Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers. OBJECTIVES: To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations. METHODS: Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays. MEASUREMENTS AND MAIN RESULTS: We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype. CONCLUSIONS: Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.

Learning-by-Teaching and Service Learning to Promote Bleeding Control Education: An Academic-Community Partnership.

BACKGROUND: Stop the Bleed is a free 1-hour class that teaches laypersons to identify and treat life-threatening bleeding. The training requires a 1:10 instructor-to-participant ratio, which creates a resource drain on volunteer instructors. Nursing students are eligible to assist instructors. PROBLEM: Our State Legislature mandated that public schools equip themselves with bleeding control kits resulting in thousands of school staff needing training. APPROACH: Our nursing school used a service learning model to aid schools. Nursing students coordinated the program, and student learning occurred through a learning-by-teaching strategy. OUTCOMES: We trained 656 community members, taught in 5 counties, and students received 320 clinical hours. If not for COVID-19 (coronavirus disease 2019), numbers would have been doubled. We developed a sustainable relationship with school nurses. Students rated the program highly with respect to meeting course objectives and preparation for professional practice. CONCLUSIONS: The program met its goals and will continue.

Extensor digitorum brevis bulk and associations with fibular motor nerve conduction amplitude.

INTRODUCTION: Prior work demonstrates that fibular compound motor action potential (CMAP) amplitude <4.0 mV predicts impairment of ankle proprioceptive precision and increased fall risk. Extensor digitorum brevis (EDB) inspection may present a simple clinical surrogate for CMAP amplitude. OBJECTIVE: (1) To estimate the inter-rater reliability of assessment of EDB bulk. (2) To determine whether inspection of EDB bulk is associated with fibular CMAP amplitude. DESIGN: Prospective inter-rater reliability study. SETTING: Academic center outpatient Physical Medicine & Rehabilitation electromyography (EMG) clinics. PARTICIPANTS: Fifty-two adult participants (102 feet). MAIN OUTCOME MEASURES: (1) Inter-rater reliability of assessment of EDB bulk. (2) Mean fibular CMAP amplitude. (3) A binary measure of fibular CMAP amplitude at/above or below a 4.0 mV threshold. RESULTS: Inter-rater reliability of EDB bulk grading was moderate (kappa: 0.65 [95% confidence interval (CI) 0.48-0.82]). The mean CMAP value was 5.9 ± 2.2 mV when bulk was normal, 3.4 ± 2.1 mV when diminished, and 0.6 ± 0.9 mV when atrophied. A multivariable analysis demonstrated that EDB bulk, distal symmetric polyneuropathy (DSP), and lumbar radiculopathy were all associated with CMAP amplitude. The sensitivity and specificity of grading muscle bulk as normal versus abnormal in detecting CMAP amplitude above or below 4.0 mV were 0.86 (95% CI 0.78-0.94) and 0.71 (95% CI 0.54-0.88), respectively. An atrophied EDB was a highly specific indicator that CMAP amplitude was abnormal (<4.0 mV) in 100% of cases (8/8). CONCLUSIONS: EDB bulk was associated with fibular CMAP amplitude. Atrophy was a highly specific indicator for CMAP amplitude below 4.0 mV. Evaluation of EDB bulk may represent a quick and easy clinical surrogate marker for CMAP amplitude and distal neuromuscular impairment.

Abstinence Funding Was Not Associated With Reductions In HIV Risk Behavior In Sub-Saharan Africa.

The President's Emergency Plan for AIDS Relief (PEPFAR) has been the largest funder of abstinence and faithfulness programming in sub-Saharan Africa, with a cumulative investment of over US $1.4 billion in the period 2004-13. We examined whether PEPFAR funding for abstinence and faithfulness programs, which aimed to reduce the risk of HIV transmission, was associated with a relative change in five outcomes indicative of high-risk sexual behavior: number of sexual partners in the past twelve months for men and for women, age at first sexual intercourse for men and for women, and teenage pregnancies. Using nationally representative surveys from twenty-two sub-Saharan African countries, we compared trends between people living in countries that received PEPFAR abstinence and faithfulness funding and those living in countries that did not in the period 1998-2013. We found no evidence to suggest that PEPFAR funding was associated with population-level reductions in any of the five outcomes. These results suggest that alternative funding priorities for HIV prevention may yield greater health benefits.

Expression of a single-copy hsp-16.2 reporter predicts life span.

The level of green fluorescent protein expression from an hsp-16.2-based transcriptional reporter predicts life span and thermotolerance in Caenorhabditis elegans. The initial report used a high-copy number reporter integrated into chromosome IV. There was concern that the life-span prediction power of this reporter was not attributable solely to hsp-16.2 output. Specifically, prediction power could stem from disruption of some critical piece of chromatin on chromosome IV by the gpIs1 insertion, a linked mutation from the process used to create the reporter, or from an artifact of transgene regulation (multicopy transgenes are subject to regulation by C elegans chromatin surveillance machinery). Here we determine if the ability to predict life span and thermotolerance is specific to the gpIs1 insertion or a general property of hsp-16.2-based reporters. New single-copy hsp-16.2-based reporters predict life span and thermotolerance. We conclude that prediction power of hsp-16.2-based transcriptional reporters is not an artifact of any specific transgene configuration or chromatin surveillance mechanism.