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Application of the STAAR Framework in Detecting Rare Variant Associations with Alzheimer's Disease and Related Dementias: Insights and Implications
No full textRare genetic variation is considered a potential source of heritability in individuals with sporadic Alzheimer's Disease and related dementias (ADRD). The STAAR framework leverages multiple functional annotations of genetic variants and combines association statistics from multiple variant aggregation-based methods, including burden, SKAT, and ACAT-V, into a single measure of significance. Using whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), we comprehensively examined the association of rare genetic variation with ADRD in 23,454 individuals (37% ADRD cases) and with cognitively healthy elder status in 13,292 individuals (13% cognitively healthy elders) from diverse populations via the STAAR framework. We identified several genes significantly associated with ADRD or cognitively healthy status. However, our analysis revealed several limitations within the STAAR framework incorporating ultra-rare variants with dichotomous outcomes. To enhance the robustness of the framework, we proposed several computational refinements, including creating a burden of ultra-rare variants and employing more precise annotations to match with expected mechanism. After implementing the proposed modifications, the association with ADRD for ZNF200 was no longer statistically significant (α=1x10
), while TBX19, PLXNB2, CARD11, and LINC01880 remained significantly associated with cognitively healthy status. We identified and addressed the computational limitations in the STAAR framework that could lead to potential spurious results for ultra-rare variant aggregates with an extremely low cumulative minor allele count. Our proposed refinements produced more robust results for associations with rare variants in the context of dichotomous outcomes
Abstract DP192: Association of Endovascular Thrombectomy With Mortality and Functional Outcomes in Large Ischemic Core: Analysis of Linked RAPID AI and Florida Stroke Registry data
No full textIntroduction: Six randomized clinical trials have shown that endovascular thrombectomy (EVT) reduces mortality and improves clinical outcomes in patients with large-core anterior circulation ischemic stroke. Whether these benefits extend to routine practice outside strict trial criteria remains uncertain. This study evaluates in-hospital outcomes among EVT-treated patients with large ischemic cores using linked data from the Florida Stroke Registry (FSR) and RapidAI imaging.
Methods: From January 2023 to December 2024, linked FSR-RapidAI data were available for 11,275 cases of acute ischemic stroke (AIS). Patients with suspected large vessel occlusion (LVO) and infarct core size measured by computed tomography perfusion (CTP) or non-contrast computed tomography (NCCT) were included. Large core was defined as an Alberta Stroke Program Early CT Score (ASPECTS) ≤5 on NCCT, or a core volume ≥70 mL with cerebral blood flow <30% on CTP. Multivariable logistic regression compared in-hospital mortality and discharge ambulation (independent or assisted vs unable or not documented) between large-core patients treated with EVT and those untreated, adjusting for demographics, NIHSS score, pre-stroke mRS, presentation timing, onset-to-arrival time, center type, admission blood pressure, and intravenous thrombolysis.
Results: Of 2,212 AIS patients, 174 (7.9%) had large-core infarcts (91% identified by CTP); 102 (59%) received EVT (Figure 1). The median age was 70.5 years (IQR 61-79), 56.3% were male, the median onset-to-arrival time was 130.5 minutes (IQR 47-518), and the median NIHSS score was 20 (IQR 14-25). Ambulation at discharge occurred in 70 patients (40.2%), and in-hospital mortality occurred in 28 patients (16.1%). In multivariable regression, EVT was associated with lower odds of death (adjusted odds ratio [aOR] 0.29; 95% CI 0.10-0.88) (Table 1a) and higher odds of ambulation at discharge (aOR 2.45; 95% CI 1.10-5.46) (Table 1b). The model demonstrated good discrimination, with an area under the receiver operating characteristic curve of 0.78 (95% CI 0.72-0.85).
Conclusions: In this multicenter cohort of AIS patients with large-core infarcts, EVT was independently associated with higher odds of ambulation at discharge and lower in-hospital mortality after adjustment for stroke severity and presentation factors. These findings support emerging trial data that EVT improves survival and functional outcomes in large-core strokes in real-world practice
MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm
No full textVascular smooth muscle cell (VSMC) degeneration is a major mechanism underlying abdominal aortic aneurysm (AAA) formation. However, the upstream signaling pathways that converge on the transcriptional machinery to drive VSMC degeneration remain elusive. Here, we integrated single-nucleus (sn) multi-omics, chromatin immunoprecipitation (ChIP)-seq, and wet lab validation to identify transcriptional effectors of VSMC-MAPK14, which we previously reported to promote AAA. Compared with wild-type (WT) mice, VSMC-Mapk14 knockout (KO) mice displayed reduced VSMC degeneration, as evidenced by decreased expression of markers of endoplasmic reticulum stress, the unfolded protein response, fibrosis, and apoptosis, after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs revealed an increased proportion of contractile cluster and a reduced proportion of fibrotic cluster in KOs. The VSMC differentiation gene program and upstream pathways were upregulated, whereas degeneration pathways, including extracellular matrix remodeling, inflammation, and apoptosis, were downregulated in KO VSMCs. snATAC-seq and validation revealed increased serum response factor (SRF) motif activity and expression but reduced RUNX2 expression in KO VSMCs. Integrative analysis of snATAC-seq, ChIP-seq, and bulk RNA-seq identified the MYOCD/SRF/CArG triad as the driver of the contractile gene program following Mapk14 loss. We further found that the expression of Bcl2, a novel MYOCD/SRF/CArG target, was increased in Mapk14 KO VSMCs. Loss of Mapk14 attenuated MRTFA protein abundance via increased ubiquitin‒proteasome degradation, which was attributed to reduced USP10 protein expression. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by suppressing SRF/MYOCD/CArG while activating RUNX2 and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and provides a basis for MAPK14-targeted therapeutic strategies for AAA
Psychometric Validation of HIV/AIDS Knowledge, Attitude, and Practice Scale Among Nursing Students in Ghana
No full textHIV/AIDS is a major public health issue in sub-Saharan Africa, posing high occupational risks for nurses. There are limited validated instruments that assess the knowledge, attitude, and practice (KAP) in African nursing education contexts. This study adapted and validated a relevant HIV/AIDS KAP instrument for nursing students in northern Ghana.
We conducted a cross-sectional survey among 373 nursing students in northern Ghana. Construct validity was evaluated using exploratory factor analysis, and internal consistency was measured using coefficient of alpha.
All the subscales of KAP demonstrated acceptable to good internal consistency (α = .712-.815). Item-level analysis confirmed the instrument's coherence and reliability.
The scale demonstrated strong psychometric properties and is suitable for assessing HIV/AIDS-related competencies among nursing students in Ghana. Future studies should confirm the factor structure of the scale
Once-daily oral paltusotine in the treatment of patients with carcinoid syndrome: Biomarker analysis results from a phase 2, randomized, parallel-group study
No full text632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668
New Onset Ulcers in a Patient with Dermatomyositis
Get PDFEcthyma gangrenosum (EG) is a rare cutaneous infection caused by Pseudomonas aeruginosa, typically affecting immunocompromised individuals. We present a 42-year-old female with dermatomyositis and recent MDA-5 antibody positivity who developed acute-onset painful ulcers on her hands, face, elbow, and chest. The patient was immunosuppressed due to medications for a previous liver transplant, including tacrolimus, mycophenolate mofetil, prednisone, and monthly intravenous immunoglobulin. Physical examination revealed shallow ulcers with central eschars and fibrinous material resembling characteristic anti-MDA5 dermatomyositis ulcers. Laboratory findings showed leukopenia, elevated erythrocyte sedimentation rate, and mildly elevated muscle enzymes. Superficial wound and tissue cultures confirmed Pseudomonas aeruginosa infection, establishing the diagnosis of ecthyma gangrenosum. The patient was successfully treated with intravenous cefepime followed by oral ciprofloxacin with complete resolution of the ulcers. This case highlights the importance of considering infectious etiologies in immunocompromised patients even when lesions appear consistent with autoimmune disease manifestations. EG can present without systemic signs of infection, emphasizing the need for prompt microbiological evaluation of suspicious lesions in immunocompromised individuals to ensure appropriate diagnosis and treatment.
Large and giant intracranial aneurysms: outcomes from the multicenter prospective SMART coils registry
Get PDFBackground Endovascular coiling for intracerebral aneurysms has been evolving. Yet, large and giant aneurysms (LAGA) remain a significant challenge in any treatment modality and carry high rates of morbidity and mortality. Method The SMART registry, a prospective, multicenter site-adjudicated trial, was used to identify patients with LAGA (Sac 10-25 mm for large and >25 mm for giant) treated with the Penumbra SMART COIL (SMART) system and compare their outcomes to patients with smaller aneurysms (SA; Sac <= 10 mm). Aneurysm occlusion per Raymond-Roy (RROC) scale, recanalization, retreatment, mortality, and serious device-related adverse events (SAEs) were analyzed. Results A total of 133/905 (14.7%) enrolled patients had LAGA with a mean (SD) aneurysm size of 13.7 (3.59) mm for LAGA and 5.8 (1.95) mm for SA. LAGA were more likely to be non-saccular (24.1% vs. 12.3%, p = 0.0007) and wide-necked (69.9% vs. 59.7%, p = 0.0268) compared to SA. Primary coiling was the main treatment modality for LAGA and SA (43.6% vs. 43.3%; p = 1.0). However, LAGA were more likely to be treated with flow diversion in addition to coiling (6.0% vs. 1.0%, p < 0.001). At 1-year follow-up: (i) RROC I-II was 82.7% in LAGA and 91.2% in SA; p = 0.0166, (ii) recanalization rates were 13.8% vs. 12.7%; p = 0.7417, and retreatment rates were 11.5% vs. 6.4%; p = 0.0648, for LAGA and SA, respectively, and (iii) all-cause mortality was 9.8% in LAGA vs. 4.7% SA; p = 0.0222. The device-related SAEs rates were low and comparable between the two study groups (4.5% vs. 4.1%; p = 0.8153). Conclusion The SMART registry demonstrated that endovascular coiling can be feasible and safe in patients with LAGA, however randomized controlled studies are needed for comparative effectiveness.</p
P-1274. Resistance to Metronidazole of Gardnerella in Women with Recurrent Bacterial Vaginosis
No full textBackground Bacterial vaginosis (BV) involves a shift from optimal dominance of vaginal Lactobacillus species to polymicrobial anaerobic communities, predominantly Gardnerella. Despite standard metronidazole treatment, recurrence occurs in 50-80% of cases within one year. While molecular profiling of the vaginal microbiome has advanced, culture-based, longitudinal data on Gardnerella spp. and its metronidazole susceptibility is limited, particularly across clinically defined recurrent and persistent BV. This study characterized the susceptibility of Gardnerella isolates to metronidazole to assess if antibiotic resistance contributes to recurrence. Methods Vaginal swabs were collected from women clinically diagnosed with BV by Amsel criteria and treated with 7-day oral metronidazole. BV status was assessed at baseline (T0), one-month (T1), and six-month (T2) after treatment. Recurrent BV was defined as T0 and T2 positive with T1 clearance; persistent BV was positive at all time points. Swabs were cultured anaerobically on NYCIII and V agar media at 37°C for 24-48 hours. Gardnerella was presumptively identified by Gram staining, colony morphology, hemolytic patterns on V agar and confirmed by 16S rRNA PCR followed by Sanger sequencing. Metronidazole susceptibility was tested using E-test strips, interpreted using CLSI anaerobic breakpoints, with ATCC 14018 G. vaginalis as a control. Results Multiple Gardnerella species, including G. leopoldii, G. swidsinskii, and G. vaginalis, were cultured and identified from both recurrent and persistent BV. In recurrent BV, T0 isolates were metronidazole sensitive, while T2 isolates from the same participant showed resistance. Persistent BV isolates demonstrated resistance at both timepoints. Conclusion Preliminary findings reveal potential shifts in Gardnerella susceptibility after treatment, specifically in recurrent BV with no resistance detectable prior to treatment. These results highlight the importance of culture-based diagnostics and longitudinal monitoring of antimicrobial susceptibility. Continued isolate identification and expanded analysis are underway to better define resistance trends and inform targeted therapeutic approaches for treatment-refractory BV. Disclosures Maria L. Alcaide, MD, Gilead: Advisor/Consultan
P-1559. Investigating the Effect of HLA-DRB1 Variants on T cell Response as a Contributing Risk Factor for Staphylococcus aureus Bacteremia
No full textBackground The impact of host genetic variability on Staphylococcus aureus bacteremia (SAB) risk is unknown. In genome-wide association studies, we identified specific HLA-class II variants associated with higher risk (HLA-DRB1*04:01 [OR = 1.121 (0.952, 1.321)] & 03:01 [OR = 1.103 (0.960, 1.269)] or lower risk (HLA-DRB1*07:01) of SAB. The aim of this study is to determine how HLA-DRB1 variants, which differ in S. aureus peptide presentation, may also differ in their ability to activate T cells and therefore protective immunity. Methods To measure differential CD4+ T cell responses elicited by HLA-class II variation, CD4 T cells isolated from healthy donor HLA-DRB1 heterozygous peripheral blood mononuclear cells were split and separately co-cultured for 72 hrs with homozygous HLA-DRB1 matched B- lymphoblastoid cell lines that were unchallenged or pulsed overnight with dead S. aureus (USA 300) across a range of concentrations (multiplicity of infection [MOI = 0.5, 5, 50]). CD4 T cell activation (CD69+ CD25+) was assessed by flow cytometry (BD Fortessa & FlowJo) using monoclonal antibodies specific for CD4 PerCP-Cy5.5, CD69-PE, and CD25-APC and expressed as mean and standard deviation (Prism). Culture supernatants were collected for cytokine quantification (ProcartaPlex) using the Luminex 200 analyzer (xPONENT). Comparisons between MOI and HLA-DRB1 allele were determined with a two-way ANOVA (Prism). Results We observed variable T cell responses to S. aureus across different HLA-DRB1 alleles. HLA-DRB1*07:01 elicited a greater fold change in CD4+ T cell activation (MOI 0.5= 2.84 ±1.5; MOI 5= 6.65 ±3.6; MOI 50= 7.96 ±4.1) compared to HLA-DRB1*04:01 (MOI 0.5= 1.48 ±0.27; MOI 5= 3.15 ±0.77; MOI 50= 4.96 ±1.7) or 03:01 (MOI 0.5 =1.95 ±0.66; MOI 5= 2.56 ±0.81; MOI 50= 2.42 ±0.86) across S. aureus concentrations. Variable CD4 T cell cytokine response to recognition of S. aureus peptide was also observed across HLA-DRB1*04:01, 03:01, and 07:01 variants. Cytokines associated with Th1 response and T cell proliferation are shown, but these markers did not reach statistical significance. Conclusion We provide in vitro evidence to suggest that HLA-DRB1 variation in S. aureus peptide presentation impacts CD4+ T cell activation and may explain the association between certain HLA-DRB1 haplotypes and SAB. Disclosures Vance G. Fowler, MD, MHS, Affinergy, Janssen, Contrafect: Advisor/Consultant|AstraZeneca; EDE; Basilea: Grant/Research Support|Debiopharm, GSK; Affinium, Basilea,: Advisor/Consultant|Destiny, Amphliphi, Armata, Akagera: Advisor/Consultant|Merck; Contrafect; Karius; Janssen: Grant/Research Support|UpToDate: Royalties|Valanbio: Stock option
P-301. PrEP Use among Women of Reproductive-Age Enrolled in the Study of Treatment and Reproductive Outcomes (STAR)
No full textBackground HIV prevention efforts in the US have primarily focused on men who have sex with men, limiting pre-exposure prophylaxis (PrEP) awareness and uptake among women. This study examines PrEP use among reproductive-age women without HIV (WWOH) enrolled in the Study of Treatment and Reproductive Outcomes (STAR), the largest cohort of reproductive-age women in the Southern US. Methods STAR is a longitudinal cohort of reproductive-age WWOH (eligible if aged 18-45 years and risk factors for HIV) in six cities (Miami, FL; Atlanta, GA; Chapel Hill, NC; Washington, DC; Birmingham, AL; Jackson, MS). Demographics, medical history, STI/HIV history, and PrEP use were self-reported. STI/HIV were assessed using commercially available tests. Results Among 362 WWOH eligible for PrEP, 36 (9.9%) reported ever using PrEP (24 current use and 12 prior use). Of those on PrEP who reported PrEP source, 6 obtained it through a clinical study, 12 from a healthcare provider, and 1 from non-medical sources. All participants who reported PrEP use had used tenofovir disoproxil/emtricitabine. Women who reported ever using PrEP were older (35 vs 31 years, p=0.001); the majority lived in Miami (53%, p=0.001); identified as non-Hispanic Black (66%, p=0.163); had an earlier sexual initiation (14.0 vs 15.8 years, p=0.004); reported more lifetime partners (34 vs 10, p=0.003); and had engaged in transactional sex in the prior 5 years (22% vs 10%, p=0.047). Though current STI rates (gonorrhea, chlamydia, syphilis, and trichomoniasis) did not differ by PrEP use, prior syphilis and chlamydia were higher among those who had ever used PrEP (19% vs 4.3%, p=0.002 and 58% vs 34%, p=0.007). Reasons to discontinue PrEP included medication cost (12, 100%), provider access (12, 100%), and periodic use (12, 100%). Conclusion Despite high vulnerability to HIV among reproductive-age women in the Southern US, PrEP use was low in this sample, and discontinuation high. Affordable and accessible novel modes of PrEP delivery, and investigation on bundling HIV PrEP with DoxyPEP are urgently needed to promote access, uptake, and sustainment of PrEP use among young women. Disclosures Daniel Westreich, PhD, Sanofi-Pasteur: Advisor/Consultant Maria L. Alcaide, MD, Gilead: Advisor/Consultan