Citations

Most patients with chest pain do not have acute myocardial infarction (AMI), yet post-AMI rule-out disposition remains variable. Detectable but sub-99th percentile high-sensitivity cardiac troponin I (hs-cTnI) provides additional prognostic information. We evaluated the economic value of hs-cTnI-guided hospitalizations among non-AMI patients. We analyzed 1481 non-AMI chest pain visits with detectable baseline hs-cTnI across 29 U.S. emergency departments (2014–2016) in the prospective HIGH-US trial using the Atellica IM TnIH assay(Siemens Healthcare Diagnostics, Tarrytown, NY, US). We compared observed standard-of-care admissions with modeled pathways incorporating hs-cTnI thresholds and risk scores, assessing admission rates, costs, and diagnostic accuracy for 30-day death/MI. Overall, 1.0% (n = 15/1481) experienced 30-day death/MI. Standard-of-care admitted 59% of patients with 93% sensitivity and 41% specificity. The modeled pathway using hs-cTnI ≥ 5 ng/L plus non-low risk scores was associated with reduced projected admission of 41%, higher specificity of 60%, and the same 93% sensitivity. Estimated per-patient diagnostic costs were lower under Scenario 1 (noninvasive diagnostic testing only; $1025 vs. $1139) and under Scenario 2 (including inpatient/invasive procedures; $2672 vs. $3536). In subgroups, higher hs-cTnI thresholds conferred further economic benefit without compromising sensitivity. Incorporating sub-99th percentile hs-cTnI thresholds alongside risk scores may support more efficient resource use while maintaining safety, although findings require prospective validation.

ABSTRACT Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty-six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid–Schiff, and Jones’ silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet’s agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet’s AC1, 0.55; 95% CI, 0.47–0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.

Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Importance Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) lacks proven relapse-preventive therapies. While clinical trials are ongoing, safety data may be limited and approved drugs are costly. Studies of interleukin 6 receptor blocker (IL-6RB) in MOGAD are limited by small numbers and no comparative studies, contributing to low use. Objective To evaluate the impact of IL-6RB therapy on relapse rates in MOGAD and compare relapse frequency with intravenous immunoglobulin (IVIG). Design, Setting, and Participants This international, multicenter, retrospective cohort study (January 1, 2015, through December 31, 2025) included a historical IVIG-treated cohort of varying doses. The study took place across sites in North and South America (US, Canada, Mexico, Argentina, Brazil, Chile, Colombia, and Peru). Patients with MOGAD (n = 116, no excluded patients) who received at least 1 dose of an IL-6RB were included. These data were analyzed in January 2026. Exposures Tocilizumab or satralizumab. Main Outcomes and Measures Annualized relapse rate (ARR) during IL-6RB therapy, time to next relapse after treatment initiation, and adverse events. Outcomes were compared with the IVIG cohort using inverse probability of treatment weighting (IPTW) adjusted for age, sex, prior ARR, and concomitant therapies. Results A total of 116 patients with MOGAD (89% relapsing) receiving IL-6RB (tocilizumab, 104 [90%] and satralizumab, 12 [10%]) were included; overall, 60.3% were female, 39.7% were male, and 18% were younger than 18 years. The median (IQR) IL-6RB treatment follow-up was 1.4 (0.7-2.5) years and 23 relapses occurred during 241.8 person-years of IL-6RB therapy. The ARR decreased from 0.64 (95% CI, 0.58-0.70) for relapsing MOGAD before IL-6RB to 0.09 (95% CI, 0.06-0.14) during IL-6RB treatment (incidence rate ratio, 0.08; 95% CI, 0.04-0.16). Adverse events occurred in 58 patients (50%), most commonly mild infections, although 10 (9%) had severe infections. In the IVIG cohort (n = 59), 30 relapses occurred over 133.8 person-years (ARR, 0.22; 95% CI, 0.15-0.32). After IPTW, IL-6RB was associated with a lower hazard ratio (HR) than the group who underwent IVIG therapy less than 1 g/kg every 4 weeks (HR, 4.5; 95% CI, 2.0-9.8), with no significant difference vs the group who underwent IVIG 1 g/kg or more every 4 weeks (HR, 2.0; 95% CI, 0.8-4.5). Conclusions and Relevance In this multicenter observational cohort, IL-6RB use in MOGAD was associated with low relapse rates and a favorable safety profile, though severe infections occurred occasionally. Relapse rates were lower than the group who underwent IVIG less than 1 g/kg every 4 weeks but not significantly different from the group who underwent IVIG 1 g/kg or more every 4 weeks. This supports IL-6RB as a potential relapse-prevention therapy in MOGAD; the wide availability and relative affordability of tocilizumab may enable broad global use.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

Abstract Objective. Modern stereotactic neurosurgery increasingly relies on bilateral and multi-trajectory workflows (e.g. deep brain stimulation (DBS), stereoelectroencephalography (sEEG)), which can exceed the reach and flexibility of conventional frame-based systems. Building on our skull-mounted Navinetics D1 platform, we present a stereotactic frame (Navinetics E1) intended to expand the reachable work envelope, enable independent bilateral targeting, and preserve mechanical accuracy and patient comfort. Approach. We designed the Navinetics E1 stereotactic frame using a center-of-arc architecture with five degrees of freedom per hemisphere ( X, Y, Z , Arc, Collar) and two operating modes: Double Arm (independent left/right arms for simultaneous bilateral targeting) and Single Arm (mechanically coupled arms). The system was designed in CAD and fabricated via carbon fiber-reinforced polylactic acid (PLA-CF) additive manufacturing. Collision-aware MATLAB simulations quantified work volume and admissible approach directions. Mechanical targeting accuracy was evaluated on a ground truth fixture (GTF) platform, with mixed-effects modeling to assess target- and trajectory-dependent effects. Operative feasibility was assessed through an intraoperative entry-point replication test relative to the D1 system. Main results. Compared to the D1, the E1 frame significantly expanded key geometric ranges, including, most notably, 0°–360° Collar rotation and posterior Y -axis reach, thereby increasing the work volume and trajectory range by factors of 3.39 and 8.42, respectively. Mean GTF targeting deviation was 0.78 ± 0.38 mm in Single Arm mode and 1.23 ± 0.36 mm (right) and 1.65 ± 0.47 mm (left) in Double Arm mode. Entry-point replication across 17 clinical cases achieved 76.5% success in overlapping the reference points, providing preliminary evidence of feasibility under real operative conditions. Significance. The E1 frame extends a compact skull-mounted platform to support broader stereotactic reach and trajectory while enabling independent bilateral workflows. These features may reduce intraoperative reconfiguration for complex DBS and sEEG cases. Future work will focus on increasing structural stiffness, improving angular readout/setting, and developing MRI-compatible implementations.

Abstract Introduction Acute interstitial nephritis is an important differential diagnosis in patients with deteriorating kidney function. Diagnosis currently requires kidney biopsy, an invasive procedure associated with risks. We hypothesized that urinary T cells may serve as a non-invasive biomarker for acute interstitial nephritis. Methods A total of 320 patients undergoing clinically indicated kidney biopsy were enrolled in a discovery cohort at Charité Berlin (n = 80), an internal validation cohort at Charité (n = 100), and an external validation cohort at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (n = 140). Urinary immune cells were assessed by flow cytometry. Renal T cell infiltration was evaluated by immunofluorescence in kidney biopsy specimens from the discovery and internal validation cohorts, including 16 patients with acute interstitial nephritis and 9 patients without acute interstitial nephritis. Additionally, CXCL9 was measured by ELISA in 102 urine samples from these cohorts. Results Across all cohorts, 27 patients (8.4%) were diagnosed with acute interstitial nephritis. In the discovery cohort, multiple urinary T cell subsets were increased in acute interstitial nephritis, with activated CD4 + effector memory T cells expressing CD38 and HLA-DR showing the strongest diagnostic performance. This marker outperformed urinary monocytes, eosinophils, and CXCL9 and was validated in both independent cohorts. Across all cohorts, the area under the receiver operating characteristic curve was 0.84 and increased to 0.91 after exclusion of 8 patients receiving corticosteroids. A cutoff of 211 activated CD4 + effector memory T cells per 100 mL urine yielded a sensitivity of 78% and a specificity of 81%. Urinary activated CD4 + effector memory T cell counts correlated with renal CD4 + and CD4 + CD38 + T cell infiltration in acute interstitial nephritis. Conclusions Urinary activated CD4 + effector memory T cells expressing CD38 and HLA-DR represent a promising non-invasive biomarker for the diagnosis of acute interstitial nephritis. Lay Summary Acute interstitial nephritis is a frequent cause of acute kidney injury and is usually diagnosed by kidney biopsy, an invasive procedure that carries risks. We investigated whether immune cells in urine could help identify AIN in a less invasive manner. In this multicenter study, urine samples from 320 patients undergoing kidney biopsy in Germany and China were analyzed. We found that a specific population of activated T cells was markedly increased in the urine of patients with AIN compared with patients with other kidney diseases. This urinary marker outperformed other immune cell types and the inflammatory cytokine CXCL9 and was successfully validated in independent cohorts from both Germany and China. Importantly, urinary activated T cell counts correlated with immune cell infiltration within the kidney. These findings suggest that urinary activated T cells may serve as a non-invasive biomarker to support the diagnosis of AIN and facilitate earlier clinical decision-making.