Protocol for a pragmatic randomized controlled trial evaluating a care pathway incorporating ultrasound-guided platelet-rich plasma injection plus physiotherapy versus physiotherapy alone in patients with L5/S1 lumbar disc herniation.

Towards self-explaining spiral tunnels: road-prototype-based facility design and visual-perception fluid assessment.

Obstructive sleep apnoea (OSA) is often underdiagnosed, highlighting the need for scalable diagnostic alternatives. The SUNSAS study compared a new device for at-home diagnosis of OSA (artificial intelligence [AI]-supported analysis of mandibular jaw movements [MJM]) with polysomnography (PSG) for time to diagnosis and treatment, and patient-reported outcomes. This prospective, multicentre, randomised, controlled, open-label study was conducted in France (October 2021-October 2024). Adults aged 18-80 years with suspected OSA were randomised (1:1) to undergo diagnostic testing using MJM monitoring (Sunrise) or PSG. Primary endpoints were assessed using hierarchical testing: 1. daytime sleepiness (Epworth Sleepiness Scale [ESS] score) at 3 months post-diagnosis and time to diagnosis; 2. time to treatment; and 3. daytime sleepiness at 3 months post-randomisation. Secondary endpoints included quality of life (Short Form-36, Quebec Sleep Questionnaire), work productivity (Work Productivity and Activity Impairment questionnaire), and positive airway pressure therapy adherence at 3 months after treatment initiation. Of 849 participants randomised (58·7% male, median age 50 years, body mass index 28·0 kg/m2, apnoea-hypopnoea index 15·2/h), 774 received a diagnosis: 133 no OSA, 239 mild OSA, 220 moderate OSA, and 182 severe OSA. Median time to diagnosis (15 vs. 106 days) and to treatment initiation (50 vs. 124 days) were significantly shorter with MJM analysis versus PSG (both p < 0·01). MJM-based diagnosis was noninferior to PSG in reducing ESS at 3 months after diagnosis (-2·26 vs. -2·29; 95% confidence interval [CI] for difference -0·85, 0·79; p = 0·01), and superior at 3 months post-randomisation (between-group difference: -1·51 (95% CI -2·17, -0·85); p < 0·01). Secondary endpoints also favoured the MJM group. OSA diagnosis based on MJM monitoring with AI-supported analysis is noninferior to PSG in reducing daytime sleepiness at 3 months after diagnosis, while significantly accelerating time to diagnosis and treatment initiation, resulting in earlier improvement in daytime sleepiness. Sunrise, with support from the French Ministry of Health through the Forfait Innovation programme.

The proliferation of large-scale, high-dimensional datasets characterized by inherent hierarchical structures presents significant challenges for conventional multiple testing procedures, which typically fail to leverage structural information to enhance statistical power. This paper introduces an Adaptive Multi-level Benjamini-Hochberg (AMBH) procedure specifically designed for hierarchical hypothesis testing. As an empirical presentation that complements and extends the theoretical framework developed in Bogomolov et al. (2021), our work emphasizes step-by-step implementation, evaluates the performance properties of the procedure from an empirical perspective, and provides a comparative analysis of differential performance attributes across procedures. The proposed method operates by recursively computing group-level p-values in a bottom-up manner and adaptively adjusting rejection thresholds in a top-down fashion, utilizing rejection counts from higher levels to inform thresholds determination at lower levels. This approach is particularly advantageous in settings where signals are clustered within specific branches of the hierarchy. We establish that the AMBH procedure controls both the group-level false discovery rate (GDR) at each level and a cluster-weighted false discovery rate (CWFDR). Numerical simulations demonstrate that AMBH achieves improved detection power and lower FDR compared with the conventional procedures. An application to flow cytometry data illustrates its effectiveness in detecting differential cell populations.

Vision-Language Models (VLMs) have demonstrated significant promise for autonomous driving due to their powerful multimodal reasoning capabilities. However, adapting VLMs from generic data to safety-critical driving contexts introduces a notable challenge known as domain shift. Existing simulation-based and dataset-driven evaluation approaches struggle to accurately replicate real-world complexities, lacking repeatable closed-loop evaluation and flexible scenario manipulation. Furthermore, current real-world testing platforms typically focus on isolated modules and do not support comprehensive interaction with VLM-based systems. Consequently, there is a critical need for a holistic testing architecture capable of integrating perception, planning, and control modules, accommodating VLM-based systems, and supporting configurable real-world testing scenarios. In this article, we address this critical gap by proposing a hierarchical real-world test platform specialized in the rigorous evaluation of VLM-integrated autonomous driving systems. Specifically, our platform features have: a lightweight, structured, and low-latency middleware pipeline specialized for seamless VLM integration; a hierarchical modular architecture enabling flexible substitution between conventional and VLM-based autonomy components, providing exceptional deployment flexibility for rapid experimentation; and sophisticated closed-loop scenario-based testing capabilities on a controlled test track, facilitating comprehensive evaluation of the entire full-stack VLM-integrated autonomous driving pipeline, from perception, reasoning, decision-making, and planning to final vehicle maneuvers. Through an extensive real-world case study, we demonstrate the effectiveness of our platform in evaluating the performance and robustness of VLM-integrated autonomous driving under diverse realistic conditions. Project page and codes: https://github.com/YupengZhouPurdue/VLMTest .

Accurate prediction of transient melt pool thermal fields in Laser Powder Bed Fusion (LPBF) is essential for understanding melt pool geometry and defect formation mechanisms, yet conventional finite element methods (FEM) impose prohibitive computational costs for parametric process exploration. A variational physics-informed neural network (VPINN) framework is presented for 3D transient thermal modeling of a GH3536 single-track LPBF scan. The framework incorporates a continuously differentiable Goldak double-ellipsoid moving heat source, temperature-dependent thermophysical property surrogates, and an effective heat-capacity treatment of latent heat associated with solid–liquid phase change and vaporization. These components are embedded in a weak-form residual-minimization scheme with octree-adaptive domain decomposition, hierarchical Legendre test functions, and sequential sliding-window time marching. Effective absorptivity is inferred jointly with the network parameters, using sparse experimental melt pool profiles as supervision. Within a parametric study covering laser powers from 100 to 140 W and scan speeds from 1000 to 1500 mm/s, the predicted melt pool width, depth, and aspect ratio agree closely with FEM benchmarks and cross-sectional optical micrograph measurements across both supervised and held-out interpolation conditions, with total relative L2 nodal temperature errors ranging from 3.23% to 6.75%. Following a one-time offline training investment of 15,323 s that simultaneously resolves the full parametric space, surrogate inference reduces per-condition query time from 3000–4000 s (FEM) to merely 4–5 s, delivering a speedup of two to three orders of magnitude and making the framework increasingly cost-effective for high-throughput parametric studies and digital-twin integration as the number of queried conditions grows.

Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs as a major public health strategy. Low-fat cow's milk is promoted as the preferred caloric replacement strategy for SSBs due to its high nutritional value and cardiometabolic advantages. Fortified soymilk is a plant-based alternative with approved health claims for cholesterol and coronary heart disease risk reduction that offers an equivalent nutritional value to cow's milk. However, given concerns about its classification as an ultra-processed food (UPF), it is unclear whether soymilk offers comparable metabolic health benefits to milk as part of clinical and public health strategies to reduce SSB intake. The Soy Treatment Evaluation for Metabolic (STEM) health trial seeks to evaluate the impact of replacing SSBs with either 2% soymilk or 2% cow's milk on liver fat and other cardiometabolic risk factors in habitual adult consumers of SSBs with obesity. Methods: The STEM trial is a 24-week, pragmatic, 3-arm, parallel, randomized trial. We recruited adults with obesity (high BMI plus high waist circumference based on ethnic specific cut-offs) consuming ≥1 SSB/day. Participants were randomized to one of three groups based on their usual SSB intake at baseline (servings/day): continued SSB (355 mL can) intake; replacement with fortified, sweetened 2% soymilk (250 mL); or replacement with 2% cow's milk (250 mL). The primary outcome is the change in intrahepatocellular lipid (IHCL) measured by 1H-MRS at 24 weeks. Hierarchical testing will be done to reduce the familywise error rate. The superiority of cow's milk to SSBs will be assessed first to establish assay sensitivity. If superiority is established, then the non-inferiority of soymilk to cow's milk will be assessed using a pre-specified non-inferiority margin of 1.5% IHCL units (assessed by difference of means using a 90% confidence interval [CI]). Analyses will be conducted according to the intention-to-treat (ITT) principle using inverse probability weighting (IPW) for superiority testing and per-protocol analyses for non-inferiority testing, using ANCOVA adjusted for age, sex, metabolic dysfunction-associated steatotic liver disease (MASLD) status, medication use, intervention dose, and baseline levels. We hypothesize that soymilk will be non-inferior to cow's milk (Clinicaltrials.gov NCT05191160). Results: Recruitment began in November 2021. A total of 3050 individuals were screened. We randomized 186 participants (62 per group) between 19 April 2022 and 16 April 2024. Participants are 57% male; with a mean [SD] age of 39.9 [11.8] years; BMI of 34.6 [6.1] kg/m2, waist circumference of 112.6 [13.8] cm; IHCL of 10.0 [8.2] % with 64.1% meeting the criteria for MASLD; and SSBs intake of 2.3 [1.3] servings/day. Conclusions: Baseline characteristics were balanced across the study arms, with participants representing adults with a high-risk metabolic phenotype, and 64.1% meeting the criteria for MASLD. Findings will contribute to evidence on the cardiometabolic benefits of soymilk, informing clinical practice guidelines and public health policy.

Bayesian prediction of aerospace system mission reliability with hierarchical and multi-fidelity test data fusion

Objective:&amp;nbsp;To analyze the testing value of hierarchical testing methods in clinical blood lipid biochemical testing. Methods:&amp;nbsp;120 subjects who required blood lipid biochemical testing received by our hospital from January 2024 to January 2025 were selected and divided into a hierarchical testing group (60 cases) and a routine testing group (60 cases) according to different testing methods. The routine inspection group adopts the full-item routine inspection method, and the graded inspection group adopts the graded inspection method, that is, the basic items of total cholesterol (TC) and triglycerides (TG) are first detected, and then high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and other items are selectively tested based on the results of the basic items. Compare the accuracy of test results, test time, test costs, and subject satisfaction between the two groups. Results:&amp;nbsp;When comparing the test results of TC, TG, HDL-C, and LDL-C between the two groups, the difference was not statistically significant (p &gt; 0.05); the inspection time of the graded inspection group was shorter than that of the conventional inspection group, the inspection cost was lower than that of the conventional inspection group, and the subject satisfaction was higher than that of the conventional inspection group (p &lt; 0.05). Conclusion:&amp;nbsp;The use of hierarchical testing methods in clinical blood lipid biochemical testing can shorten testing time, reduce testing costs, and improve subject satisfaction while ensuring testing accuracy, and has high clinical application value.

Objective:Current methods of assessing cannabis-related attentional bias such as modified Stroop tasks are characterized by several limitations, including low reliability. The goal of the present study was to explore the reliability and utility of a novel methodological tool that is a proxy for eye-tracking—MouseView.js—to examine cannabis-related attentional bias.Method:Canadian postsecondary students (N = 580) freely viewed 30 image pairs of neutral and cannabis stimuli using MouseView.js. Participants also completed self-report measures of cannabis use, including problematic cannabis use. Reliability coefficients (Cronbach’s alpha and split-half) were calculated to estimate the internal consistency of cannabis images, neutral images, and dwell difference scores. A hierarchical testing strategy was used to examine whether image (neutral vs. cannabis) and cannabis use status (non-use, recreational use, problematic use), as well as the interaction between image and cannabis use status, explain variation in dwell times.Results:A total of 368 participants (64.4%) did not use cannabis, 138 (23.8%) used cannabis recreationally, and 74 (12.8%) used cannabis at problematic levels. The reliability estimates for cannabis images, neutral images, and attentional bias scores ranged from acceptable to excellent. There was a main effect of image, such that all participants spent more time viewing cannabis relative to neutral images, indicative of an attentional bias. The main effects for cannabis use status and interactions between cannabis use status and image type were not statistically significant.Conclusions:Taken together, the present findings suggest MouseView.js may be a reliable method to assess cannabis-related attentional biases.

Effect of Baduanjin on Blood Pressure Among Individuals With High-Normal Blood Pressure: A Multicenter, Open-Label, Blinded-Outcome Randomized Controlled Trial.

In Fabry disease (FD, OMIM #301500), a rare lysosomal storage disorder, the glucosylceramide synthase inhibitor lucerastat acts as substrate reduction therapy. The Phase 3, prospective, double-blind, placebo-controlled, 6-month, randomized clinical trial, MODIFY (NCT03425539), aimed to evaluate the efficacy, safety, and tolerability of lucerastat in adults with FD with moderate-to-severe neuropathic pain. The single-arm, open-label extension (OLE) (NCT03737214) evaluated the longer-term safety and tolerability of lucerastat over 72 months. Lucerastat 1000 mg twice daily (n = 80), compared with placebo (n = 37), failed to affect neuropathic pain at Month-6, with no significant difference between treatment groups (LSM difference -0.42 [95% CI -1.23, 0.40], p = 0.32) (primary endpoint). In contrast, a decrease in baseline plasma Gb3 was observed at Month-6 in lucerastat-treated participants but not placebo-treated participants (LSM difference -873.53 ng/mL [95% CI -1097.53, -649.53], p < 0.0001; NS due to hierarchical testing). In an unplanned OLE Month-18 interim analysis, the eGFR slope (mL/min/1.73m2/year) in 93 participants with pre- and post-randomization (23-month median lucerastat exposure) eGFR data was -3.50 (-5.04, -1.969) and -1.48 (-2.64, -0.33), respectively. Lucerastat was safe and well tolerated. Lucerastat's strong pharmacodynamic effect did not translate into an effect on neuropathic pain. The potential effect of lucerastat on renal function requires further investigation (Trial registration NCT03425539, NCT03737214; 2017-003369-85, 2018-002210-12. The studies were sponsored by Idorsia Pharmaceuticals Ltd).

STrategies for antithrombotic tRreatment following transcatheter edge-to-edge repair in patients with severe mitral regurgitation: Rationale and design of STAR-TEER trial.

BackgroundC3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear.MethodsWe conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline.ResultsA total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, −67.2% [95% confidence interval {CI}, −74.9 to −57.2] vs. 2.9% [95% CI, −8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred.ConclusionsPegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.)

Sebaceous carcinoma (SC) is a prevalent neoplasm of the eyelid, ranking second to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in incidence. In some Asian regions, the incidence of SC is as high as 50% with a high risk of invasion and recurrence. Diagnosis of SC is still challenging owing to its atypical histological features and variable immunohistochemical profiles, especially in poorly differentiated ones. Therefore, it is critical to identify more precise immunohistochemical makers for the prediction of SC. In this study, we performed a double-blind, retrospective analysis using tissue microarrays to evaluate the diagnostic accuracy of TRPS1, GATA3, and adipophilin in a cohort with 98 SCs, 56 BCCs, and 55 SCCs. Receiver operating characteristic curves analysis and DeLong’s test were used to confirm the applicability of these markers. Binary logistic regression was applied to construct a cancer classification model, with model validity confirmed through likelihood ratio tests (Δ-2LL = 255.937, p < 0.001) and pseudo-R² metrics (Cox & Snell R² = 0.706, Nagelkerke R² = 0.803, McFadden R² = 0.578). Variable contributions were assessed via hierarchical likelihood ratio tests and Wald analyses, revealing significant discriminative power of TRPS1 score (OR = 524.410, p < 0.001) and other predictors. Our results revealed that the combination of above three markers significantly enhanced the diagnostic performance compared to individual ones. Notably, TRPS1 and GATA3 demonstrated superior discriminatory power in distinguishing SC from BCC and SCC to adipophilin. In poorly differentiated SCs, TRPS1 exhibited a markedly higher diagnostic efficacy than GATA3 and adipophilin. In addition, TRPS1 exhibited higher AUC values than GATA3 and adipophilin in differentiating primary and recurrent SCs, although the difference was not significant. Collectively, our findings indicate that the TRPS1/GATA3/adipophilin-based model demonstrated excellent discriminatory efficacy for eyelid malignancies (Kappa = 0.784, micro-average F1 = 0.882, AUC-ROC = 0.964 [95%CI:0.934–0.994]), achieving clinical-grade performance.

The graph-based approach to multiple testing is an intuitive method that enables a study team to represent clearly, through a directed graph, its priorities for hierarchical testing of multiple hypotheses, and for propagating the available type-1 error from rejected or dropped hypotheses to hypotheses yet to be tested. Although originally developed for single-stage nonadaptive designs, we show how it may be extended to two-stage designs that permit early identification of efficacious treatments, adaptive sample size re-estimation, dropping of hypotheses, and changes in the hierarchical testing strategy at the end of stage one. Two approaches are available for preserving the familywise error rate in the presence of these adaptive changes, the value combination method, and the conditional error rate method. In this investigation, we will present the statistical methodology underlying each approach and will compare the operating characteristics of the two methods in a large simulation experiment.

Measurement of gravitational waves can provide precision tests of the nature of black holes and compact objects. In this Letter, we test Giddings' nonviolent nonlocality proposal, which posits that quantum information is transferred via a nonlocal interaction that generates metric perturbations around black holes. In contrast to firewalls, these quantum fluctuations would be spread out over a larger distance range-up to a Schwarzschild radius away. In this Letter, we model the modification to the gravitational waveform from nonviolent nonlocality. We modify the nonspinning EOBNRv2 effective one body waveform to include metric perturbations that are due to a random Gaussian process. We find that the waveform exhibits random deviations which are particularly important in the late inspiral-plunge phase. We find an optimal dephasing parameter for detecting this effect with a principal component analysis. This is particularly intriguing because it predicts random phase deviations across different gravitational wave events, providing theoretical support for hierarchical tests of general relativity. We estimate the constraint on the perturbations in nonviolent nonlocality with events for the LIGO-Virgo network and for a third-generation network.

Complete versus culprit lesion-only revascularisation for acute myocardial infarction (Complete Revascularisation Trialists' Collaboration): an individual patient data meta-analysis of randomised trials.

Widely used to treat multiple sclerosis, dimethyl fumarate (DMF) is a prodrug metabolized in vivo to monomethyl fumarate (MMF) and methanol; the latter is a gastrointestinal (GI) irritant. GI adverse events (AEs) commonly cause DMF discontinuation. Tegomil fumarate (TMF) comprises two MMF moieties joined by tetraethylene glycol, a low molecular polyethylene glycol (PEG). TMF is cleaved in vivo to MMF and the pharmacologically inactive PEG. This randomised, double-blind study compared the GI tolerability of TMF 348mg and DMF 240mg, administered twice daily, in healthy adults (3:1 female:male ratio) aged 18-55years. Participants completed daily questionnaires in an electronic diary, including the Modified Overall Gastrointestinal Symptom Scale (MOGISS), Modified Acute Gastrointestinal Symptom Scale, Flushing Symptom Questionnaire and an ad hoc quality of life assessment. The primary endpoint was the area under the curve (AUC) for each individual MOGISS symptom over 5weeks of treatment. Between-group treatment differences for each MOGISS symptom AUC were analysed using hierarchical testing in a predefined sequence starting with abdominal pain. The study enrolled 210 participants; the full analysis set comprised 208 (155 females, 53 males). While AUC values were lower for TMF than DMF for most MOGISS symptoms, the between-group difference for abdominal pain was not statistically different (p=0.0513) so all subsequent statistical analyses were considered exploratory. MOGISS total and composite score, the number of days with symptoms and number of symptoms were lower with TMF than DMF. Fewer participants receiving TMF (57.7%) versus DMF (73.6%) reported GI AEs or discontinued because of GI AEs (TMF n=0, DMF n=2). The between-group difference for the AUC of MOGISS abdominal pain score was not statistically different. However, compared with DMF, TMF showed improved GI tolerability profile in terms of self-assessed GI events and GI AEs leading to discontinuation.

Background Dual antiplatelet therapy (DAPT) with aspirin and ticagrelor is standard treatment for ST-elevation myocardial infarction (STEMI). While the optimal ticagrelor dose is established, the ideal aspirin maintenance dose remains debatable, particularly in East Asian populations who demonstrate enhanced bleeding sensitivity with standard antiplatelet regimens compared to Western populations. Methods The Low-dose Evaluation of Aspirin in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention (LEAST) trial is a multicenter, randomized, double-blind, placebo-controlled trial comparing low-dose (50 mg/d) versus standard-dose (100 mg/d) aspirin combined with ticagrelor (90 mg twice daily) in Chinese STEMI patients post-percutaneous coronary intervention. A total of 3612 patients will be enrolled from 34 centers across China using stratified randomization by age and multivessel disease status. The primary endpoint is 12-month composite of cardiac death, non-fatal myocardial infarction, non-fatal stroke, and ischemia-driven target vessel revascularization (non-inferiority testing with 1.5% absolute difference margin). The key secondary endpoint is Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding (superiority testing). A hierarchical testing strategy ensures bleeding benefits are only claimed when ischemic safety has been established. Results This trial will provide evidence regarding optimal aspirin maintenance dose in Chinese STEMI patients receiving DAPT with ticagrelor. The findings may support development of population-specific antithrombotic strategies that better balance efficacy and safety in East Asian populations. Conclusion The LEAST trial addresses an important knowledge gap regarding optimal aspirin dosing in Chinese STEMI patients and may influence future guideline recommendations for acute coronary syndrome management in Asian populations. Trial Registration ClinicalTrials.gov (NCT06756945)