Citations

Abstract Objective Myositis is a heterogeneous family of inflammatory myopathies. We sought to define the differential expression of cytokines, cytokine receptors and immune checkpoint genes in muscle biopsies from patients with different forms of myositis in order to characterize patterns of inflammation in each. Methods Bulk RNA-sequencing was performed on muscle biopsy samples from 669 patients, including 105 with DM, 80 with immune-mediated necrotizing myopathy (IMNM), 65 with anti-synthetase syndrome, 53 with IBM, 19 with anti-PM/Scl myositis, 310 with other inflammatory or genetic myopathies and 37 controls with normal tissue (NT). Myositis clinical groups and autoantibody subgroups were analysed separately. Expression data were analysed for 338 genes encoding cytokines, cytokine receptors and immune checkpoints. Myositis group-specific genes were identified from this list by finding genes that were specifically differentially expressed in one group compared with all samples and compared with NT (α < 0.001). Results IBM patients had the most differentially overexpressed genes (71) among all clinical groups, including 37 that were IBM-specific. Among the top genes were several involved in type 1 inflammation, including CCL5, CXCR3, CCR5, CXCL9 and IFNG. Anti-Jo1 and anti-PM/Scl patients exhibited differential overexpression of a similar set of genes, while DM patients exhibited differential overexpression of a different set of genes involved in type 1 inflammation. IMNM patients had the least number of differentially overexpressed genes with no predominant inflammatory pattern. Conclusion Each myositis clinical group and autoantibody subgroup had differentially overexpressed inflammatory mediators, including a strong type 1 inflammatory gene signature in IBM.

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.

Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we present a novel, Generative AI–based drug design approach to promote targeted degradation of Aβ42 via the ubiquitin–proteasome system (UPS), using E3 ligase–directed molecular glues. We systematically evaluated the ternary complex formation potential of Aβ42 with three E3 ligases (CRBN, VHL, and MDM2) through structure-based modeling, ADMET screening, and docking. We then developed a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) to generate ligase-specific small molecules, incorporating protein sequence embeddings and torsional angle-aware molecular graphs. Our results demonstrate that this generative model can produce chemically valid, novel, and target-specific molecular glues capable of facilitating Aβ42 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases.

PURPOSE Initial reports indicate that access to contemporary therapies currently used in North America for the treatment of multiple myeloma (MM) varies internationally. No studies have quantitatively reported the extent of disparities in the access to MM therapies worldwide, with a goal to investigate access to MM therapies and barriers globally. METHODS From June 18 to July 15, 2023, an electronic survey was distributed to 176 oncologists treating MM outside the United States. MM drugs were categorized by accessibility, with the cutoff for adequate access set at 60% of respondents affirming easy/moderate access. RESULTS Ninety-five (54%) respondents from 33 countries completed the survey. Fifty-one percent of the respondents were from university-based academic programs, and 17% of the responders treated only plasma cell disorders. Most respondents had adequate access to noncellular MM therapies, except for isatuximab, ixazomib, selinexor, and elotuzumab. Among the cellular therapies, 17% had access to Chimeric Antigen Receptor T-cell therapy, whereas 23% had access to approved T-cell engagers (TCEs). Financial stress on patients and health care systems has emerged as a primary barrier to global inaccessibility of treatment drugs. CONCLUSION Global access to novel MM therapies remains challenging, and we have identified barriers and suggested strategies to bridge this gap.

e13154 Background: Triple-negative breast cancer (TNBC) is a less common but highly aggressive subtype of breast cancer with poor prognosis and limited therapeutic options. Despite advancements in oncology, significant survival disparities persist among racial, histologic, and socio-demographic groups. This study investigates these disparities and identifies factors contributing to unequal outcomes, providing actionable insights for improving care. Methods: Data on TNBC cases from 2000 to 2021 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, encompassing 17 registries and 76,265 patients. Patients were categorized by stage, marital status, age, race, and histology. Kaplan-Meier survival analysis was used to estimate median survival with 95% confidence intervals (CI), and the log-rank test assessed differences across groups. Cox proportional hazards regression determined the magnitude of disparities. A p-value < 0.05 was considered statistically significant. Results: Among the 76,265 patients analyzed, those with distant-stage disease had the poorest median survival (51 months; 95% CI: 46–60), compared to localized-stage patients (128 months; 95% CI: 127–129). The youngest cohort (15–19 years) exhibited the lowest survival (43 months), while individuals aged 80–84 had a median survival of 79 months (95% CI: 76–84). South Asians, particularly Pakistani individuals, had the shortest survival among racial groups (83 months). Single patients had lower survival (116 months) compared to married or divorced individuals. Histologically, median survival was 113 months (95% CI: 103–120) for epithelial neoplasms and 78 months for mucoepidermoid neoplasms. All observed differences were statistically significant (p < 0.05). Conclusions: Localized-stage TNBC, individuals aged 40–44, and patients from White or Black racial groups exhibited better survival outcomes, as did those with cystic, mucinous, or serous histologies compared to epithelial neoplasms. Addressing these disparities through tailored treatment strategies and improved access to care is critical. Limitations of this study include the lack of treatment-level data and the potential influence of unmeasured confounders. Stage Marital Status Age Group at Diagnosis Distant Localized Single Divorced 15-19 40-44 80-84 Median Survival(LCL-UCL) 51(46-60) 128(127-129) 116(114-118) 127(124-129) 43(14-NA) 132(130-135) 79(76-84) Neoplasm Histology Race Epithelial Muco-epidermoid Cystic, Mucinous& Serous Pakistani OtherAsian Black White Median Survival(LCL-UCL) 113 (103-120) 78(63-NA) 142(123-NA) 83 (63-NA) 97(91-108) 123 (121-125) 126 (125-127) LCL= Lower Confidence Limit, UCL= Upper Confidence Limit.

e23024 Background: Efforts to address disparities in clinical trial participation have increased over the past 30 years. Strict eligibility criteria in phase III interventional trials may exacerbate these disparities, limiting access and raising concerns about generalizability. Chronic lymphocytic leukemia (CLL), the most common chronic leukemia in adults, primarily affects older individuals and those with comorbidities, emphasizing the need for inclusive research. This study aimed to explore changes in eligibility criteria for phase III interventional CLL trials over 15 years. Methods: Clinical trial data were obtained from ClinicalTrials.gov, focusing on Phase 3 interventional studies related to CLL. The search used "chronic lymphocytic leukemia," filtered for adults aged 18–64 and older adults aged 65+. Trials enrolling patients between January 1, 2004, and December 1, 2019, were included. Trial designs, endpoints, and eligibility criteria were primarily extracted from published protocols when available and supplemented with information from ClinicalTrials.gov. Studies not specific to CLL, those evaluating supplements or vaccines, lacking a control arm, being single-center, or without investigational products were excluded from the data analysis. Data were grouped into three periods (2004–2008, 2009–2013, 2014–2019), and one-way ANOVA was used to assess differences in average eligibility criteria across these periods. Results: A total of 103 clinical trials were identified, with 47 included in the final analysis. Most were industry-funded (37 trials, 81%), while 10 (19%) were non-industry-funded. Regarding treatment settings, 60% targeted untreated patients, 32% focused on relapsed/refractory patients, and 9% included both. Interventions included chemoimmunotherapy (40%), targeted therapies (21%), combined approaches (36%), and other types (2%). The average number of eligibility criteria increased over time: 23.86 (IQR 14; range 12–39) in Period 1, 32.05 (IQR 19; range 18–59) in Period 2, and 46.25 (IQR 26.5; range 13–70) in Period 3. One-way ANOVA confirmed a significant difference across periods (F = 7.35, p < 0.001), showing a significant increase in the average number of criteria over time. Conclusions: Over 15 years, the number of eligibility criteria in phase III interventional CLL trials significantly increased, nearly doubling from 23.86 (2004–2008) to 46.25 (2014–2019). While this may improve internal validity, it risks excluding older patients and those with comorbidities, who are most affected by CLL. These findings highlight the need to balance scientific rigor with equitable access to ensure generalizability.

e17530 Background: Cervical cancer remains a significant public health challenge, especially in low-resource settings such as Vietnam. HPV self-collection offers a promising avenue for improving screening uptake, yet its acceptance depends on addressing knowledge gaps and sociocultural barriers. This study aims to explore the perceptions of Vietnamese women in regard to HPV and HPV self-collection, emphasizing strategies for health promotion and disease prevention. The aims of this study were to summarize responses to a 51-item survey regarding perceptions of HPV self-collection in Vietnamese women between 30 and 65 years old, as well as to compare survey responses according to age, religion, education level, marital status, and frequency of doctor visits in the past year. Methods: A survey of 538 women aged 30–65 assessed cervical cancer knowledge, attitudes toward HPV self-collection, cost concerns, and communication preferences. Associations between demographic factors and perceptions were analyzed using Wilcoxon rank sum, Kruskal-Wallis, and Fisher’s exact tests (p < 0.05). Results: While 84.4% of respondents were aware of cervical cancer, only 59.0% had knowledge of HPV, and 41.3% were familiar with self-collection. Most women (82.5%) recognized the importance of cervical cancer prevention; however, only 45.5% viewed self-collection as equally effective as doctor-administered testing. For negative self-collection recorded results, 64.3% felt reassured, yet 81.1% preferred secondary confirmation by a doctor (p<0.01). Cost concerns were notable, with 56.5% willing to pay 400,000 VND but fewer accepting higher costs. Education significantly influenced responses, with higher-educated women demonstrating greater awareness and confidence in self-collection (p < 0.001) . Importantly, participants identified doctors and healthcare professionals as trusted sources of information, when compared to other sources of information such as television and government officials, underscoring the role of health promotion campaigns. Conclusions: Effective health promotion strategies are critical to increasing HPV self-collection uptake in Vietnam. Public health campaigns should prioritize education to address misconceptions, emphasize the efficacy of self-collection, and reduce stigma. Programs that leverage trusted communication channels, such as healthcare providers, can foster trust and improve participation. Efforts to ensure affordability and accessibility are essential to achieving equitable and widespread cervical cancer prevention.

e15520 Background: Fruquintinib is a highly selective tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, which play a critical role in angiogenesis and tumor growth. As a novel anti-angiogenic agent, Fruquintinib has demonstrated promising efficacy in the treatment of various advanced malignancies, including metastatic colorectal cancer. However, concerns about its cardiovascular safety have emerged, given that VEGFR inhibition is often associated with cardiovascular adverse events. Methods: We conducted a systematic search through PubMed, Scopus, Embase, and Web of Science to identify randomized controlled trials and cohort studies that assessed the safety of Fruquintinib compared with placebo in patients with metastatic colorectal and other cancers. The evaluated outcomes included hypertension, coronary artery disease, cerebrovascular accidents, peripheral artery disease, heart failure, thromboembolism, arrhythmias, aortic dissection, and superior vena cava syndrome. Two independent reviewers screened the titles/abstracts based on predefined inclusion and exclusion criteria, followed by a full-text review of potentially relevant studies. Any disagreements between the reviewers were resolved through consultation with a third reviewer to ensure the accuracy and consistency of the study selection. Results: Fifteen reports were included in our study. Out of 3832 patients taking Fruquintinib monotherapy, a total of 997 developed hypertension with a pooled estimate incidence of 0.329 (95% CI: 0.248, 0.410; P < 0.001). In comparison to placebo, Fruquintinib was associated with significantly higher odds of developing hypertension (OR: 6.856; 95% CI: 5.071, 9.268; P < 0.001). Compared to Regorafenib, Fruquintinib demonstrated an OR of 1.549 (95% CI: 0.804, 2.983; P = 0.191) for the development of hypertension. Additionally, patients taking Fruquintinib had a pooled estimate incidence of 0.041 (95% CI: 0.021, 0.060, P < 0.001) for thromboembolism development with an OR of 2.092 (95% CI: 0.813, 5.385; P = 0.126) compared to placebo. Other reported cardiovascular side effects included sinus tachycardia, superior vena cava syndrome, peripheral edema, heart failure, myocardial enzymes elevation, and vascular access complications. Conclusions: Our study found that Fruquintinib is associated with significant cardiovascular risks, with hypertension being the most common adverse event, while thromboembolism did not reach statistical significance. Therefore, close monitoring for treatment-related cardiovascular events should be considered in these patients.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Abstract Introduction Sexually transmitted viruses (STVs), including Human Immunodeficiency Virus (HIV), Human Papillomavirus (HPV), Herpes Simplex Virus (HSV), and Hepatitis B Virus (HBV), present major public health challenges due to their high prevelance, chronicity, and transmission rates. Extending beyond immediate health impacts, these viruses affect sexual health and function through mechanisms including chronic inflammation, psychological stress, social stigma, and adverse effects of treatment. While the link between STVs and sexual disorders is acknowledged, it is underexplored in the literature, particularly concerning female sexual health. Current research largely focuses on male sexual dysfunction, especially erectile disorder and its treatment. This review investigates the relationship between STVs and female sexual disorders, examining physiological, psychological, and social factors contributing to sexual health concerns. Enhancing our understanding of this relationship could support clinicians in identifying sexual health concerns in female patients with STVs and providing targeted interventions to optimize sexual health outcomes. Objective This systematic review aims to examine existing literature on the relationship between STVs and female sexual disorders, identifying specific dysfunctions (e.g., pain, desire, arousal, and satisfaction) associated with each virus, underlying mechanisms, and discussing clinical and research implications. Methods A comprehensive literature search was conducted in September 2024 across four databases: Ovid MEDLINE, Ovid EMBASE, Scopus, and Web of Science. A total of 523 references were identified, with 139 duplicates removed, leaving 384 studies for screening based on inclusion and exclusion criteria. Searches combined MeSH (Medical Subject Headings) terms and keywords to capture relevant studies. MeSH terms included “Sexual Dysfunction, Physiological,” “Sexual Dysfunction, Psychological,” “Papillomavirus Infections,” “Herpesvirus 2, Human,” “Hepatitis B,” and “HIV.” Additional keywords included “sexual dysfunction,” “HSV,” “hepatitis,” “HPV,” “woman,” “women,” and “female.” The search was limited to English-language studies. Results A total of 384 studies met the inclusion criteria, with findings revealing associations between specific STVs and various types of female sexual dysfunction. HSV was notably associated with dyspareunia during outbreaks due to genital ulcers, as well as with psychosexual issues linked to concerns about transmissibility and the stigma of visible lesions, negatively affecting intimate relationships. HIV was associated with multifactorial sexual dysfunction, encompassing psychological impacts such as fear of transmission and health-related anxiety, as well as physiological effects like decreased sexual desire from antiretroviral therapy and lipodystrophy. HPV’s relationship with sexual disorders was variable, with some studies connecting it to heightened depression and anxiety following diagnosis, which diminished sexual desire. For HBV, sexual dysfunction correlated with the severity of liver dysfunction, as chronic liver disease in women impairs hormone metabolism and increases sex hormone-binding globulin (SHBG) levels, leading to suppression of the hypothalamic–pituitary-gonadal axis. Conclusions This review highlights a notable relationship between STVs and female sexual dysfunction, emphasizing the need for comprehensive care that addresses both management of the infection and sexual health concerns. Routine screening for sexual health concerns in women with STVs is recommended, along with interdisciplinary approaches to address these complex impacts. Improved recognition and management of sexual disorders in this context can enhance both sexual health outcomes and overall quality of life in affected individuals. Disclosure No.