Citations

Older adults are susceptible to infections in part due to waning of immune memory. To uncover mechanisms of a long-lasting immune memory, we contrasted varicella zoster virus antigen–specific memory T cell responses in adults vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine conferring durable protection only when given at young age or with an adjuvanted component vaccine eliciting long-lasting immunity in older adults. Unlike VZV-specific CD4 + T cells, CD8 + T cells exhibited profound age-sensitive changes including memory subset shifts, reduced T cell receptor diversity, and loss of stem-like features. Vaccination of older adults with the adjuvanted vaccine did not restore CD8 + defects but selectively enhanced T helper 17 (T H 17) CD4 + T cells and prevented their conversion into regulatory T cells, likely through lipid metabolic regulation. Thus, durable vaccine efficacy with aging relies on antigen-specific T H 17 cells that compensate for CD8 + T cell defects.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

Abstract Background Quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic value in cardiac PET, but their widespread use is limited by the technical demands of dynamic imaging protocols. We evaluated the feasibility of using artificial intelligence (AI) to predict MBF and MFR from static and gated PET images, without the need for dynamic acquisition. Methods A machine learning (XGBoost) model was trained on 82Rb PET multi-center dataset using static perfusion imaging, injected dose, hemodynamic measures, clinical data and CT-derived features (including body composition) from the hybrid CT attenuation scan. Model performance was evaluated externally in an independent cohort. Results In total, 10,566 (derivation-cohort) and 7,842 (external-cohort) patients were included in this multi-center study. On the external-cohort, AI approach achieved an Area under the curve (AUC) of 0.92 (0.92–0.93) for abnormal stress MBF and 0.91 (0.90–0.92) for abnormal MFR; Intra-class correlation (ICC) 0.80 (0.78–0.82) and 0.78 (0.76–0.79), respectively. AI MFR closely mirrored the prognostic performance of measured MFR, showing nearly identical Kaplan–Meier risk stratification (both p<0.0001) and maintaining strong, and independently significant associations with all-cause mortality (HR 3.4 [2.8–4.2] vs. 4.6 [3.6–5.8]; both p<0.001), and demonstrated similar added value to perfusion for mortality prediction. Conclusion AI-predicted virtual stress MBF and MFR assessment using static and gated PET data is feasible and generalizable across cohorts. By removing the dependency on dynamic acquisitions, this approach has the potential to broaden the clinical adoption of flow quantification. STRUCTURED GRAPHICAL ABSTRACT PET: Positron Emission Tomography, CT: Computed Tomography, MFR: Myocardial Flow Reserve Key Question: Can machine learning models trained on dynamic PET datasets accurately predict regional stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) from static image features, physiological parameters, and CT-based anatomical measures? Key Finding: Artificial intelligence can accurately estimate MBF and MFR from non-dynamic PET data, with strong agreement to reference standards. Take-home Message: By eliminating reliance on dynamic PET acquisitions, machine-learning has the potential to broaden clinical adoption of quantitative flow assessment.

Case: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification. Scoliosis may develop and progress rapidly, especially during adolescence. We report 4 patients with FOP and scoliosis during early adolescence: A 12-year-old girl underwent T4-S2 posterior spinal fusion (PSF); another 12-year-old girl underwent T4-S2 PSF; a 13-year-old boy underwent T3-L4 PSF; and a 14-year-old girl was managed nonoperatively because the complex deformity and ankylosed shoulders could not be adequately balanced with surgery. Conclusion: In patients with FOP, surgical intervention can reduce thoracic deformity and improve pulmonary function but carries substantial risks, including heterotopic ossification.

Abstract Background Mitral regurgitation (MR) and tricuspid regurgitation (TR) are prevalent valvular heart diseases associated with significant morbidity and mortality. Traditional echocardiography faces limitations in availability, cost, consistency, and reliability, leading to misdiagnosis and undertreatment. The application of artificial intelligence (AI) to echocardiographic scans has the potential to address these challenges. Methods This study evaluates the performance of an AI algorithm on an external population. The algorithm utilizes deep learning networks to analyze echocardiographic exams for diagnosing atrioventricular valve disorders. We tested the algorithm on transthoracic echocardiography data collected from a single center between 2013 and 2023. The model's performance was compared to ground truth values using two classification schemes: distinguishing between normal-mild and moderate-severe regurgitation, and categorizing results into four groups: normal, mild, moderate, and severe. Results The MR cohort included 280 patients, while the TR cohort comprised 298 patients. The model demonstrated a robust ability to identify clinically significant (moderate and above) atrioventricular valve regurgitation. The MR model achieved an area under the curve (AUC) of 0.98 (95% CI: 0.97–0.99), with 91% accuracy, 95% sensitivity, and 89% specificity. In comparison, the TR model exhibited an AUC of 0.96 (95% CI: 0.94–0.98), with 84% accuracy, 91% sensitivity, and 80% specificity. Conclusion The model demonstrated high diagnostic accuracy and reliability in assessing atrioventricular valve regurgitation severity, highlighting its potential as a valuable clinical tool. The findings underscore the role of AI in complementing expert evaluations and improving access to effective diagnostics, with future applications potentially including point-of-care diagnosis and monitoring of disease progression.

Since its introduction into medical terminology by Lord Henry Cohen in 1941, the term “neurapraxia” has become established in the neurological and neurosurgical lexicon, although it is often misused or misspelled. It denotes a transient dysfunction of a peripheral nerve, as distinct from axonotmesis and neurotmesis, which describe more significant structural injuries to a peripheral nerve. To expand our understanding of neurapraxia, it is necessary to examine the phenomenon in both temporal and spatial contexts. This study examines neurapraxia in: (A) Time—(1) the origins of the term neurapraxia and (2) the time-course of a neurapraxic injury and its recovery, and (B) Space—(3) the microstructure of a neurapraxic injury and (4) the locations of neurapraxic injuries within the peripheral nervous system. We demonstrate that the term neurapraxia encompasses both a temporal and a spatial definition. In time, it applies to transient peripheral nerve palsy, from which recovery occurs before there is sufficient time for axonal regeneration, typically within a few weeks. In space, there is a histopathological change limited to localized demyelination in nerves lined by epineurium and myelinated by Schwann cells. Nerves distal to the spine qualify as nerves to which the term neurapraxia can apply; however, cranial nerves and spinal nerve roots (including cauda equina) are inconsistent with this owing to the variability in myelinating cells along their course (oligodendroglia proximally, i.e., central glial segment), the absence of an epineurial covering, and exposure to cerebrospinal fluid.

Abstract Background Cardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular (CV) benefits and are recommended for T2DM patients with atherosclerotic CVD (ASCVD). However, real-world data on their adoption in high-risk populations, particularly myocardial infarction (MI) and stroke survivors, remain limited. Purpose To assess real-world utilization of GLP-1RAs and SGLT2i among T2DM patients with ASCVD focusing on trends, disparities by age, sex, and region from 2015 to 2023. Methods A nationwide cohort study using data from the National Registry of Reimbursed Health Services (2015–2023), covering all reimbursed health services in the Czech Republic. Patients with nonfatal MI (ICD-10: I21, I22) or stroke (I63, I64) and confirmed T2DM were included. Prescriptions were identified at the event or within 12 months post-event. Utilization trends were analyzed, and logistic regression was used to determine predictors of medication use. Results Among 116,218 MI patients (median age:68 years, 33.5% women), 53,128 (46%) had T2DM (median age:71 years, 37% women). Within 12 months post-MI, 2.1% received GLP-1RAs and 10.6% received SGLT2i, with increasing trends from 0.3% (2015) to 4.8% (2023) (GLP-1RAs) and 0.4% (2015) to 34.8% (2023) (SGLT2i). Women were less likely to receive SGLT2i (aOR: 0.70 [95%CI:0.65–0.74]), while no significant difference was observed for GLP-1RAs (aOR:0.98 [95%CI:0.86–1.12]). Older patients (&gt;70 years) had lower odds of receiving GLP-1RAs (aOR:0.31 [95%CI:0.27–0.36]) and SGLT2i (aOR:0.53 [95%CI:0.50–0.56]). Prescription rates were highest in Prague (3.1% GLP-1RAs; 13.5% SGLT2i) and lowest in the Moravian-Silesian Region (1.4% GLP-1RAs; 8.8% SGLT2i). Among 164,729 stroke patients (median age:73 years, 49% women), 78,562 (48%) had T2DM (median age:75 years, 50% women). Within 12 months post-stroke, 1.2% received GLP-1RAs and 3.7% received SGLT2i, with increasing trends from 0.2% (2015) to 2.8% (2023) (GLP-1RAs) and 0.1% (2015) to 10.4% (2023) (SGLT2i). Women were less likely to receive GLP-1RAs (aOR:0.82 [95%CI:0.72–0.95]) and SGLT2i (aOR:0.57 [95%CI:0.52–0.62]). Older patients (&gt;70 years) had lower odds of receiving GLP-1RAs (aOR:0.31 [95%CI:0.27–0.36]) and SGLT2i (aOR:0.40 [95%CI:0.37–0.44]). Regional disparities were notable, with prescription rates varying from 0.8–2.1% (GLP-1RAs) and 2.4–5.2% (SGLT2i). Conclusions Prescribing rates for GLP-1RAs and SGLT2i have increased over the past eight years but remain low, even among MI and stroke survivors. Women, older patients, and those in lower-income regions are significantly less likely to receive these therapies. Targeted interventions are needed to improve secondary prevention in high-risk diabetic populations and to address these disparities.Myocardial infarction patients Stroke patients

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Abstract Background Cancer therapies have prolonged survival in lymphoma. However, lymphoma patients may develop significant coronary artery disease (CAD), which may be treated by percutaneous coronary intervention (PCI). The characteristics and outcomes of lymphoma patients treated by PCI are not well studied. Methods We reviewed lymphoma patients undergoing PCI at our institution between 2010 and 2020 and compared them to a cohort without cancer. Patient characteristics and predictors of long-term mortality and major adverse cardiac events (MACE) (death, myocardial infarction, target lesion revascularization) were studied using descriptive statistics and survival analysis utilizing a Cox proportional hazards model. Results Of the 11,953 patients in the study cohort, 83 had a history of lymphoma meeting study criteria. Lymphoma patients, as compared to non-lymphoma patients were similar with respect to age, sex, hypertension, diabetes, hyperlipidemia, prior MI, and prior PCI (all p=ns). Over a median follow-up of 3.9 (1.0, 5.0) years, the mortality at 5 years was higher in lymphoma versus non-lymphoma patients (47.5% vs 29.8%) (P=0.005) (Figure). After adjusting for age, sex, hypertension, diabetes, shock, smoking status, heart failure, and chronic renal disease, lymphoma was an independent predictor of mortality (OR 1.59; 95% CI 1.07-2.36, p=0.02). Lymphoma was not independently associated with MACE. Discussion Lymphoma patients undergoing PCI have significantly lower survival rates than non-cancer controls. After accounting for important cardiac risk factors, lymphoma was independently associated with higher long term mortality.