Maternal Recall of Obstetric Office-Based Activities That Promote Antepartum Tetanus-Diphtheria-Acellular-Pertussis Vaccination.

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.

Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.

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.

Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

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.

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

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.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

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.

Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance.

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.

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

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.

Feasibility pilot trial for the Trajectories of Recovery after Intravenous propofol versus inhaled VolatilE anesthesia (THRIVE) pragmatic randomised controlled trial.

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.

Needles in a Haystack: Finding Qualitative and Quantitative Collaborators in Academic Medical Centers.

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.

Discriminative Accuracy of the CAPTURE Tool for Identifying Chronic Obstructive Pulmonary Disease in US Primary Care Settings.

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.

Association of Severe Acute Respiratory Syndrome Coronavirus 2 Infection With Early Breastfeeding.

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.

Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study.

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.

A data-driven approach finds RNA polymerase III antibody and tendon friction rubs as enrichment tools for early diffuse scleroderma trials.

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.

Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial.

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.

Machine-learning classification identifies patients with early systemic sclerosis as abatacept responders via CD28 pathway modulation.

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.

Factors Influencing Maternal Antepartum Tdap Vaccination.

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.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

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.

A genomic meta-analysis of clinical variables and their association with intrinsic molecular subsets in systemic sclerosis.

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.

Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome.

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.