BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.
IMPORTANCE:Reliable early response biomarkers for overall survival (OS) are lacking for patients receiving immune checkpoint inhibitor (ICI) therapy for advanced non-small cell lung cancer (NSCLC). Existing imaging-based measures, such as Response Evaluation Criteria in Solid Tumors (RECIST) and tumor volume change (TVC), have limited predictive value for long-term outcomes, and advanced imaging-based biomarkers may enhance decision-making in clinical practice and clinical trials. OBJECTIVE:To develop and validate a fully automated deep-learning imaging-based biomarker using pretherapy and 12-week follow-up computed tomography (CT) scans. DESIGN, SETTING, AND PARTICIPANTS:This prognostic study used retrospectively collected HER data from routine clinical practice (RCP) and clinical trial data from 2013 to 2023. A model using serial CT scans, Serial CT response score (Serial CTRS) was developed using a RCP discovery dataset, validated with 10 US and European institution RCP test datasets, and independently validated on a multinational clinical phase 1 trial of dostarlimab (GARNET). Participants were adults with advanced NSCLC starting ICIs in the period from 2013 to 2021 (RCP discovery), from 2013 to 2022 (RCP test), or from 2017 to 2018 (GARNET). INTERVENTIONS:ICI monotherapy or combination therapy in the first-line or later-line setting. MAIN OUTCOMES AND MEASURES:Cox proportional hazards regression and receiver operating characteristic-area under the curve modeled associations between Serial CTRS and OS. RESULTS:The study included 1830 patients (RCP discovery, 1171 patients; RCP test, 605 patients; GARNET, 54 patients) with a median (IQR) age of 67 (19-95) years; 1000 participants were male (55%), and 830 were female (45%). Serial CTRS was associated with OS in multivariable analysis controlling for age, sex, programmed death-ligand 1 expression, histologic profile, and tumor volume (hazard ratio [HR] for 10%-point higher probability of 12-month OS, 0.74 [95% CI, 0.70-0.79] for RCP test; 0.45 [95% CI, 0.32-0.65] for GARNET). Serial CTRS outperformed RECIST and TVC in OS risk discrimination, with higher HRs distinguishing low-survival and high-survival groups in RCP test (HR, 6.19; 95% CI, 4.12-9.28) and GARNET (HR, 18.00; 95% CI, 5.40-59.97). Predictive value persisted across programmed death-ligand 1 and RECIST subgroups, including stable disease. CONCLUSIONS AND RELEVANCE:In this prognostic study of patients with advanced NSCLC receiving ICI treatment, the fully automated biomarker Serial CTRS predicted OS more effectively than resource-intensive RECIST and TVC measurements using the same scans.
Modular dual mobility (MDM) cups are widely used in primary total hip arthroplasty (THA) to reduce dislocation, but their impact on range of motion (ROM) to impingement versus single-mobility (SM) cups remains uncertain. In this paired robotic-simulation study, 108 primary robotic-assisted THAs were virtually planned twice with CT-based software, once with an SM cup and once with an MDM cup. Cup and stem orientation were optimised to restore intra-articular length and global offset within 5 mm of the contralateral hip and to avoid impingement. ROM to first impingement was measured in extension/external rotation (ER), flexion/internal rotation (IR) with physiological pelvic tilt, and flexion/IR with 20° adduction. The mode of first impingement (intra-articular, extra-articular, or mixed) was recorded. Compared with SM, MDM cups increased ROM to impingement in extension and ER but slightly reduced ROM in flexion and IR at several test positions. Maximal extension to impingement and ER in extension were higher with MDM, whereas flexion with pelvic anteversion and IR at 100° flexion were lower. ROM to impingement was not uniformly greater with MDM, and first contact often shifted from intra-articular implant-on-implant impingement toward extra-articular impingement. In robotic THA, MDM cups provide selective gains in ROM to impingement and shift the impingement towards extra-articular structures rather than providing a global increase in safe ROM. Clinically, MDM may suit patients needing extension/ER reserve or with anterior instability risk, and planning should consider osteophytes and bony constraints. Further prospective clinical validation is warranted.
For a century P-value is routinely used in almost every research paper with a threshold of 0.05 to reject the null hypothesis. The aim of this short review was to discuss the validity of this arbitrary (yet sacred) threshold. The history of P-value shows that very quickly, practitioners had found a simple method that appealed to them, while statisticians saw no great need to curb this enthusiasm, which seemed consensual. However, heavy reliance on P-values is of concern because of potential misuse and misinterpretation. The main pitfalls of P<0.05 are the dichotomized approach with a black-or-white judgement, possible false positive results, lack of information about magnitude of the effect, clinical relevance, and use out of context. These pitfalls explain why several statisticians and researcher recommend abandoning, not the P-value itself but the threshold of 0.05 and the term "statistical significance". We are faced with a paradigm shift by demoting P-value from its threshold-screening role and using alternative tools such as Bayesian methods, effect size with confidence intervals, more stringent thresholds, pragmatic trials, and the minimal clinically important difference. This will require statisticians, researchers, publishers, and health care decision makers to radically change the way they interpret scientific data by abandoning century-old dichotomous analysis-a true revolution to come.
Performing a total hip arthroplasty (THA) in obese patients is known to be associated with an elevated rate of complications. The use of dual mobility cups (DMC) has already been proven for decreasing dislocation episodes in high-risk populations. This is an observational cohort study evaluating the functional and radiological outcomes of DMC across BMI categories namely healthy, overweight and obese populations. This is a retrospective multi-centric study of 419 patients who underwent a primary THA with a DMC (THA-DMC) from 2006 to 2022. The patients were divided in three groups according to their BMI and were evaluated clinically with the modified Hip Harris Score (mHHS) and radiologically. Post-operative complications were recorded during the follow-up period. The mean age of the included patients was 70 ± 13.19 years (p = 0.006). The mean follow-up period was nine ± 6.2 years. At final follow-up, the mean modified HHS score was 85.56 ± 6.09 in the normal weight subgroup vs 92.39 ± 4.89 in the overweight subgroup and 89.24 ± 4.40 in the obese subgroup (p = 0.2). Three patients, one in the overweight and two in the obese subgroups, had a traumatic dislocation unrelated to the surgery. No cases of intraprosthetic dislocations were observed. Two patients in the obesity subgroup required additional surgeries for septic complication. The radiological assessment revealed no signs of migration or tilting of the components. Osteolysis was detected in 4 cases with non-progressive lines and no symptoms at last follow up. Heterotopic ossifications were observed in 15 asymptomatic patients. Three patients had a traumatic peri-prosthetic fracture. The use of a contemporary dual mobility cup in obese patients seems to yield excellent functional and radiological outcomes with a complication rate comparable to that of a non-obese population. Comparative studies with conventional cups are needed to confirm or infirm our results.
