Systemic determinants of brain health in ageing.

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.

Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescuing and cancer mutations.

Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes associated with poorer overall survival. Chr1q+, and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of the clonal burden. Chr1q+ and U2AF1S34 mutated clones were pre-malignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Like known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp-CH had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows the identification of patients at a higher risk of cancer development.

Impact of systolic dominant pulmonary venous flow morphology on outcomes after mitral transcatheter edge-to-edge repair.

BACKGROUND: The prognostic significance of intraprocedural pulsed-wave Doppler analysis of pulmonary venous flow (PVF) during mitral transcatheter edge-to-edge repair (TEER) remains understudied. We aimed to investigate the prognostic value of systolic dominant-PVF (SD-PVF) morphology post-TEER. METHODS: In a retrospective analysis from December 2019 to December 2022, patients undergoing mitral TEER were categorized into SD-PVF and systolic blunting (SB)-PVF groups based on post-TEER morphology. The primary endpoint was a composite of all-cause mortality or heart failure hospitalization at 1 year. We investigated the association of PVF morphology post-TEER with the primary endpoint at 1 year using Cox regression and compared the prognostic accuracy of PVF variables through receiver operating characteristic (ROC) curve analysis. RESULTS: Among 187 patients (mean age 76.4 ± 10.5 years, 51.3% primary etiology), residual mitral regurgitation (MR) ≤mild was observed in 147 (82.4%) patients and 105 (56.2%) had SD-PVF post-TEER. Patients with SD-PVF had a lower incidence of >2+ residual MR after clip deployment, at 30 days (2.1% vs. 13.1%; p = 0.005) and at 1 year (1.4% vs. 9%; p = 0.08). SD-PVF post-TEER was independently associated with the primary endpoint (HR = 0.59, 95% CI = 0.39-0.87; p = 0.009). ROC curve analysis of the prognostic accuracy of SD-PVF demonstrated an AUC of 0.64 (95% CI = 0.54-0.73), comparable to other quantitative measures of PVF. CONCLUSION: Assessing PVF morphology after clip deployment offers a simple prognostic tool for patients undergoing mitral TEER. Multicenter cohorts will be necessary to further investigate its prognostic value.

Development of electronic health record based algorithms to identify individuals with diabetic retinopathy.

OBJECTIVES: To develop, validate, and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHRs). MATERIALS AND METHODS: We developed and validated electronic health record (EHR)-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in 3 independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet 1 of the following 3 criteria: (1) 2 or more dates with any DR ICD-9/10 code documented in the EHR, (2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or (3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology examination. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology examination. RESULTS: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.91 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV = 0.94; NPV = 0.86) and lower in MGB (PPV = 0.84; NPV = 0.76). In comparison, the algorithm for DR implemented in Phenome-wide association study (PheWAS) in VUMC yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62 000 DR cases with genetic data including 14 549 African Americans and 6209 Hispanics with DR. CONCLUSIONS/DISCUSSION: We demonstrate the robustness of the algorithms at 3 separate healthcare centers, with a minimum PPV of 0.84 and substantially improved NPV than existing automated methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Association of Baseline Tricuspid Regurgitation With Health Status and Clinical Outcomes After TAVR and Mitral TEER.

BACKGROUND: Tricuspid regurgitation (TR) is associated with worse clinical outcomes after transcatheter aortic valve replacement (TAVR) and mitral transcatheter edge-to-edge repair (M-TEER), but little is known about its association with health status outcomes. OBJECTIVES: The aims of this study were to explore, using the Society of Thoracic Surgeons and American College of Cardiology TVT (Transcatheter Valve Therapy) Registry, the association between baseline TR and health status after TAVR and M-TEER and to determine if baseline TR was associated with clinical endpoints. METHODS: Health status was assessed using Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score in patients enrolled in the TVT Registry who underwent isolated TAVR or M-TEER between January 2019 and June 2021. The association among baseline TR and KCCQ-OS score, being alive and well, and clinical outcomes was examined. RESULTS: In total, 130,097 TAVR patients (13.1% with moderate TR, 2.3% with severe TR) and 19,593 M-TEER patients (33.2% with moderate TR, 14.7% with severe TR) were included. Mean KCCQ-OS scores were lower with severe vs moderate vs none to mild TR at baseline prior to TAVR (39.4 ± 24.2 vs 45.2 ± 24.7 vs 51.3 ± 25.3; P < 0.01) or M-TEER (38.1 ± 23.9 vs 41.9 ± 24.7 vs 45.4 ± 25.2; P < 0.01) and similarly at 30 days and 1 year. The odds of being alive and well at 1 year were lower with moderate or severe TR before TAVR (adjusted OR: 0.79 [95% CI: 0.74-0.85] and adjusted OR: 0.81 [95% CI: 0.70-0.94], respectively) and severe TR before M-TEER (adjusted OR: 0.53; 95% CI: 0.40-0.71). Furthermore, moderate or severe TR before TAVR was associated with higher 1-year mortality and readmission, whereas moderate or severe TR before M-TEER was associated with higher 1-year mortality. CONCLUSIONS: In a large cohort of U.S. patients who underwent TAVR or M-TEER, greater baseline TR was associated with worse health status and clinical outcomes. Understanding adverse outcomes of TR in patients with coexisting valvular abnormalities is important, especially with rapidly evolving transcatheter tricuspid valve interventions.

A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Safety and efficacy of immunosuppressive therapy for elderly patients with severe aplastic anaemia.

Uncertainty remains regarding the safety and tolerability of immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CSA) in older patients. We retrospectively analysed two prospective clinical trials of IST in treatment-naïve severe aplastic anaemia (SAA) to assess safety in older compared to younger patients. Patients ≥18 years of age who had received IST with ATG and CSA +/- eltrombopag (EPAG) were included. Pre-treatment baseline characteristics and co-morbidities were assessed as predictors of therapy-related complications in younger (<60 years) versus older (≥60 years) patients. Out of 245 eligible patients, 54 were older and 191 were younger. Older patients had a similar frequency of SAEs, ICU admissions and hospital length of stay compared to younger patients. Older patients had a higher frequency of cardiac events related to IST, but none resulted in death. Older patients had worse long-term overall survival, and more relapse and clonal evolution post-IST. However, older patients who responded to IST had a similar survival at a median follow-up to younger patients. Disease-related factors and limited therapeutic options in refractory disease likely contribute to poorer outcomes in older patients, not complications of upfront IST. Therefore, IST should be considered first-line therapy for most older SAA patients.

3-Year Outcomes From the Evolut Low Risk TAVR Bicuspid Study.

BACKGROUND: Outcomes from transcatheter aortic valve replacement (TAVR) in low-surgical risk patients with bicuspid aortic stenosis beyond 2 years are limited. OBJECTIVES: This study aimed to evaluate 3-year clinical and echocardiographic outcomes from the Evolut Low Risk Bicuspid Study. METHODS: The Evolut Low Risk Bicuspid Study is a prospective, multicenter, single-arm study conducted in 25 U.S. CENTERS: Patients with severe aortic stenosis at low surgical risk with bicuspid aortic valve anatomy (all subtypes) underwent TAVR with a self-expanding, supra-annular Evolut R or PRO (Medtronic) bioprosthesis. An independent clinical events committee adjudicated all deaths and endpoint-related adverse events, and a central echocardiographic core laboratory assessed hemodynamic endpoints. RESULTS: An attempted implant was performed in 150 patients from December 2018 to October 2019. The mean age was 70.3 ± 5.5 years, 48% (72/150) of the patients were women, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.3% (Q1-Q3: 0.9%-1.7%). Sievers type 1 was the dominant bicuspid morphology (90.7%, 136/150). The Kaplan-Meier rates of all-cause mortality or disabling stroke were 1.3% (95% CI: 0.3%-5.3%) at 1 year, 3.4% (95% CI: 1.4%-8.1%) at 2 years, and 4.1% (95% CI: 1.6%-10.7%) at 3 years. The incidence of new permanent pacemaker implantation was 19.4% (95% CI: 12.4%-29.6%) at 3 years. There were no instances of moderate or severe paravalvular aortic regurgitation at 2 and 3 years after TAVR. CONCLUSIONS: The 3-year results from the Evolut Low Risk Bicuspid Study demonstrate low rates of all-cause mortality or disabling stroke and favorable hemodynamic performance.

Opportunistic Infections, Mortality Risk, and Prevention Strategies in Patients With Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.

Impact of Left Atrial Pressure on Outcomes After Mitral Transcatheter Edge-to-Edge Repair.

BACKGROUND: Increased left atrial pressure (LAP) has been associated with adverse outcomes after mitral transcatheter edge-to-edge repair (M-TEER). We sought to evaluate outcomes based on differences in postprocedural LAP measured after the final clip deployment. METHODS: We included consecutive patients who underwent M-TEER at our institution between 2014 and 2022 with LAP monitoring. Patients were stratified into 3 groups according to tertiles of post-TEER mean LAP. Outcomes were assessed using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: We included 273 patients (mean age, 76.8±10.8 years; 42.5% women; 78.4% White). The mean post-TEER LAP was 8.7±1.7 mm Hg in tertile 1 (n=85), 14.4±1.6 mm Hg in tertile 2 (n=95), and 21.9±3.8 mm Hg in tertile 3 (n=93). In comparison with tertile 1, both tertiles 2 and 3 were associated with increased risk of all-cause mortality or heart failure hospitalization at 2 years (adjusted hazard ratio [adjHR], 2.27 [95% CI, 1.25-4.12] and adjHR, 3.00 [95% CI, 1.59-5.64], respectively). Among patients with primary mitral regurgitation, higher LAP was associated with increased risk of 2-year all-cause mortality or heart failure hospitalization (tertile 2 versus 1: adjHR, 3.00 [95% CI, 1.37-6.56]; tertile 3 versus 1: adjHR, 5.52 [95% CI, 2.04-14.95]). However, in patients with secondary mitral regurgitation, neither being in tertile 2 (adjHR, 1.53 [95% CI, 0.55-4.24]) nor tertile 3 (adjHR, 2.18 [95% CI, 0.82-5.77]) were associated with the composite outcome compared with tertile 1. Any degree of LAP reduction following M-TEER was associated with lower mortality or heart failure hospitalization compared with no LAP reduction (adjHR, 0.59 [95% CI, 0.39-0.88]). CONCLUSIONS: Elevated LAP after M-TEER was associated with increased 2-year risk of mortality or heart failure hospitalization. Exploration of reasons for elevated LAP after M-TEER and ways to lower it warrant further investigation.

Adaptive selection at G6PD and disparities in diabetes complications.

Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.

Skin Manifestations of VEXAS Syndrome and Associated Genotypes.

Importance: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations. Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. Design, Setting, and Participants: This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland. Main Outcomes and Measures: To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS. Results: Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]). Conclusions and Relevance: Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Proceedings of the Think Tank for Osteosarcoma Medical Advisory Board.

A "Think Tank for Osteosarcoma" medical advisory board meeting was held in Santa Monica, CA, USA on February 2-3, 2024. The goal was to develop a strategic approach to prevent recurrence of osteosarcoma. Osteosarcoma metabolism and the genomic instability of osteosarcoma, immunotherapy for osteosarcoma, CAR-T cell therapy, DeltaRex-G tumor-targeted gene therapy, repurposed drugs, alternative medicines, and personalized medicine were discussed. Only DeltaRex-G was voted on. The conclusions were the following: No intervention has been demonstrated to improve survival in a clinical trial. Additionally, the consensus (10/12 in favor) was that DeltaRex-G without immunotherapy may be administered for up to one year. Phase 2/3 randomized studies of DeltaRex-G should be performed to determine whether the incidence of recurrence could be reduced in high-risk individuals. Furthermore, a personalized approach using drugs with minimal toxicity could be attempted with the acknowledgement that there are no efficacy data to base this on. Repurposed drugs and alternative therapies should be tested in mouse models of osteosarcoma. Moreover, unmodified IL-2 primed Gamma Delta (NK) cell therapy may be used to prevent recurrence. Lastly, rapid development of CAR-T cell therapy is recommended, and an institute dedicated to the study of osteosarcoma is needed.

RecQ helicase expression in patients with telomeropathies.

BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.

Association between elevated fibrosis-4 index of liver fibrosis and risk of hemorrhagic stroke.

BACKGROUND: Cirrhosis is associated with an increased risk of hemorrhagic stroke. Liver fibrosis, typically a silent condition, is antecedent to cirrhosis. The objective of this study was to test the hypothesis that elevated Fibrosis-4 (FIB-4) index, indicating a high probability of liver fibrosis, is associated with an increased risk of hemorrhagic stroke. METHODS: We performed a cohort analysis of the prospective United Kingdom Biobank cohort study. Participants 40-69 years old were enrolled between 2007 and 2010 and had available follow-up data until March 1, 2018. We excluded participants with prevalent hemorrhagic stroke or thrombocytopenia. High probability of liver fibrosis was defined as having a value >2.67 of the validated FIB-4 index. The primary outcome was hemorrhagic stroke (intracerebral or subarachnoid hemorrhage), defined based on hospitalization and death registry data. Secondary outcomes were intracerebral and subarachnoid hemorrhage, separately. We used Cox proportional hazards models to evaluate the association of FIB-4 index >2.67 with hemorrhagic stroke while adjusting for potential confounders including hypertension, alcohol use, and antithrombotic use. RESULTS: Among 452,994 participants (mean age, 57 years; 54% women), approximately 2% had FIB-4 index >2.67, and 1241 developed hemorrhagic stroke. In adjusted models, FIB-4 index >2.67 was associated with an increased risk of hemorrhagic stroke (HR, 2.0; 95% CI, 1.6-2.6). Results were similar for intracerebral hemorrhage (HR, 2.0; 95% CI, 1.5-2.7) and subarachnoid hemorrhage (HR, 2.2; 95% CI, 1.5-3.5) individually. CONCLUSIONS: Elevated FIB-4 index was associated with an increased risk of hemorrhagic stroke.

Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.

Purpose: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution. Materials and Methods: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans. Results: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03). Conclusion: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.