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Complete revascularization improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD); however, the optimal timing of noninfarct-related artery intervention during the index procedure, immediate revascularization (IR) versus a staged approach (SR), remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials comparing SR and IR in patients with STEMI and MVD. The primary outcome was major adverse cardiovascular events. Secondary outcomes included all-cause and cardiovascular mortality, recurrent myocardial infarction, unplanned ischemia-driven revascularization, stent thrombosis, stroke, major bleeding, acute kidney injury, and heart failure hospitalization. Random-effects models with Hartung–Knapp adjustment were used. Trial sequential analysis assessed evidence conclusiveness, and the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation. Eight randomized trials, including 5077 patients (2556 SR; 2521 IR), were analyzed. No significant differences were observed between SR and IR for major adverse cardiovascular events [odds ratios (ORs), 1.07; 95% confidence intervals (CI), 0.76–1.49], recurrent myocardial infarction (OR, 1.30; 95% CI, 0.80–2.14), cardiovascular mortality (OR, 0.76; 95% CI, 0.51–1.13), or all-cause mortality (OR, 0.75; 95% CI, 0.54–1.06). Rates of stent thrombosis, stroke, unplanned ischemia-driven revascularization, major bleeding, acute kidney injury, and heart failure hospitalization were also comparable. Trial sequential analysis indicated insufficient information size to draw definitive conclusions, and the certainty of evidence ranged from very low to low. In patients with STEMI and MVD, staged and immediate complete revascularization provide comparable ischemic, safety, and mortality outcomes. Current evidence supports clinical equipoise, and revascularization timing should be individualized pending results from adequately powered trials.

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Background/Objectives: Primary spinal sarcomas, encompassing both bone and soft tissue histotypes, demand individualized reconstruction due to heterogeneous tumor biology, anatomic complexity, and host environments compromised by radiation, systemic therapy, or prior surgery. This narrative review reframes post-resection spinal reconstruction through a precision-medicine lens. Methods: A structured literature review was performed using PubMed and Scopus, targeting articles published between 2000 and 2026. Searches encompassed spinal sarcoma reconstruction, radiation and fusion, biologic reconstruction, and emerging technologies. Results: Tumor grade, radiation exposure, and systemic therapy timing emerge as multiplicative determinants of reconstructive environment quality, with drug-class-specific perioperative effects warranting stratified management. Vascularized bone grafts achieve reliable fusion in compromised hosts where avascular constructs fail. A precision-oriented reconstructive ladder is proposed as a conceptual, hypothesis-generating framework to guide strategy selection. Hybrid PSI-VBG constructs may further expand reconstructive possibilities. The evidence base remains largely composed of small, retrospective series. Conclusions: Individualized strategies anchored in tumor biology and host environment are the cornerstone of durable spinal sarcoma reconstructions. The proposed framework requires prospective, multi-institutional validation. Standardized outcome definitions, prospective registries, and histotype-stratified analyses are needed to advance the field.

Background The diagnosis of periprosthetic joint infection (PJI) is facilitated by consensus identification of synovial biomarkers, which may be aided by targeted microbial next generation sequencing (NGS) of synovial fluid. The primary objective of the study was to evaluate NGS performance across 3 years to ICM 2018 minor criteria for PJI. Methods Synovial fluid specimens submitted from 2020–2022 by outpatient surgical clinics to MicroGenDX for matched synovial biomarker and NGS analysis were selected for retrospective analysis. Synovial biomarkers tested included C-reactive protein (CRP), white blood cell (WBC) count, and polymorphonuclear (PMN) leukocyte percentage. Synovial fluid analysis compared NGS microbial positivity with positive incidence of PJI determined by scoring of synovial biomarkers using ICM 2018 minor criteria for infection. Results The overall sensitivity, specificity, and accuracy of NGS to ICM diagnosed PJI across 2,011 specimens was 76.4% [95% CI, 0.723–0.801], 92.3% [0.91–0.94], and 88.7% [0.87–0.90], respectively. When comparing the diagnostic performance of NGS and individual biomarkers to infection, NGS was more specific to PJI than synovial CRP (specificity = 0.894, 95% CI: 0.88–0.91), but not PMN or WBC. NGS was positive in 7.7% of ICM negative samples. NGS positive: ICM negative samples were associated with significantly elevated synovial PMN ( p = 0.001) and WBC ( p < 0.0001) compared to NGS negative: ICM negative samples. Across all samples, NGS positivity was associated with significantly elevated results for all tested biomarkers ( p < 0.0001). Eight bacterial species dominated the composition in 68% of samples, whereas 46 different microbes were dominant in the remaining third. Conclusion Microbial targeted NGS positivity was concordant with ICM minor criteria for PJI and should be considered a useful tool for diagnosis. There is a low risk of false positive detections comparable to ICM biomarkers. Elevated biomarkers in NGS positive: ICM negative samples may indicate infection occurring that is poorly captured by the three measured synovial biomarkers. Uncommon species are collectively common to PJI and NGS is uniquely positioned to detect such species as they are frequently missed by conventional microbiological testing, including culture and quantitative PCR. These results suggest formal diagnostic schemes would benefit from the addition of NGS as a diagnostic criterion.

Abstract Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

ABSTRACT Aims Exercise capacity is a powerful predictor of cardiovascular risk. In patients unable to exercise, body composition analysis can potentially be used to estimate cardiorespiratory fitness. We developed a body composition “fitness” score, then validated its utility in two external populations. Methods and Results We included patients from four sites undergoing single photon emission computed tomography (SPECT) and twelve sites undergoing positron emission tomography (PET). We quantified body composition using deep learning. We evaluated associations between body composition and good exercise capacity (defined as completing ≥7 minutes on a Bruce protocol) then developed a body composition “fitness” score. We then assessed the associations of “fitness” score with exercise capacity and all-cause mortality in external populations. In total, 36471 patients were included with median age 67 (interquartile range 58 – 74). Median skeletal muscle density was higher among patients with good exercise capacity. In the external SPECT population, the body composition “fitness” score had higher prediction performance for good exercise capacity (AUC 0.771, 95% CI 0.752 – 0.789) than age (AUC 0.717, p<0.01). In the external PET population, high body composition “fitness” score was associated with lower cardiovascular death (adjusted hazard ratio 0.70, 95% CI 0.62 – 0.79, p<0.001). Conclusions We demonstrated that a comprehensive body composition “fitness” score could identify patients with good cardiorespiratory fitness. This approach transforms routinely acquired CT data into a surrogate marker of fitness which can be applied in patients undergoing PET, or other CT imaging, where exercise testing is not performed. Graphical Abstract Overview of study design. The overall population (n=36471) was split as outlined above. Body composition was analyzed from available computed tomography imaging. The distribution of body composition measures were analyzed in the combined single photon emission computed tomography (SPECT) populations. A body composition “fitness” score was derived to predict good exercise capacity in the internal population, with associations assessed in the two external testing populations.

Background Female sex hormones used in feminizing hormone therapy (FHT) may influence activation and persistence of HIV pre‐exposure prophylaxis (PrEP) medications. The clinical relevance of this interaction remains unclear, particularly for transgender and cisgender women (TGW and CGW). To address this gap, we examined drug metabolites in HIV susceptible cells isolated from blood and rectal tissues of TGW and CGW. Materials and Methods We enrolled 23 TGW, 13 on FHT and 10 CGW. Participants received five directly observed daily PrEP doses: emtricitabine 200 mg with either tenofovir disoproxil fumarate 300 mg (FTC/TDF) or tenofovir alafenamide 25 mg (FTC/TAF). Blood and rectal tissue samples were obtained. Mononuclear and CD4 + cells were isolated and analysed for intracellular triphosphorylated nucleotides (TFVdp and FTCtp) and total nucleotide pools (pTFV and pFTC) using HPLC‐MS/MS. Serum hormone concentrations were quantified via enzyme immunoassay. Results and Conclusion Total nucleotide pools (pTFV and pFTC) correlated with active metabolites (TFVdp and FTCtp) in blood and rectal CD4 + cells ( r 2 > 0.75, p < .001). No significant differences in pTFV or pFTC concentrations were observed between high and low oestradiol groups in either CGW or TGW ( p > .1). No correlation was observed between serum oestradiol concentrations and nucleotide concentrations. TAF resulted in 6.8‐fold higher median pTFV concentrations in blood CD4 + cells ( p < .001) but eightfold lower median pTFV concentrations in rectal CD4 + cells compared to TDF ( p = .008). These findings suggest that neither endogenous hormonal fluctuations in CGW nor exogenous FHT in TGW adversely impact intracellular PrEP pharmacology in key HIV target cells.

INTRODUCTION: Normalized quality of life represents a crucial long-term treatment goal in Crohn's disease (CD). We evaluated the effect of risankizumab (RZB) vs ustekinumab (UST) on achieving clinically meaningful improvements in patient-reported outcomes in the phase 3b head-to-head SEQUENCE study. METHODS: Adults with moderate-to-severe CD whose previous anti-tumor necrosis factor therapy failed were randomized 1:1 to recommended induction and maintenance doses of RZB or UST. The proportion of patients who achieved Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, and improvements in 36-item short-form health survey physical and mental component summary (physical component summary and mental component summary, respectively) scores was evaluated at weeks 24 and 48. The proportion of patients experiencing improvement in select symptoms of the IBDQ was reported. RESULTS: Analysis included 520 patients (RZB: N = 255; UST: N = 265). At week 24, greater proportions(all P ≤ .01) of RZB- vs UST-treated patients achieved IBDQ response (75.3% vs 64.2%), IBDQ remission (52.5% vs 30.9%), and improvements in 36-item short-form health survey physical component summary (65.9% vs 53.2%). At 24 weeks, lower proportions (all P ≤ .05) of RZB- vs UST-treated patients experienced fatigue (51.4% vs 69.1%), difficulty sleeping (37.7% vs 54.3%), depression (34.1% vs 42.6%), anxiety (34.1% vs 49.8%), and bowel urgency (27.1% vs 40.0%) all of the time to some of the time. Improvements were sustained through week 48. DISCUSSION: RZB was more effective than UST in achieving sustained clinically meaningful patient-reported outcome improvements including IBDQ response and remission, and in reducing frequency of select symptoms of the IBDQ through week 48 among patients with moderate-to-severe CD.