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Key Points Pediatric preemptive kidney transplantation rates in the United States vary by socioeconomic status (SES). The HOUsing-based index of SES, an individual-level SES measure derived from residential addresses, effectively predicts pediatric preemptive kidney transplant rates. Background Preemptive kidney transplantation in children is associated with better patient and graft survival compared with transplants after dialysis. However, preemptive kidney transplantation rates in children remain low. This study aimed to evaluate the effect of socioeconomic status (SES) on preemptive transplantation in children. Methods Our study included 173 Minnesota-resident pediatric kidney transplant recipients (younger than 18 years) transplanted at the University of Minnesota from 2010 to 2020. Using the HOUsing-based index of SES (HOUSES) index, a validated, individual SES measure based on housing units categorized into quartiles (Q1: lower SES; Q2–Q4: higher SES), we applied mixed-effects multivariable logistic models to examine the effects of HOUSES on preemptive kidney transplants and pretransplant dialysis duration. Results Of 173 pediatric kidney transplant recipients, 46 (26.6%) received a preemptive transplant, and of 109 recipients with dialysis duration data, 39 (35.8%) received dialysis for >1 year. After adjusting for age at kidney failure, sex, donor type, insurance type, and underlying cause of kidney failure, we observed significantly lower odds of preemptive transplantation among Q1 recipients compared with Q2–4 recipients (adjusted odds ratio, 0.31; 95% confidence interval, 0.11 to 0.90; P = 0.03). Conclusions Using the HOUSES index, we found significant socioeconomic disparities in preemptive kidney transplantation rates among children.

ABSTRACTBackground and AimsNerve conduction studies (NCS) are integral to diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but their role in predicting treatment outcomes remains underexplored. This study evaluates NCS changes at first follow‐up (first NCS changes) as predictors of treatment success in CIDP, focusing on their correlation with clinical outcomes over time.MethodsNewly diagnosed CIDP patients meeting the 2021 EAN/PNS criteria were retrospectively evaluated. Baseline and first follow‐up NCS parameters were compared with clinical outcomes, assessed by the Neuropathy Impairment Score (NIS) and Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. All patients received first‐line immunotherapy (intravenous immunoglobulin, corticosteroids, or plasma exchange).ResultsOf 39 treated patients, 26 (66.7%) were responders based on improving NIS trends, while 13 (33.3%) were nonresponders. Responders showed significant improvements at the first follow‐up in fibular compound muscle action potential (CMAP) amplitude, ulnar CMAP amplitude, summated CMAP amplitudes, and fibular motor conduction velocity. Changes in fibular CMAP amplitude consistently correlated with NIS (R = −0.8 to −0.6, p ≤ 0.004) and INCAT disability score improvements (R = −0.6 to −0.3, p ≤ 0.032) across all follow‐up intervals up to 60 months. Ulnar and summated CMAP amplitude changes also correlated with clinical outcomes, though their associations were less sustained than those of fibular CMAP amplitude.InterpretationThe first change in fibular CMAP amplitude is a reliable biomarker for predicting CIDP treatment response, with ulnar and summated CMAP amplitudes as alternatives when the fibular response is absent. Our findings highlight the utility of first NCS changes in monitoring and predicting treatment outcomes in CIDP.

Objectives The impact of body mass index (BMI) on cardiovascular risk in rheumatoid arthritis (RA) is unclear. RA characteristics may influence the association between BMI and risk. Disease activity, which predicts cardiovascular risk, is associated with obesity only among anticitrullinated antibody (ACPA)-positive patients. Biologics alter body composition and mitigate cardiovascular risk in RA. We explored the association of BMI with cardiovascular risk and whether this varied across ACPA status and biologic use. Methods We evaluated 3982 patients from an international observational cohort. Outcomes included (a) first major adverse cardiovascular event (MACE) encompassing myocardial infarction, stroke or cardiovascular death; and (b) all events comprising MACE, angina, revascularisation, transient ischaemic attack, peripheral arterial disease and heart failure. Multivariable Cox models stratified by centre risk evaluated the impact of BMI, ACPA, biologics and their two- and three-way interactions on outcomes. Results We recorded 192 MACE and 319 total events. No main effects of BMI, ACPA or biologics were observed. A three-way interaction between them on MACE (p-interaction<0.001) and all events (p-interaction=0.028) was noted. Among ACPA negative patients, BMI was inversely associated with MACE (HR 0.38 (95% CI 0.25 to 0.57)) and all events (HR 0.67 (0.49 to 0.92)) in biologic users but not non-users (p-for-interaction <0.001 and 0.012). Among ACPA-positive patients, BMI was associated with MACE (HR 1.04 [1.01–1.07]) and all events (HR 1.03 (1.00 to 1.06)) independently of biologic use. Conclusions BMI is inversely associated with cardiovascular risk only among ACPA-negative biologic users. In contrast, BMI is associated with cardiovascular risk in ACPA-positive patients independently of biologic use.

Background Cancers persist despite expression of immunogenic neoantigens and ongoing antitumor immune responses. While some occult tumors likely are cleared by effective antitumor immune responses, the targeted antigens are not easily identifiable as those tumors spontaneously disappear. Methods We used mouse models with a defined antigenic protein mimicking tumor-specific neoantigens to address the nature of these spontaneous anti-tumor immune responses. Results BALB/c (H-2d ) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite ongoing immune responses targeting tumor-specific model antigens. Meanwhile, congenic BALB.B (H-2b ) and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in a major histocompatibility complex (MHC)-II dependent manner. Adoptive transfer and immune cell depletion strategies revealed CD4+ T cells and CD20+ B cells are crucial mediators of the protective response in H-2b mice. Furthermore, passive transfer of immune serum from mice rejecting their tumors confers resistance in tumor antigen-tolerant animals with an inversely proportional relationship between tumor outgrowth and the amount of rat-erbB2 specific antibody present in tumor-bearing mice. Introduction of the rat-erb2 ectodomain into other H-2b tumor models also promotes their spontaneous tumor rejection. Notably, the tumor microenvironments differ in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflecting the differences between effective and ineffective tumor immune responses. Conclusions We find that the effective antitumor immunity targeting neoantigens in these breast cancer models is determined by MHC-II-restricted presentation of optimal cancer-associated antigens. These responses are dependent on CD4+ T cells, B cells, and antigen-specific antibodies.

Goal of this study was to examine the impact of immunotherapy on overall survival (OS) in patients with female genital tract melanoma (GTM). This retrospective cohort study utilized the National Cancer Database to identify individuals with invasive vulvar or vaginal melanoma diagnosed between 2004 and 2019. Kaplan–Meier plots and multivariate Cox regression were used to describe the impact of immunotherapy on OS and to examine predictors of OS among those who received immunotherapy for those with vulvar or vaginal melanoma. Of the 870 patients with vaginal melanoma, 23.6% received immunotherapy. Receiving immunotherapy for treatment of vaginal melanoma was associated with improved OS (median: 21.8 versus 18.9 months; P = 0.01); this association remained after adjustment for other prognostic factors [hazard ratio (HR), 0.77; 95% confidence interval (CI), 0.62–0.95; P = 0.01]. The survival advantage was more pronounced among those who did not receive primary surgical resection (median: 18.6 versus 12.2 months; P = 0.0009). Among 3123 patients with vulvar melanoma, 15.3% received immunotherapy. Receiving immunotherapy for treatment of vulvar melanoma was associated with an improvement in OS (median: 43.6 versus 57.7 months; P = 0.06; HR, 0.86; 95% CI, 0.74–1.00; P = 0.04). Survival benefit was more pronounced when restricted to patients with advanced or unknown stage disease (median OS, 31.6 versus 24.2 months; P = 0.002; adjusted HR, 0.74; 95% CI, 0.61–0.89; P = 0.002) and among the small subset who did not receive primary surgical resection (median: 19.8 versus 9.6 months; P = 0.0005). Immunotherapy was associated with improved OS in patients with female GTM, with some subsets particularly benefitting.

Abstract In this article, we highlight the contributions of passive experiments that address important exercise‐related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical “knockout” animal models among human research participants. Natural experiments are gleaned from data sets that allow population‐based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879‐4907, 2023.

Introduction Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%–50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission. Methods and analysis The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure. Ethics and dissemination The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn’s & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals). Trial registration number NCT05230173 .