Citations

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Background: Frequent pivoting, rotation, and deep hip flexion place football players at high risk for femoroacetabular impingement (FAI), a leading cause of hip pain in this population. Previous studies have primarily focused on professional National Football League athletes undergoing mixed surgical techniques, including labral debridement. Limited data exist on outcomes in younger, amateur players treated with labral repair. Purpose: To report return to sport (RTS) rates and functional outcomes at a minimum 5-year follow-up in primarily active high school and college football players undergoing primary hip arthroscopy with labral repair for FAI. Study Design: Case series, Level of evidence, 4. Methods: All football players who underwent primary hip arthroscopy with labral repair for FAI between 2010 and 2019 were identified from an institutional database. Collected data included descriptive data, radiographic parameters, surgical details, and reoperations. At a minimum 5-year follow-up, RTS outcomes and patient-reported outcome measures (PROMs), such as the Modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS), were evaluated. Results: A total of 36 hips in 27 male athletes (mean age, 18 years; body mass index, 28.1 kg/m 2 ) were included. The majority of athletes competed at the high school (70%) or collegiate level (26%). Mean preoperative radiographic measurements were as follows: lateral center-edge angle, 31.6°; Tönnis angle, 4.1°; and alpha angle, 61.4°. Femoroplasty and acetabuloplasty were performed in 100% and 86% of cases, respectively. Also, 84% of players returned to football, all at the same or higher level than before surgery. At a mean follow-up of 9.8 years, all PROMs improved significantly from baseline ( P < .002). Outcome scores at follow-up were as follows: mHHS 90.5; HOS-Activities of Daily Living, 94.5; HOS-Sports-Specific Subscale, 91.1; and visual analog scale (VAS) pain with use, 2.3/10; VAS pain at rest, 1.3/10; and surgical satisfaction, 8.5/10. No patients required revision surgery. However, 2 patients (7%) underwent reoperations—including 1 for heterotopic ossification excision and 1 for periacetabular osteotomy. Conclusion: American football players who underwent primary hip arthroscopy with labral repair for FAI achieved excellent long-term outcomes, with high RTS rates at the same or higher levels, and improvements in PROMs and patient satisfaction. Despite favorable outcomes, nonmedical factors, such as graduation, may influence RTS in competitive athletes, particularly at the high school and collegiate levels.

476 Background: Lack of standardized reporting and collection of patient-reported outcomes (PROs) limits cross-trial comparisons of first-line IO-based regimens for mRCC. Prospectively collected real world data may fill this important knowledge gap. Pts with stable/improved QoL at 3 mo versus baseline have longer median OS than pts with worse/unobserved HRQoL versus baseline (Cella, 2024). Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology), no prior systemic therapy (ST), and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. Descriptive statistics are used to show PRO score changes from baseline. We evaluate longitudinal change from baseline in PRO scores using least squares mean (LSM). Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Higher score indicates better QOL. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Results: As of 10/1/25, 360 pts were managed with ST, including 266 pts on IO-based combinations: 35 cabozantinib + nivolumab (C+N), 49 lenvatinib + pembrolizumab (L+P), 40 axitinib + pembrolizumab (A+P), and 142 ipilimumab + nivolumab (I+N). Overall median follow-up is 12.1 mos (IQR 6, 24). Age, sex and race were similar across regimens. Prior nephrectomy (50%) was lower than in trials. C+N and L+P pts had less clear cell (56 and 65%) versus A+P and I+N pts (94 and 82%). A+P pts had more favorable IMDC risk (19%) and less poor risk (14%). Baseline QOL was variable across regimens, with L+P generally the lowest. Absolute changes in PROs from enrollment to mo 3 (early change) by regimen are shown in the Table. LSM change from baseline in FKSI-19 and FKSI-DRS favored IO-IO versus IO-TKI at 3 mos but not at 6 mos (not shown). Conclusions: While early change in PROs did not meet the MID threshold between the IO-TKI and I+N cohorts, different patterns of early change are apparent among specific IO-TKI regimens. IO-TKI regimens exhibited higher variation in early PRO change vs I+N. As the data matures, we will associate baseline PROs and early PRO changes with early death and other outcomes. Clinical trial information: NCT04919122 . 3 month change. Instrument C+N (N=35) L+P (N=49) A+P (N=40) All IO-TKI(N=124) I+N(N=142) FKSI-19, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.3 (11) 2.8 (13) -3.2 (12) -0.2 (12) 0.7 (10) Median (IQR) 1.4 (-7, 6) 5.0 (-7, 11) -1.0 (-14, 5) 1.4 (-10, 8) -0.3 (-5, 6) FKSI-DRS, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.8 (5) 1.5 (7) -1.8 (6) -0.3 (6) 0.8 (5) Median (IQR) -0.5 (-5, 3) 2.0 (-5, 5) -1.0 (-5, 3) 0.0 (-5, 4) 0.0 (-2, 4) FACT-G, N (%) 27 (77) 32 (65) 29 (73) 88 (71) 102 (72) Mean (SD) 2.1 (14) 5.2 (16) -3.5 (15) 1.4 (15) 0.3 (13) Median (IQR) 4.0 (-4, 10) 1.2 (-6, 13) -6.4 (-11, 4) 1.6 (-8, 10) 1.6 (-7, 8)

Abstract Recent advances in long-read transcriptome sequencing enable high-throughput profiling of full-length RNA isoforms in bulk, single-cell, and single-nucleus samples. However, long-read datasets typically contain a mixture of complete and partial transcripts, leading to pervasive ambiguity in read-to-isoform assignment and complicating accurate isoform identification and quantification, particularly in the absence of reliable reference annotations. These challenges are further amplified in single-cell and single-nucleus samples, where coverage is sparse and transcriptional heterogeneity is high. Here, we present the Long Read Alignment Assembler (LRAA), a unified and versatile computational framework for isoform identification and quantification from long-read RNA sequencing data across bulk, single-cell, and single-nucleus transcriptomic samples. LRAA combines splice-graph based structural modeling with expectation maximization based optimization to probabilistically resolve ambiguous read assignments and improve isoform abundance estimation. The framework supports quantification-only, reference-guided, and fully reference-free (de novo) modes of analysis within a single methodological paradigm. We benchmarked LRAA using both simulated and genuine long-read datasets spanning sequencing standards and whole transcriptomes. Central to this evaluation is a novel benchmarking strategy based on Multiplexed Overexpression of Regulatory Factors (MORFs), which provides biologically expressed, barcoded isoforms with unambiguous read-level ground truth. Across all benchmarks, including MORFs, synthetic spike-ins, and whole-transcriptome datasets, LRAA consistently outperformed state-of-the-art methods in isoform identification accuracy, sensitivity, and expression quantification. Finally, we demonstrate the biological utility of LRAA by resolving cell-type-specific isoform usage across peripheral blood immune cell populations and by detecting a pathogenic cryptic isoform of STMN2 with associated transcriptional changes in single-nucleus RNA-seq data from frontal cortex tissue of an individual with frontotemporal dementia (FTD). Together, these results establish LRAA as a robust and general solution for resolving transcript diversity in complex biological systems, from development to disease.

Abstract Background: Exercise capacity (VO 2peak ) predicts mortality in adult patients with CHD. There is a lack of paediatric exercise capacity data based on specific CHD lesions, limiting the ability to contextualise interpretation based on expected performance during testing. The primary aim of this study was to establish VO 2peak percentiles for paediatric patients with repaired CHD undergoing treadmill-based cardiopulmonary exercise testing (CPET). Methods: Retrospective analysis of CPET data from 2004 to 2022. CPETs were analysed for patients with CHD aged 6–18 years. Patients with repaired CHD were categorised based on their most haemodynamically significant CHD lesion. Percentiles and age-based trends were plotted for each group. Results: A total of 887 patients were included. CHD patients were divided into ten diagnostic subgroups. The mean percent expected VO 2peak for each of the subgroups were as follows: Atrial and ventricular septal defect (94.5 ± 25.1%), pulmonary valve repair (88.1 ± 18.4%), aortic valve repair (92.7 ± 16.4%), tricuspid and mitral valve repair (81.3 ± 20.4%), coarctation of the aorta (93.6 ± 18.8%), transposition of the great arteries (90.5 ± 19.4%), double outlet right ventricle and truncus arteriosus (80.5 ± 16.2%), tetralogy of Fallot (85.6 ± 20.9%), left ventricle dominant Fontan (74.7 ± 18.3%), and right ventricle dominant Fontan (75.7 ± 16.7%). Conclusion: There is a varying degree of reduced exercise capacity in paediatric patients with repaired CHD. Univentricular hearts and tricuspid and mitral valve repair have the lowest VO 2peak . These CHD-specific percentiles may help providers risk-stratify and counsel patients with CHD.

Importance Acute invasive fungal rhinosinusitis (AIFRS) is a rapidly progressive and potentially life-threatening infection that predominantly affects immunocompromised patients. Recent advances in diagnostic imaging, antifungal therapy, and surgical techniques may have altered its incidence, morbidity, and mortality. Objective To evaluate temporal trends in the pooled proportion, morbidity, and mortality of AIFRS in immunocompromised patients and assess the association of diagnostic and therapeutic advances. Data Sources Systematic searches of Ovid MEDLINE, Ovid Embase, PubMed, Scopus, Web of Science, Cochrane, and Google Scholar from 1977 through October 20, 2025, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Study Selection Prospective, retrospective, and cross-sectional studies and case series reporting pooled proportion, morbidity, or mortality of AIFRS in immunocompromised patients were included. Non-English articles, reviews, editorials, and studies with fewer than 10 patients were excluded. Data Extraction and Synthesis Two independent reviewers extracted data using standardized templates; disagreements were resolved by consensus. Risk of bias was assessed using the Newcastle-Ottawa Scale and Murad tool for case series. Random-effects meta-analysis generated pooled proportion, morbidity, and mortality rates with 95% CIs. Heterogeneity was quantified using I 2 statistics. Meta-regression and sensitivity analyses evaluated temporal trends and study-level effects. Main Outcomes and Measures Pooled proportion, morbidity, and mortality rates of AIFRS stratified by publication period (1983-2012 vs 2013-2025). Results A total of 205 studies comprising 48 437 immunocompromised patients (median [range] age, 49.4 [5.2-68.8] years), including 10 311 (21.3%) with AIFRS, were analyzed. The pooled proportion was 11.8% (95% CI, 7.9%-17.2%), rising to 16.6% (95% CI, 8.7%-29.2%) in studies from 2013 to 2025. Overall mortality was 31.2% (95% CI, 28.3%-34.3%), declining from 41.9% (95% CI, 35.0%-49.1%) before 2013 to 28.2% (95% CI, 25.1%-31.4%) after 2013. Morbidity was 37.0% (95% CI, 32.9%-41.4%), with similar rates across periods (39.3% before 2013 vs 36.4% after 2013). The most common complications were vision loss, exophthalmos/proptosis, and orbital exenteration. Conclusions and Relevance This systematic review and meta-analysis suggests that the pooled proportion of AIFRS among immunocompromised patients has increased while mortality has declined, reflecting advances in diagnostic and therapeutic approaches. Early detection and aggressive management remain critical to improving outcomes.