20966 research outputs found
Sort by
A comparison of supersaturated designs and orthogonal arrays
No full textThe purpose of a screening experiment is to accurately and cost-efficiently identify the few most influential factors from among the many studied. Two types of screening experiments use orthogonal arrays (OAs) and supersaturated designs (SSDs), respectively. The first requires the number of runs n to be a multiple of 4 and greater than the number of factors k, while the second is a bolder approach wherein n\u3ck. In this study, we compare the performance of OAs with SSDs, using both simulation and a method based on the probability of perfect sign recovery under the Lasso. Our findings indicate that for the scenarios considered, OAs that were far from saturation had similar performance to those that were only slightly above saturation, slightly supersaturated designs required effects between 1.5 and 2 times larger than those for the OAs in order to have similar screening performance, and very supersaturated designs were clearly less effective than the OAs even when detecting effects up to three times as large
Maternal Cardiometabolic Risk Factors in Pregnancy and Offspring Blood Pressure at Age 2 to 18 Years
No full textIMPORTANCE: Higher blood pressure in early life may signal cardiovascular disease over the life course, but determinants of blood pressure in early life are poorly understood.
OBJECTIVE: To examine the association of maternal cardiometabolic risk factors during pregnancy with offspring blood pressure from age 2 to 18 years and explore whether the association is modified by offspring sex and race and ethnicity.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from the Environmental Influences on Child Health Outcomes program between January 1, 1994, and March 31, 2023. Three common maternal cardiometabolic risk factors during pregnancy were examined: prepregnancy obesity, gestational diabetes, and hypertensive disorders of pregnancy (HDP).
EXPOSURE: Maternal cardiometabolic risk factors were retrieved and harmonized from medical records and questionnaires.
MAIN OUTCOMES AND MEASURES: Offspring systolic blood pressure (SBP) and diastolic blood pressure (DBP) percentiles adjusted for age, sex, and height were calculated.
RESULTS: Among 12 480 mother-offspring pairs (mean [SD] maternal age during pregnancy, 29.9 [6.4] years; 856 of 12 303 identifying as Asian [7.0%]; 1908 as Black [15.5%]; 2305 as Hispanic [18.7%]; 6522 as White [52.3%], and 712 as other [5.8%] race and ethnicity), at least 1 maternal cardiometabolic risk factor was present in 5537 (44.4%), with prepregnancy obesity being the most prevalent (3072 [24.6%]), followed by HDP (1693 [13.6%]) and gestational diabetes (805 [6.5%]). Offspring born to mothers with any cardiometabolic risk factors had higher SBP (4.88 percentile points; 95% CI, 3.97-5.82 percentile points) and higher DBP (1.90 percentile points; 95% CI, 1.15-2.64 percentile points) at their first blood pressure measurement, after adjusting for potential confounders, compared with their counterparts without any risk factors. Hypertensive disorders of pregnancy, alone or with either prepregnancy obesity or gestational diabetes, was significantly associated with higher offspring blood pressure. These associations were generally more significant among female compared with male offspring and among Black compared with other racial and ethnic groups. Among 6015 offspring who had 2 or more blood pressure measures, maternal cardiometabolic risk factors were associated with an increased rate of blood pressure change from age 2 to 18 years (SBP percentile, 0.5 [95% CI, 0.2-0.8] per year; DBP percentile, 0.7 [95% CI 0.5-1.0] per year).
CONCLUSIONS AND RELEVANCE: These findings suggest that protecting pregnant individuals from cardiometabolic risk factors may promote healthier blood pressure in the next generation
A Rare Event With High Acuity: A Case of Autonomic Dysreflexia
No full textAutonomic dysreflexia (AD) presents a unique circumstance that many learn about in school but seldomly see in clinical practice. In this case study, AD is identified in a higher-level spinal cord injury (SCI) than what is typically imagined. In this case, physical and pharmacologic techniques are used to mitigate AD. Additionally, the procedure is still performed using various pharmacologic agents and collaborative efforts from the surgical and anesthesia team. A unique discussion on differentials and treatment options for AD is then presented. In conclusion, anesthesia providers must recognize AD such as triggers, understand signs/symptoms, and administer prompt treatment to ensure safety of SCI patients
Chronic Total Occlusion Percutaneous Coronary Intervention: Present and Future
No full textChronic total occlusion percutaneous coronary intervention has evolved into a subspecialty of interventional cardiology. Using a variety of antegrade and retrograde techniques, experienced operators currently achieve success rates of 85% to 90%, with an incidence of major periprocedural complications of ≈2% to 3%. Several developments in equipment (new microcatheters and guidewires, novel reentry devices), imaging (computed tomography angiography guidance, intravascular imaging for reentry), techniques (intraocclusion contrast injection, advanced subintimal tracking and reentry), and artificial intelligence (automated computed tomography image analysis and prediction of the likelihood of crossing success with various techniques) could further improve outcomes. Global collaboration and rapid dissemination of new developments accelerate the pace of progress. While innovation is exciting and necessary, adhering to the basic principles of chronic total occlusion percutaneous coronary intervention (such as continual assessment of risks and benefits, meticulous angiographic review, and use of dual injection) remains critical for achieving optimal patient outcomes
Guselkumab for Moderate to Severe Scalp Psoriasis Across All Skin Tones: Cohort B of the VISIBLE Randomized Clinical Trial
No full textIMPORTANCE: Varying hair textures and hair care practices contribute to nuances in clinical presentation and management of scalp psoriasis across diverse patient populations. Cohort B of the VISIBLE trial enrolled participants with moderate to severe scalp psoriasis and skin of color, across the skin-tone spectrum.
OBJECTIVE: To evaluate efficacy, quality of life, and adverse event outcomes of guselkumab, 100 mg, among participants with moderate to severe scalp psoriasis and skin of color over 48 weeks.
DESIGN, SETTING, AND PARTICIPANTS: This ongoing phase 3b, randomized clinical trial at 45 sites in the US and Canada enrolled adults with skin of color and moderate to severe scalp psoriasis (scalp surface area [SSA] ≥30%; Psoriasis Scalp Severity Index [PSSI] ≥12; scalp-specific Investigator\u27s Global Assessment [ss-IGA] score ≥3; ≥1 nonscalp plaque). Data were collected from September 2022 to June 2024.
INTERVENTIONS: Randomized participants (3:1) received guselkumab, 100 mg, at weeks 0, 4, and every 8 weeks, or placebo at weeks 0, 4, and 12, then guselkumab at weeks 16, 20, and every 8 weeks.
MAIN OUTCOMES AND MEASURES: Coprimary end points were ss-IGA score of 0 or 1 (ss-IGA 0/1) and 90% or greater improvement in PSSI (PSSI 90) at week 16 (guselkumab vs placebo). Major secondary end points included ss-IGA 0 (complete scalp clearance), PSSI 100, percentage changes from baseline in PSSI and SSA, changes from baseline in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) symptoms score, and 4-point or greater reduction in Scalp Itch Numeric Rating Scale (NRS) score.
RESULTS: Of 108 participants (81 randomized to guselkumab; 27 randomized to placebo), 100 (92.6%) completed 48 weeks of treatment. The mean (SD) age overall was 42.5 (13.6) years, and 58 participants (56.9%) were male. At the week 16 primary end point, in the guselkumab (n = 76) vs placebo (n = 26) groups, respectively, response rates were as follows: ss-IGA 0/1, 68.4% (n = 52) vs 11.5% (n = 3) (P \u3c .001); PSSI 90, 65.8% (n = 50) vs 3.8% (n = 1) (P \u3c .001); ss-IGA 0, 57.9% (n = 44) vs 3.8% (n = 1) (P \u3c .001); PSSI 100, 59.2% (n = 45) vs 3.8% (n = 1) (P \u3c .001); 4-point or greater reduction in Scalp Itch NRS score (in those with a baseline score of at least 4), 69.4% (n = 50 of 72) vs 24.0% (n = 6 of 25) (P \u3c .001). Guselkumab efficacy increased and was maintained through week 48, when guselkumab-randomized participants achieved mean (SD) percentage improvements in PSSI and SSA of 94.6% (12.2%) and 94.8% (16.2%), respectively, and 51 (67.1%) achieved ss-IGA 0. DLQI and PSSD symptoms score least-squares mean changes were -9.7 (95% CI, -11.1 to -8.2) vs -2.2 (95% CI, -4.8 to 0.4) (P \u3c .001) and -44.8 (95% CI, -50.6 to -39.1) vs -8.3 (95% CI, -18.4 to 1.9) (P \u3c .001), respectively, with sustained improvements through week 48. Through week 16, infections were the most common adverse events in the guselkumab (n = 12; 14.8%) and placebo (n = 1; 3.7%) groups.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, after 3 doses of guselkumab, most participants achieved significant scalp clearance and clinically meaningful quality-of-life improvements; improvements increased and were maintained through week 48.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05272150
Multicenter Clinical Performance Evaluation of the NeuMoDx CT/NG Assay 2.0
No full textBACKGROUND: Given the continued increases in rates of both Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection, additional diagnostic assays may be useful in increasing access to testing for these sexually transmitted infections. We evaluated the performance of the NeuMoDx CT/NG Assay 2.0 on the NeuMoDx-96 and NeuMoDx-288 Molecular Systems.
METHODS: The clinical sensitivity and specificity of the assay were assessed when used with (1) endocervical swabs, (2) self- and clinician-collected vaginal swabs, and (3) first-catch urine specimens (female and male). Results were compared with a patient infection status based on US Food and Drug Administration-cleared assays.
RESULTS: The NeuMoDx CT/NG Assay 2.0 demonstrated high sensitivity and specificity in both symptomatic and asymptomatic participants. All specimen types other than endocervical swabs had ≥95% sensitivity and \u3e99% specificity for both pathogens. For endocervical samples, sensitivities were 93.2% and 93.3% for CT and NG, respectively. There was no difference in performance based on platform. The frequency of invalid results was low (\u3c 1%).
CONCLUSIONS: The NeuMoDx CT/NG Assay 2.0 demonstrated performance similar to currently US Food and Drug Administration-cleared assays, with the added choice of a moderate- (96-sample) or a high-throughput (288-sample) platform. The system therefore offers solutions to laboratories running lower volumes of testing that may obviate the need for outsourcing to larger reference laboratories
Long-Term Efficacy and Safety of Selective PPARδ Agonist Seladelpar in Primary Biliary Cholangitis: ASSURE Interim Study Results
No full textINTRODUCTION: The objective of these analyses was to evaluate interim data from the ongoing, open-label, long-term efficacy and safety ASSURE study of seladelpar, a selective peroxisome proliferator-activated receptor δ agonist, in primary biliary cholangitis.
METHODS: Patients rolling over from the phase 3, randomized, placebo-controlled, 12-month RESPONSE study or with previous participation in earlier legacy seladelpar studies were enrolled. Interim evaluations included composite biochemical response (alkaline phosphatase \u3c 1.67 upper limit of normal, total bilirubin ≤ upper limit of normal, and alkaline phosphatase decrease ≥15%), pruritus numerical rating scale (NRS) change among patients with a baseline score ≥4, and safety.
RESULTS: At interim cutoff, 337 patients were enrolled and received ≥1 seladelpar 10 mg dose: 54 placebo-treated and 104 seladelpar-treated from RESPONSE and 179 from legacy studies. The composite response rate at RESPONSE completion was 62% (79/128) with seladelpar and 20% (13/65) with placebo. After 12 months in ASSURE, among patients who rolled over from RESPONSE, response rates were 72% (21/29) in patients continuing seladelpar and 94% (15/16) in crossover seladelpar patients. In legacy trial patients, response rates were 73% (120/164) and 70% (69/99) after 12 and 24 months of treatment in ASSURE, respectively. The NRS decrease at RESPONSE completion in seladelpar-treated patients with baseline NRS ≥4 (-3.4) was maintained after 6 additional months of treatment (-3.8); changes were similar in crossover seladelpar (-3.8) and legacy patients (-3.5) after 6 months of treatment in ASSURE. No seladelpar-related serious adverse events were reported.
DISCUSSION: Seladelpar demonstrated durable improvements in cholestatic biomarkers and pruritus in patients with primary biliary cholangitis with up to 2 years of treatment and remained overall safe with long-term use. Clinicaltrials.gov: NCT03301506
The Role of Renal Denervation in HFpEF
No full textHeart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous clinical syndrome characterized by signs and symptoms of heart failure despite normal or near-normal ejection fraction. It is a debilitating chronic disease that affects millions of people worldwide, and due to the paucity of evidence-based pharmacological treatments for HFpEF, nonpharmacological approaches as potential therapeutic alternatives are of growing interest. As a result, renal denervation (RDN), initially developed as a therapeutic tool for resistant hypertension, has become an area of active clinical interest. RDN is a catheter-based procedure that targets the renal sympathetic pathways, aiming to reduce neurohormonal activation and mitigate maladaptive cardiac remodeling. Preclinical studies in animal models have demonstrated that RDN can improve cardiac and vascular fibrosis, reduce renal inflammation, control hypertension, and alleviate endothelial dysfunction. Recent clinical studies have further highlighted the potential benefits of RDN in patients with HFpEF and uncontrolled hypertension. In this review, we aim to outline the pathophysiology of HFpEF and demonstrate the complex clinical interplay involved in how RDN impacts the heart. Moreover, we discuss the present status of clinical studies on RDN and explore its therapeutic potential as a viable treatment for HFpEF
Cluster headache vs. labor: A comparative perspective on acute pain during and after delivery
No full textModeling Glioma Stem Cell-Mediated Tumorigenesis Using Zebrafish Patient-Derived Xenograft Systems
No full textGlioblastoma (GBM) is an aggressive brain tumor associated with high post-therapy recurrence and very poor survival rates. One of the factors contributing to the aggressive nature of this disease is the level of heterogeneity seen at the phenotypic and genetic level. Glioma stem cells (GSCs) are stem-like cells within the tumor with the ability to self-renew and give rise to different types of cells within the tumor, hence giving rise to the heterogeneity found in GBM. GSCs are often implicated in the resistance of glioma to standard of care radiation and chemotherapy. The physical niche within a tumor mass supports stemness and aggressive characteristics of GSCs, hence, experimental systems providing a relevant tumor microenvironment (TME) are critical for adequate assessment of molecular mechanisms regulating GSC populations. Although mouse models continue to be an integral part of an in vivo experimental design, they are neither time- nor cost-efficient. Danio rerio (zebrafish) patient-derived xenografts (PDXs) overcome several of the obstacles of the mammalian systems. Zebrafish constitute a robust, easily reproducible experimental model allowing for relevant investigation of GSC populations with TME. This chapter describes methods required for generation of zebrafish PDXs to study aspects of GSC-mediated tumorigenesis and interactions with the TME