review framework as an educational tool and guideline for biostatisticians navigating review boards and panels. We briefly describe the approach to developing the framework, and we provide a comprehensive checklist and guidance on review of each protocol element. We posit that the biostatistical reviewer, through their breadth of engagement across multiple disciplines and experience with a range of research designs, can and should contribute significantly beyond review of the statistical analysis plan and sample size justification. Through careful scientific review, we hope to prevent excess resource expenditure and risk to humans and animals on poorly planned studies., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Objective: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline., Methods: Nondemented PD participants with cholinergic deficits were identified with [ 18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4β2* nAChR occupancy after subacute oral varenicline treatment was measured with [ 18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability., Results: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements., Interpretation: Varenicline occupied α4β2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4β2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142., (© 2021 American Neurological Association.)

Objectives: To evaluate the concordance between maternal report of antepartum tetanus, diphtheria, pertussis (Tdap) vaccination and vaccination status documented in the electronic medical record (EMR), as well as factors associated with discordance., Study Design: A survey was completed by a convenience sample of postpartum patients in a New York metropolitan hospital. The survey collected patients' demographic information, health beliefs, and whether they received Tdap vaccine during this pregnancy. The patient's Tdap vaccination status was abstracted from the EMR, a combination of data gathered from the obstetrician and patient's hospital record. Kappa statistics measured the agreement between maternal report and EMR on antepartum Tdap vaccination. Univariate and multivariable logistic regression analyses were performed to identify maternal characteristics associated with discordance., Results: Of the 1571 patients with Tdap status available in the EMR, 1549 patients (92%) reported on receipt status for Tdap vaccination during pregnancy; 1328 maternal reports (86%) agreed with the EMR for Tdap status (kappa = 0.72, 95% CI 0.68-0.75). Several factors were statistically significant in multivariable analyses: lower income was associated with greater discordance (ie, overreporting; P = .02), as well as certain health beliefs including "Pregnant women should be concerned about the possibility of pertussis in their babies" (aOR 2.86, 95% CI 1.02-8.04) and "My friends would probably think getting a Tdap vaccine is a good idea" (aOR 2.36, 95% CI 1.11-4.99)., Conclusions: Maternal recall of Tdap vaccination during pregnancy is consistent with the EMR. This supports the value of maternal report in determining Tdap vaccination status, which is especially important when vaccination records are not available., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ ( K i 0.08-0.18 nM vs Ape13 K i 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Db z g; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, K i 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Db z g, K i 0.08 nM) are the most potent Ape13 analogues activating the Gα 12 pathways ( 53 , EC 50 Gα 12 2.8 nM vs Ape13, EC 50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro ( t 1/2 5.8-7.3 h in rat plasma) and in vivo .

Objectives: American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse systemic sclerosis. ACR-CRISS is a weighted score and includes five core set measures: modified Rodnan skin score, FVC% predicted, health assessment questionnaire-disability index, and patient and clinician global assessments., Methods: We analysed core set measures from 354 participants who participated in three placebo-controlled trials. We generated 10 development datasets, randomly selected from 2/3 of the participants, stratified by study and treatment group. The remaining participants (1/3 of the participants) formed the validation sets. Risk differences (RDs) between active and placebo treatments were calculated by averaging over the replicate datasets; bootstrap 95% CIs for the RDs to estimate the magnitude of treatment effects., Results: In the development sets (n=237), the proportion of participants in the active group had statistically higher improvement in >1 of 5 core set measures versus the placebo group. For example, the proportion who improved by ≥20% in ≥3 core set measures was 49.4% in the active versus338.9% in the placebo; RD: 10.5%, 95% CI4.9 % to 16.1%. In the validation sets (n=117), the proportion who improved by ≥20% in ≥3 core set measures was 50.3% in the active versus35.63% in the placebo (RD:114.8%, 95% CI 3.1% to225.7%). Similar trends were seen with larger percentage cut-offs., Conclusion: Revised CRISS, as assessed by the proportion of participants who improved by a certain percentage in ≥3 of 5 core set measures, is a potential new composite outcome measure., Competing Interests: Competing interests: DK reports grants from NIH/NIAMS, grants from Immune Tolerance Network, grants and personal fees from Bayer, grants from Bristol Myers Squibb, grants from Horizon, grants from Pfizer, personal fees from Acceleron, personal fees from Acetlion, personal fees from Amgen, personal fees from Blade Therapeutics, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Corbus, personal fees from Cytori, personal fees from Galapagos, personal fees from Genentech/Roche, personal fees from GSK, personal fees from Horizon, personal fees from Merck, personal fees from Mitsubishi Tanabe Pharma, personal fees from Regeneron, personal fees from Sanofi-Aventis, personal fees from United Therapeutics, other from Impact PH, personal fees from Eicos Sciences, and personal fees and other from CiviBioPharma/Eicos Sciences outside the submitted work. SH has nothing to report. CJFL reports other from Genentech during the conduct of the study; other from Genentech outside the submitted work and owns stock in Roche. CS reports statistical consulting from Eicos Sciences outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study sought to determine cardiopulmonary exercise (CPX) predictors of the combined outcome of durable mechanical circulatory support (MCS), transplantation, or death at 1 year among patients with ambulatory advanced heart failure (HF)., Background: Optimal CPX predictors of outcomes in contemporary ambulatory advanced HF patients are unclear., Methods: REVIVAL (Registry Evaluation of Vital Information for ventricular assist devices [VADs] in Ambulatory Life) enrolled 400 systolic HF patients, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles 4-7. CPX was performed by 273 subjects 2 ± 1 months after study enrollment. Discriminative power of maximal (peak oxygen consumption [peak VO 2 ]; VO 2 pulse, circulatory power [CP]; peak systolic blood pressure • peak VO 2 ], peak end-tidal pressure CO 2 [PEtCO 2 ], and peak Borg scale score) and submaximal CPX parameters (ventilatory efficiency [VE/VCO 2 slope]; VO 2 at anaerobic threshold [VO 2 AT]; and oxygen uptake efficiency slope [OUES]) to predict the composite outcome were assessed by univariate and multivariate Cox regression and Harrell's concordance statistic., Results: At 1 year, there were 39 events (6 transplants, 15 deaths, 18 MCS implantations). Peak VO 2 , VO 2 AT, OUES, peak PEtCO 2 , and CP were higher in the no-event group (all p < 0.001), whereas VE/VCO 2 slope was lower (p < 0.0001); respiratory exchange ratio was not different. CP (hazard ratio [HR]: 0.89; p = 0.001), VE/VCO 2 slope (HR: 1.05; p = 0.001), and peak Borg scale score (HR: 1.20; p = 0.005) were significant predictors on multivariate analysis (model C-statistic: 0.80)., Conclusions: Among patients with ambulatory advanced HF, the strongest maximal and submaximal CPX predictor of MCS implantation, transplantation, or death at 1 year were CP and VE/VCO 2, respectively. The patient-reported measure of exercise effort (Borg scale score) contributed substantially to the prediction of outcomes, a surprising and novel finding that warrants further investigation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407)., Competing Interests: Funding support and Author Disclosures Supported by U.S. National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) contract HHSN268201100026C, and National Center for Advancing Translational Sciences grant UL1TR002240. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, or the US Department of Health and Human Services. Dr. Lanfear has received research grants from NHLBI (R01HL132154), Amgen, Bayer, and Janssen; and is a consultant for Amgen, Janssen, Ortho Diagnostics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival., Study Design: Cohort analysis of clinical trial participants., Setting & Participants: Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone., Predictors: Reduction in proteinuria measured during 26 weeks after initiating treatment., Outcomes: Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization., Analytical Approach: Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome., Results: 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m 2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44)., Limitations: Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years., Conclusions: These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials., (Copyright © 2020 National Kidney Foundation, Inc. All rights reserved.)

Background: Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects., Methods: Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation., Results: SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc., Conclusion: In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.

Chronic obstructive pulmonary disease (COPD) often remains undiagnosed and untreated. To date, COPD screening/case finding has not been designed to identify clinically significant COPD , disease ready for therapies beyond smoking cessation. Herein, we describe the ongoing prospective, pragmatic cluster-randomized controlled trial to assess specificity and sensitivity of the C OPD A ssessment in P rimary Care T o Identify U ndiagnosed R espiratory Disease and E xacerbation Risk (CAPTURE) tool consisting of 5 questions and peak expiratory flow. The tool is designed to identify clinically significant COPD (forced expiratory volume in 1 second [FEV 1 ] to forced vital capacity [FVC] ratio <.70 plus FEV 1 % predicted <60% or increased risk for exacerbation) and the trial will explore the impact of CAPTURE-based screening on COPD diagnosis and treatment rates in primary care patients. Of a total planned enrollment of 5000 English- or Spanish-speaking patients 45 to 80 years of age without a prior COPD diagnosis from 100 primary care practices, a total of 68 practices and 3064 patients have been enrolled in the study. Practices are centrally randomized to either usual care or clinician receipt of patient-level CAPTURE results. All clinicians receive basic COPD education with those in intervention practices also receiving CAPTURE interpretation education. In a single visit, patient participants complete a CAPTURE screening, pre- and post-bronchodilator spirometry and baseline demographic and health questionnaires to validate CAPTURE sensitivity, specificity, and predictive value of identifying undiagnosed, clinically significant COPD. One-year follow-up chart reviews and participant surveys assess the impact of sharing versus not sharing CAPTURE results with clinicians on clinical outcomes including level of respiratory symptoms and events and clinicians' initiation of recommendation-concordant COPD care. This is one of the first U.S. studies to validate and assess impact of a simple COPD screening tool in primary care., Competing Interests: B. Yawn has served on the advisory board of and received personal fees from: GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Teva, nDD and Novartis. M. Han reports grants from the National Heart, Lung and Blood Institute, and the COPD Foundation, during the conduct of the study. She has received personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Merck and Mylan, and non-financial support from Novartis and Sunovion, outside the submitted work. B. Make reports serving on medical advisory boards for AstraZeneca, Boehringer Ingelheim, Circassia, GlaxoSmithKline, Sunovion, Theravance, Phillips, Science 24/7, Spiration, and Verona. In addition, he received research grants, controlled by National Jewish Health, from AstraZeneca, GlaxoSmithKline, Pearl, Sunovion, and the National Heart Lung and Blood Institute. He provided CME for the Academy for Continued Health Care Learning, the American College of Chest Physicians, Catamount Medical, Eastern Pulmonary Society, Eastern VA Medical Center, Hybrid Communications, Novartis, Mt. Sinai Medical Center, WebMD, Medscape, National Jewish Health, Projects in Knowledge, Ultimate Medical Academy and Wolters Kluwer Health. He has served on data safety monitoring boards for AstraZeneca, Shire, Spiration, and Takeda. D. Mannino was an employee and shareholder of GlaxoSmithKline at the time of this study. N. Leidy is employed by Evidera, a health care research firm that provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. In this salaried position, Dr. Leidy works with a variety of companies and organizations but receives no payment or honoraria directly from these organizations for services rendered, with the exception of honoraria received for her advisor role on several National Institutes of Health and Food and Drug Administration-funded programs: PATIENTS, PCAR, and NUCOAT. F. Martinez reports receiving grants from GlaxoSmithKline during the conduct of the study. He has received personal fees from AstraZeneca, Boehringer Ingelheim, the Canadian Respiratory Society, CME Outfitters, CSL Behring, Dartmouth University, the France Foundation, Gala, Genentech, GlaxoSmithKline, Inova Fairfax, MDMagazine, NYP Methodist Hospital Brooklyn, Miller Communications the National Associate for Continuing Education, Novartis, New York University, Patara/Respivant, Pearl, Peer View, Physicians Education Resource, ProMedior, Rare Diseases Healthcare Communications, Rockpointe Communications, Sanofi/Regeneron, Sunovion, Teva, University of Alabama, Birmingham, UpToDate, Vindico, and WebMD/Medscape. He has received non-financial support from AstraZeneca, Boehringer Ingelheim, the Canadian Respiratory Society, CME Outfitters, CSL Behring, Genentech, GlaxoSmithKline, Inova Fairfax, MDMagazine, NYP Methodist Hospital Brooklyn, Miller Communications, the National Association for Continuing Education, Novartis, Patara/Respivant, Peer View, Rare Diseases Healthcare Communications, Sanofi/Regeneron, Sunovion, Teva, Veracyte, WebMD/Medscape, Zambon and ProTerrixBio. He has served on advisory board for AstraZeneca, Boehringer Ingelheim, Chiesi, CSLBering, Gala, Genentech, GlaxoSmithKline, Pearl,Sanofi/Regeneron, Sunovion, Teva, and Zambon and a steering committee for Afferent/Merck. Authors Brown, Meldrum, Murray, Spino, Bronicki, Tapp, Dolor, Joo, Knox, Zittleman, and Thomashow have nothing to declare., (JCOPDF © 2021.)

Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse podocytes exposed to palmitic acid for 24 h followed by an insulin stimulation. Renal function and pathology were evaluated at 25 weeks of age to confirm the DN development. Our results demonstrate that saturated FFA activated the serine/threonine kinases IκB kinase (IKK)β/IκBα and mTORC1/S6K1, but not protein kinase C and c-jun N-terminal kinase, in podocytes and glomeruli of db/db mice. Activation of both kinases promoted serine 307 phosphorylation of IRS1, a residue known to provoke IRS1 inhibition. Using IKK, mTORC1 and ceramide production inhibitors, we were able to blunt IRS1 serine 307 phosphorylation and restore insulin stimulation of Akt. In conclusion, our results indicate that FFA and diabetes contribute to insulin resistance through the activation of IKKβ and S6K1 leading to podocyte dysfunction and DN.

Objective: Restoring quadriceps muscle strength following anterior cruciate ligament reconstruction (ACLR) may prevent the posttraumatic osteoarthritis that affects over 50% of knees with ACLR. However, a fundamental gap exists in our understanding of how to maximize muscle strength through rehabilitation. Neurological deficits and muscle atrophy are 2 of the leading mechanisms of muscle weakness after ACLR. High-intensity neuromuscular electrical stimulation (NMES) and eccentric exercise (ECC) have been shown to independently target these mechanisms. If delivered in succession, NMES and then ECC may be able to significantly improve strength recovery. The objectives of this study were to evaluate the ability of NMES combined with ECC to restore quadriceps strength and biomechanical symmetry and maintain cartilage health at 9 and 18 months after ACLR., Methods: This study is a randomized, double-blind, placebo-controlled, single-center clinical trial conducted at the University of Michigan. A total of 112 participants between the ages of 14 and 45 years and with an anterior cruciate ligament rupture will be included. Participants will be randomly assigned 1:1 to NMES combined with ECC or NMES placebo combined with ECC placebo. NMES or NMES placebo will be delivered 2 times per week for 8 weeks beginning 10 to 14 days postoperatively and will be directly followed by 8 weeks of ECC or ECC placebo delivered 2 times per week. The co-primary endpoints are change from baseline to 9 months and change from baseline to 18 months after ACLR in isokinetic quadriceps strength symmetry. Secondary outcome measures include isometric quadriceps strength, quadriceps activation, quadriceps muscle morphology (cross-sectional area), knee biomechanics (sagittal plane knee angles and moments), indexes of patient-reported function, and cartilage health (T1ρ and T2 relaxation time mapping on magnetic resonance imaging)., Impact: The findings from this study might identify an intervention capable of targeting the lingering quadriceps weakness after ACLR and in turn prevent deterioration in cartilage health after ACLR, thereby potentially improving function in this patient population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Detailed understanding of longitudinal behavior, response to therapy, and applicable biomarkers for interstitial lung diseases (ILDs) is lacking. There is a need for a large multicenter registry that provides researchers and clinicians access to well-characterized data not limited to patients with idiopathic pulmonary fibrosis. The Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) is a database that collects baseline and longitudinal demographic and clinical information about patients with ILDs in the United States. The objective of this study is to describe the patient population, data collection process, and opportunities for retrospective and prospective research with the PFF-PR. Individuals 18 years or older who had ILD diagnosed and who were seen at PFF-PR centers who provided informed consent were eligible to participate. Baseline and longitudinal demographic, spirometric, radiographic, morbidity, and mortality data are recorded into a secure electronic data capture system. Starting in 2016, the PFF-PR has collected data on 2,003 patients at 42 clinical sites in the United States. At the time of enrollment, the mean age of participants was 68 years old. Most (62%) of participants were male, and 58% had a positive smoking history. The mean forced vital capacity was 69% predicted, and the mean diffusing capacity of the lung for carbon monoxide was 43% predicted. Forty-one percent of patients were using supplemental oxygen, and 39% were on antifibrotic therapy. Reasons for attrition were mostly death or transplant, with low rates of loss to follow-up or withdrawal. The PFF-PR is a large multicenter United States-based registry that provides researchers and clinicians access to well-characterized ILD patient data.

Background: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months., Methods: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406., Findings: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-labelextension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (-6·6 [SD 6·4]), with further improvement seen during the open-label extension period (-9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (-3·7 [SD 7·6]), with a further improvement at month 18 (-6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo-abatacept group (12 adverse events, one serious adverse event) and in 11 patients in theabatacept-abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension., Interpretation: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis., Funding: Bristol-Myers Squibb and National Institutes of Health.