Citations

Summary Chimeric antigen receptor T cells directed against CD‐19 are highly effective therapies for various subtypes of B‐cell non‐Hodgkin lymphoma (NHL). We have studied the impact of patient‐specific lymphocyte growth kinetics after lymphoid depletion chemotherapy on both long‐term outcomes and toxicity in patients with diffuse large B‐cell non‐Hodgkin lymphoma (DLBCL). The growth of the lymphocyte populations early after chimeric antigen receptor T‐cell (CAR‐T) therapy is well described by an exponential function and the growth rate of the cells appears to be one of the most critical determinants of overall survival in these patients. The maximum lymphocyte peak and the area under curve for lymphocytes within the first 4 weeks after CAR‐T therapy had no impact on survival. Receiver operator characteristic analysis determined that a replication rate ≥0.3876/day is associated with superior rates of complete response and durable responses. This threshold is associated with higher grades of cytokine release syndrome and the need for tocilizumab. However, patients with this threshold have a median overall survival of 3.04 years compared to 1.035 years for patients with slower lymphocyte replication ( p = 0.0206). The major determinant of depth of response and durability of response to CAR‐T in NHL is the speed of lymphocyte expansion.

The 6th edition of the WHO Classification of Breast Tumours introduces both major and minor changes based on recent advances in our understanding of breast biology, developments in diagnostic modalities, identification of specific molecular targets and new treatment regimens necessitating modifications to pathology reporting and tumour biomarker categorisation. This review summarises the main changes that strive towards a classification of global relevance. In invasive carcinoma, predictive factors increasingly inform modern breast cancer treatment. The 6th edition provides an update on HER2 reporting categories following the DESTINY‐Breast 04 and 06 trials. Terminologies used to classify invasive tumours are clarified, with the term ‘variant’ now reserved for molecular/genetic alterations. Invasive lobular carcinoma (ILC) with extracellular mucin is recognised as a new diagnostic entity with prognostic implications. The diagnosis of mucinous carcinoma (MC) is reserved for mucin secreting carcinomas with grade 1 or 2 morphology and a favourable biomarker profile. The diagnosis of malignant phyllodes tumours requires only four of the original five adverse histological criteria. Classification of neuroendocrine tumours (NETs) is revised, recognising that the unified model, promoted in the 5th edition, is difficult to apply to the breast. New approaches to the classification of adenomyoepithelioma are discussed but the 5th edition system is broadly retained. A new section on ‘Small Diagnostic Samples’ outlines the merits of non‐operative biopsy diagnosis, the B coding system and the importance of multidisciplinary review. Changes to diagnostic practice and the emerging role of artificial intelligence, with advantages and challenges, are discussed in a new section on ‘Digital Pathology’.

Cisgender males remain less likely to report depressive symptoms or initiate mental health conversations with primary care providers. Guided by the Health Belief Model and Gender Role Theory, this study examined how cisgender males perceive and address depression, with a focus on their comfort with the Patient Health Questionnaire-9 and factors influencing their willingness to discuss mental health concerns. An anonymous mixed-methods survey link was disseminated to 62 cisgender males between November 2024 and January 2025. Quantitative items assessed preferences for mental health discussions, willingness to initiate conversations, and experiences with the PHQ-9. Qualitative responses were analyzed to identify perceived barriers, attitudes toward screening, and beliefs shaped by masculine role norms and health-belief constructs. Most participants (n = 48, 77.42%) preferred in-person mental health discussions with primary care providers. Half (n = 31, 50%) had previously received a mental health screener. Despite this, a large majority (n = 54, 87.10%) reported comfort completing screeners such as the PHQ-9 independently. However, n = 14 (22.58%) were unlikely to initiate mental health conversations. Qualitative findings revealed 3 dominant themes stigma, fear, and trust, that shaped comfort with screening and willingness to disclose symptoms. The HBM highlighted perceived barriers and low perceived susceptibility, while GRT contextualized how masculine norms discouraged disclosure. Cisgender males show readiness to engage with depression screeners when tools are accessible, yet stigma, fear, and trust remain central influences on disclosure. Integrating the PHQ-9 into routine primary care with deliberate conversations and strengthening patient-provider trust may enhance early identification of depression.

Introduction Blood-based biomarkers offer a promising, minimally invasive approach to Alzheimer’s disease (AD) diagnosis, yet validation in admixed populations remains limited. We investigated whether plasma biomarkers predict CSF-defined AD pathology in a Brazilian cohort. Methods Seventy-eight older adults [including individuals with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and cognitively unimpaired controls] underwent cognitive testing, neuroimaging, and plasma biomarker assessment. CSF data were available for symptomatic participants (MCI and SCD; n = 61), and regression and ROC analyses were performed in the subset with both CSF and APOE genotyping data ( n = 53). Plasma Aβ42, p-Tau181, p-Tau217, t-Tau, and derived ratios were quantified. Multivariable logistic regression and ROC analyses evaluated prediction of abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42, adjusting for age, sex, and APOE ε4 status. Results Approximately 25% of individuals with MCI exhibited abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42 ratios. Moderate correlations were observed between plasma and CSF biomarkers (r > 0.4), particularly for Aβ42/p-Tau217 and p-Tau217. In adjusted models, plasma p-Tau217 and the Aβ42/p-Tau217 ratio independently predicted abnormal CSF pathology. Each one standard deviation increase in p-Tau217 was associated with 3.53–4.83-fold higher odds of abnormal CSF ( p ≤ 0.003). In contrast, higher Aβ42/p-Tau217 ratios were associated with substantially lower odds of pathology, with each one standard deviation increase corresponding to a 91%–93% reduction in risk ( p ≤ 0.002). The ratio showed stronger associations than p-Tau217 alone. ROC analyses demonstrated good discrimination. For CSF p-Tau181/Aβ42, Aβ42/p-Tau217 achieved an AUC of 0.88 (83% sensitivity, 85% specificity), compared with 0.83 for p-Tau217. For CSF t-Tau/Aβ42, both biomarkers yielded AUCs of 0.89. Discussion Plasma Aβ42/p-Tau217 and p-Tau217 effectively identify CSF-defined AD pathology in an admixed cohort. While higher p-Tau217 levels were associated with increased odds of pathology, higher Aβ42/p-Tau217 ratios were associated with lower pathological burden and demonstrated stronger effect sizes, supporting the added value of combining amyloid and tau biomarkers. These findings provide initial evidence for local validation of blood-based AD biomarkers in Brazil.

ABSTRACT The HLA‐DQB1*03:506:01:01 allele is characterised by a single nucleotide substitution in codon 130 in exon 3.

Abstract Background Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy (HCM) management, yet Doppler-based measurements are technically demanding and require expertise. Objective To develop a multi-view deep learning model capable of classifying LVOT obstruction (> 20mmHg) using routine 2D echocardiographic windows without reliance on Doppler imaging. Methods We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from three standard transthoracic echocardiographic views to classify LVOT gradients. Results Training was performed on a derivation cohort (N = 1833) from a tertiary care system in the United States, with model performance evaluated on an internal held-out test set (N = 275) and a Korean external validation cohort (N = 46). Single-view baselines showed limited discrimination (external AUROCs 0.47–0.70). Conversely, domain-specific foundational model (EchoPrime) achieved superior single-view performance (AUROCs 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an AUROC of 0.84 on the external cohort with significant population-shift. Conclusions These results suggest LVOT physiology is encoded in routine 2D imaging and can be leveraged for clinically relevant gradient classification without Doppler input- proposed AI-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal HCM management.

Background The PREPARE trial (Pragmatic Randomized trial Evaluating Pre-operative Alcohol skin solutions in Fractured Extremities), published in February 2024, demonstrated that 0.7% iodine povacrylex in 74% isopropyl alcohol reduced surgical site infections in patients with closed fractures compared with chlorhexidine gluconate in 70% isopropyl alcohol. Prior studies have shown that the translation of clinical trial findings into routine clinical practice and surgical procedures frequently takes longer than a decade, and strategies to accelerate implementation in orthopaedic surgery remain poorly defined. Engaging in a multifaceted implementation strategy with minimal barriers to entry for providers may be able to reduce this time to widespread adoption. Questions/purposes (1) Can the low-cost single-center dissemination efforts of the PREPARE trial results change antiseptic usage? (2) If a true practice change occurs, can the change be sustained over time without additional dissemination efforts? (3) Does the adoption of new evidence vary between fellowship-trained orthopaedic trauma surgeons and orthopaedic trauma surgeons who are not fellowship-trained? (4) What is the economic impact of a practice change to iodine povacrylex on hospital purchasing costs? Methods This was a retrospective, historically controlled comparative study of patients who underwent operative treatment of an extremity fracture at a single, urban, Level I academic trauma center before and after a dissemination effort aimed at increasing PREPARE trial awareness. A multifaceted dissemination strategy consisting of surgeon and nursing education, posted reminders, and supply chain support was implemented at the study site in February 2024. Patients were analyzed across three time periods: before dissemination (January 2020 to January 2024), during the transition (February 2024), and after dissemination (March 2024 to July 2025). An electronic medical record query identified patients with operative fracture management procedural codes who had a recorded antiseptic skin prep in the surgical flow sheet between January 2020 and July 2025. A total of 4822 patients were identified, and 222 duplicate entries were excluded, leaving 4600 patients for analysis (3351 before dissemination, 49 transitional, and 1200 after dissemination). To validate the completeness of our electronic health record query, we performed manual random sampling of monthly operative case logs, confirming that this query strategy successfully identified all patients with the relevant Current Procedural Terminology codes (that is, there were no exclusions for lack of antiseptic documentation). There were no differences in patient demographics, including sex, ethnicity, open fractures, or the distribution of upper and lower extremity fractures. Choice of surgical skin antiseptic was compared before and after dissemination using a log-binomial model. Results Dissemination efforts changed antiseptic use patterns with an immediate increase in iodine povacrylex use from 0.8% (27 of 3351) before intervention to 86% (1033 of 1200) after intervention (OR 765 [95% confidence interval 488 to 1197]; p < 0.001). This high level of use remained stable throughout the 17-month postintervention period without any additional dissemination efforts (p = 0.20 for trend). Adoption was higher among fellowship-trained trauma surgeons (94.8% increase) compared with surgeons without trauma fellowship training (34.7% increase). Hospital antiseptic product purchasing data, which reflect usage and restocking and were used as a secondary metric of practice change, also demonstrated an increase in iodine povacrylex demand and decline in chlorhexidine demand. Conclusion A targeted and multifaceted dissemination strategy led to rapid adoption of iodine povacrylex for use as the preferred surgical skin antisepsis in fracture surgery at our institution, which was sustained over the 17-month postintervention period. This finding contrasts with a historically slow uptake of surgical trial evidence into clinical practice. Pragmatic, low-cost approaches such as surgeon leadership, team-based multidisciplinary education, workflow reminders, and supply chain readiness may help to accelerate translation of evidence into orthopaedic practice. Future studies should evaluate the long-term sustainability of practice changes, surgical site infection outcomes, and generalizability across institutions. Level of Evidence Level III, therapeutic study.

Post-transplant thrombotic microangiopathy (PT-TMA) is a serious and underrecognized complication of kidney transplantation, associated with substantially reduced allograft survival. Its heterogeneous presentations, ranging from systemic to renal-limited forms, and multifactorial etiologies complicate timely diagnosis and management. Complement activation is central across all etiologies, either as a primary driver of disease in recurrent complement-mediated TMA (also known as atypical hemolytic uremic syndrome or aHUS) or as an amplifier in de novo PT-TMA (dnTMA). Accurate diagnosis requires a combination of clinical assessment, laboratory evaluation, and histopathologic examination, with particular attention to complement abnormalities, donor/recipient risk factors, and potential triggers. Management must be individualized, encompassing supportive care, optimization of immunosuppression, complement blockade, and plasmapheresis in select cases. Histologic features and clinical risk factors can guide prognosis, and scoring systems provide valuable tools for risk stratification. Despite advances in therapy, long-term outcomes remain suboptimal, particularly in antibody-mediated rejection (AMR)-related cases. Ongoing research is essential to clarify the optimal context for the use of anti-complement therapy, and to develop effective prophylactic and therapeutic strategies while maintaining adequate immunosuppression.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126