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Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study
No full textBACKGROUND: Type I interferon (IFN) pathway activation has been associated with severe systemic sclerosis. We aimed to examine the association of serum IFN scores with disease activity and outcomes in two cohorts of patients with diffuse cutaneous systemic sclerosis. METHODS: In this retrospective cohort study, we included adult (aged \u3e18 years) patients with diffuse cutaneous systemic sclerosis enrolled in the US Prospective Registry of Early Systemic Sclerosis (PRESS; incident cohort) or in the UK observational cohort (Stratification for Risk of Progression in Scleroderma [STRIKE]; prevalent cohort) registries and healthy controls (volunteers). Sera were analysed by Myriad-Rules Based Medicine\u27s Luminex xMAP Technology Multiplex Assay (Austin, TX, USA), and IFN scores were generated using concentrations of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11. Patients were classified as IFN-high (vs IFN-low) when mean sum of the natural logarithm of the six chemokines was greater than (or within) two standard deviations of healthy controls. The main outcome measures were the baseline and the minimal clinically important differences for modified Rodnan Skin Score, forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), and Health Assessment Questionnaire-Disability Index at 12 months. A person with lived experience of systemic sclerosis was involved in writing the report. FINDINGS: Patients with diffuse cutaneous systemic sclerosis in the PRESS incident cohort were recruited between April 1, 2012, and Jan 1, 2019, and healthy controls and patients in the STRIKE prevalent cohort were recruited between Dec 1, 2014, and Dec 1, 2018. IFN scores were generated for 110 patients in the incident cohort (mean age 50·2 years [SD 15·0], 76 [69%] women and 34 [31%] men, 87 [79%] White) and 72 patients in the prevalent cohort (mean age 51·7 years [SD 10·9], 50 [69%] women and 22 [31%] men, 64 [89%] White), and 32 healthy controls (mean age 47·0 years [SD 12·4]; 19 [59%] women and 13 [41%] men; 24 [75%] White). 50 (45%) of 110 patients in the incident cohort and 27 (38%) of 72 patients in the prevalent cohort were classified as IFN-high. In the incident cohort, patients classified as IFN-high had worse baseline disease compared with patients classified as IFN-low, as assessed by mean predicted FVC (72·0% [SD 18·9] vs 85·3% [18·5]; p=0·0028), DLCO (56·8% [SD 21·6] vs 76·6% [25·3]; p=0·0008), and median Health Assessment Questionnaire-Disability Index (1·4 [IQR 0·8-2·0] vs 0·8 [0·4-1·5]; p=0·0033). Differences in FVC and DLCO persisted at last follow-up (median 34 months [IQR 19·8- 54·0] for FVC and median 34 months [IQR 22·5- 54·0] for DLCO). In the prevalent cohort, patients classified as IFN-high had a shorter median disease duration (2·2 years [IQR 0·7-8·2] vs 5·0 years [1·9-10·0]; p=0·035) compared to those classified as IFN-low, and worse 12-month lung outcomes independent of baseline FVC or immunosuppression (5% relative worsening of FVC in nine [39%] of 23 patients with IFN-high vs seven [17%] of 41 patients with IFN-low; p=0·051). Moreover, cumulative 5-year mortality was 24·9% (95% CI 14·9-39·7) for IFN-high versus 8·6% (3·6-19·9) for IFN-low (p=0·052). INTERPRETATION: Serum IFN score assessment for patients with diffuse cutaneous systemic sclerosis could identify patients with high disease activity who are more likely to have worse 12-month prognosis and overall survival. FUNDING: National Scleroderma Foundation, National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Rheumatic Disease Research Core Centers, National Institute of Health Research Leeds Biomedical Research Centre, and Kennedy Trust for Rheumatology Research
Management of Fasciitis in a Mariner on a Disabled Sailboat in the Middle of the Pacific
No full textA 57-y-old sailor (Patient S) with a history of chronic lymphocytic leukemia departed from Hawaii on his sailboat. On the morning of his departure, he sustained a small laceration to his right foot while walking on the beach. During the next 1-2 d, this laceration became superficially infected. Four days after setting sail, a rogue wave hit the boat in bad weather, splitting the mainsail and damaging the ship\u27s communication equipment. Over the next 3 d, Patient S experienced worsening of his wound infection to the point that by Day 7, when George Washington Maritime Medical Access was contacted to initiate medical management, Patient S had developed a full-fledged necrotizing fasciitis in his right lower extremity. Despite attempts to treat the infection while at sea, Patient S eventually required a complex medical evacuation from the middle of the Pacific Ocean
Phenobarbital Addition to Alcohol Withdrawal Treatment Offers Better Outcomes than Dexmedetomidine in Hospitalized Patients
No full textBackgroundThis study directly compares outcomes of phenobarbital and dexmedetomidine as adjuncts to symptom-triggered benzodiazepine treatment for alcohol withdrawal syndrome (AWS).MethodsThis is a retrospective cohort analysis at a single tertiary referral institution in a major urban center in the United States. In hospitalized patients above 18 years with AWS between May 1, 2018, and July 31, 2021 we compared the hospital length of stay (LOS), ICU LOS, mechanical ventilation incidence and duration of patients who received dexmedetomidine versus phenobarbital as adjuncts to lorazepam-based treatment. Patients were divided into two cohorts based on treatment they received - dexmedetomidine/lorazepam (DEX) versus phenobarbital/lorazepam (PHENO). The use of phenobarbital or dexmedetomidine was left to the discretion of the treating bedside physician.ResultsOne hundred fifty-six patients met inclusion criteria with 102 patients (65%) in the DEX group and 54 patients (35%) in the PHENO group. The PHENO group had a lower probability of intubation (OR 0.33, 95% CI 0.15-0.70, p = 0.005) and shorter hospital LOS (IRR 0.45, 95% CI 0.31-0.64, p \u3c 0.001), and ICU LOS (IRR 0.58, 95% CI 0.34-1.00, p = 0.050). For both hospital and ICU LOS, the PHENO group had shorter LOS than dexmedetomidine at lower doses of lorazepam (\u3c3 mg), but this protective effect diminished at higher doses of lorazepam, at a rate of 10% (hospital LOS, IRR 1.10, 95% CI 1.05-1.16, p \u3c 0.001) and 6% (ICU LOS, IRR 1.06, 95% CI 0.99-1.13, p = 0.074) per milligram increase in lorazepam.ConclusionsA symptom- triggered lorazepam regimen including early phenobarbital administration for severe alcohol withdrawal syndrome is associated with lower hospital LOS and need for intubation compared to a symptom triggered lorazepam regimen with dexmedetomidine adjunct
CCTA-Derived Coronary Plaque Burden Offers Enhanced Prognostic Value Over CAC Scoring In Suspected CAD Patients
No full textAIM: To assess the prognostic utility of coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) - derived quantitative plaque metrics for predicting adverse cardiovascular outcomes. METHODS AND RESULTS: The study enrolled 2,404 patients with suspected CAD but without prior history of CAD. All participants underwent CAC scoring and CCTA, with plaque metrics quantified using an artificial intelligence (AI)-based tool (Cleerly, Inc). Percent atheroma volume (PAV) and non-calcified plaque volume percentage (NCPV%), reflecting total plaque burden and the proportion of non-calcified plaque volume normalized to vessel volume, were evaluated. The primary endpoint was a composite of all-cause mortality and non-fatal myocardial infarction (MI). Cox proportional hazards models, adjusted for clinical risk factors and early revascularization, were employed for analysis.During a median follow-up of 7.0 years, 208 patients (8.7%) experienced the primary endpoint, including 73 cases of MI (3%). The model incorporating PAV demonstrated superior discriminatory power for the composite endpoint (AUC = 0.729) compared to CAC scoring (AUC = 0.706, p = 0.016). In MI prediction, PAV (AUC = 0.791) significantly outperformed CAC (AUC = 0.699, p \u3c 0.001), with NCPV% showing the highest prognostic accuracy (AUC = 0.814, p \u3c 0.001). CONCLUSIONS: AI-driven assessment of coronary plaque burden enhances prognostic accuracy for future adverse cardiovascular events, highlighting the critical role of comprehensive plaque characterization in refining risk stratification strategies
Is an earlier onset of focal epilepsy associated with atypical language lateralization? A systematic review, meta-analysis and new data
No full textRight and bilateral language representation is common in focal epilepsy, possibly reflecting the influence of epileptogenic lesions and/or seizure activity in the left hemisphere. Atypical language lateralization is assumed to be more likely in cases of early seizure onset, due to greater language plasticity in childhood. However, evidence for this association is mixed, with most research based on small samples and heterogenous cohorts. In this preregistered meta-analysis we examined the association between age at seizure onset and fMRI-derived language lateralization in individuals with focal epilepsy. The pooled effect size demonstrated a correlation between an earlier onset and rightward language lateralization in the total sample (r = 0.1, p = .005, k = 58, n = 1240), with no difference in the correlation between age at seizure onset and language lateralization between left and right hemisphere epilepsy samples (Q=62.03, p = .302). In exploratory analyses of the individual participant data (n = 1157), we demonstrated strong evidence that a logarithmic model fits the data better than a linear (BF=350) or categorical model with 6 years of age as a cut-off (BF=36). These findings indicate that there is a small but significant relationship between age at seizure onset and language lateralization. The relationship was consistent with theories of language plasticity proposing an exponential decline in plasticity over early childhood. However, given that this effect was subtle and only found in larger sample sizes, an early age at seizure onset would not serve as a good indicator of atypical language lateralization on the individual patient level
Efficacy and Safety of Higher Doses of Levofloxacin for MDR-TB: A Randomized Placebo-controlled Phase 2 Trial
No full textBACKGROUND: Evaluation of optimal dosing has generally been inadequate during TB drug development. Fluoroquinolones are central to TB treatment. We aimed to determine the dose of levofloxacin needed to achieve maximal efficacy and acceptable safety and tolerability as part of a multidrug TB regimen. METHODS: Opti-Q was an international, multi-center, randomized, placebo-controlled, phase II trial. Eligible participants with TB resistant to isoniazid and rifampicin but susceptible to fluoroquinolones (MDR-TB) were randomized to receive one of four weight-adjusted once-daily doses of levofloxacin given for 24 weeks(168 doses): 11mg/kg(750mg), 14mg/kg(750mg/1000mg), 17 mg/kg(1000mg/1250mg) or 20mg/kg(1250mg/1500mg) alongside a multidrug regimen. The primary efficacy outcome was time to sputum culture conversion and the primary safety outcome was grade 3 or higher adverse events. FINDINGS: 111 participants were randomized from three sites in South Africa and Peru. 83(75%) had cavities on chest x-ray, 55(50%) had a smear grading of 3+, median BMI was 20.4 kg/m. Median levofloxacin AUC/MIC was 573, 633, 918 and 1343 across the four treatment arms. There was no difference in time to culture conversion on solid or liquid media by treatment arm (stratified log-rank p=0.282), by tertile of AUC/MIC (p=0.350), or by dose received (p=0.723); 69.3%, 74.8%, 70.6% and 78.3% achieved culture conversion after 8 weeks on solid media respectively across the treatment arms; 64.6%, 69.5%, 52.6% and 69.6% in liquid culture. More participants experienced a grade 3-5 adverse event by dose (37.0% and 16.0% in the highest and lowest dose groups respectively, p=0.042, Cochran-Armitage test for trend) and by tertile of AUC (p=0.011). INTERPRETATION: As part of a multidrug regimen, doses of levofloxacin above 1000mg resulted in greater exposures and increased frequency of adverse events but did not result in faster time to sputum culture conversion. A dose of 1000mg daily can achieve the target exposure in nearly all adults and was well tolerated. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT0191839
ILAE neuroimaging task force highlight: The utility of multimodal neuroimaging in diagnostic and presurgical workup of drug-resistant focal epilepsy
No full textThe ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy, consistent with ILAE\u27s educational mission. In patients with drug-resistant focal epilepsy who are candidates for surgical intervention, the identification of structural abnormalities is a strong predictor of favorable postoperative seizure outcomes. When conventional imaging is insufficient, the integration of multimodal neuroimaging data with structural, metabolic, and functional imaging modalities is often helpful. The following two illustrative cases from two different centers highlight the challenges and needs to integrate the information from multiple imaging modalities for a more accurate diagnosis and resection planning of drug-resistant focal epilepsies. This approach can increase the number of patients eligible for surgery while minimizing the risk of postoperative deficits
Identification of potential susceptibility loci for non-small cell lung cancer through whole genome sequencing in circadian rhythm genes
No full textLung cancer is a malignant tumor with a high morbidity and mortality rate worldwide, causing an increasing disease burden. Of these, the most common type is non-small cell lung cancer (NSCLC), which accounts for 80-85% of all lung cancer cases. Genetic research is crucial for continuously discovering susceptibility genes related to lung cancer for in-depth study. The role of genetic predisposition in the development of NSCLC, particularly within circadian rhythm pathways known to govern various physiological processes, is increasingly acknowledged. Yet, the association between genetic variants of circadian rhythm-related genes and NSCLC susceptibility among Chinese populations is not fully understood. This study carried out a two-phase (discovery and validation stages) research design to identify genetic variants associated with NSCLC risk within the circadian rhythm pathway. We employed extensive whole-genome sequencing (WGS) for 1,104 NSCLC cases and 9,635 controls. FastGWA-GLMM was used for single-locus risk association analysis of NSCLC, and we screened candidate SNPs in the validation set that comprised 4,444 cases and 174,282 controls from the Biobank Japan Project (BBJ). Furthermore, GCTA-COJO conditional analysis was utilized to confirm SNPs related to NSCLC risk. Finally, potential genetic variations that may regulate gene expression were explored in GTEx and QTLbase. RNA sequencing data were utilized for transcriptomic verification. Our study identified eight candidate SNPs associated with NSCLC susceptibility within the circadian rhythm pathway that met the requirement with P \u3c 0.05 in both the discovery and validation populations. After conditional analysis, five of these SNPs remained. The A allele of CUL1 rs78524436 (OR = 1.18, 95%CI: 1.09-1.29, P = 7.99e-5) and the A allele of TEF rs9611588 (OR = 1.06, 95%CI: 1.02-1.10, P = 1.28e-3) were associated with an increased risk of NSCLC. The A allele of FBXL21 rs2069868 (OR = 0.86, 95%CI: 0.80-0.96, P = 4.78e-4), the T allele of CSNK1D rs147316973 (OR = 0.76, 95%CI: 0.65-0.88, P = 5.93e-4), and the A allele of RORA rs1589701 (OR = 0.94, 95%CI: 0.91-0.98, P = 3.40e-3) were associated with a lower risk of NSCLC, separately. The eQTL results revealed an association between RORA rs1589701 and TEF rs9611588 with the expression levels of RORA and TEF, respectively. Transcriptome data indicated that RORA and TEF showed lower expression levels in tumor tissues compared to normal tissues (P \u3c 0.001). Moreover, poorer survival was observed in patients with lower RORA and TEF expressions (log-rank P \u3c 0.05). Our findings spotlight potential susceptibility loci within circadian rhythm pathway genes that modulate NSCLC carcinogenesis, which enriches the understanding of the genetic susceptibility of NSCLC in the Chinese population and provides a more solid basis for exploring the biological mechanism of circadian rhythm genes in NSCLC
Association between behavioural risk factors for hypertension and concordance with the Dietary Approaches to Stop Hypertension dietary pattern among South Asians in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study
No full textSouth Asians are among the fastest-growing immigrant population group in the United States (U.S.) with a unique disease risk profile. Due in part to immigration and acculturation factors, South Asians engage differently with behavioural risk factors (e.g. smoking, alcohol intake, physical activity, sedentary behaviour, and diet) for hypertension, which may be modified for the primary prevention of cardiovascular disease. Using data from the Mediators of Atherosclerosis in South Asians Living in America cohort, we conducted a cross-sectional analysis to evaluate the association between behavioural risk factors for cardiovascular disease and diet. We created a behavioural risk factor score based on smoking status, alcohol consumption, physical activity, and TV watching. We also calculated a Dietary Approaches to Stop Hypertension (DASH) dietary score based on inclusion of relevant dietary components. We used both scores to examine the association between engaging with risk factors for hypertension and the DASH diet among a cohort of South Asian adults. We found that participants with 3-4 behavioural risk factors had a DASH diet score that was 3 units lower than those with no behavioural risk factors (aβ: -3.25; 95% CI: -4.28, -2.21) and were 86% less likely to have a DASH diet score in the highest category compared to the lowest DASH diet score category (aOR: 0.14; 95% CI: 0.05, 0.37) in the fully adjusted models. These findings highlight the relationship between behavioural risk factors for hypertension among South Asians in the U.S