Transformations of Progesterone by Subcellular Fractions of Human Skin

Homogenates of human skin metabolize progesterone-4-14C to the same products as whole skin. Studies with subcellular fractions obtained by differential centrifugation indicate the presence in skin of a membrane-bound 5α-reductase and a soluble 20α-hydroxysteroid dehydrogenase (20α-HSD), both of which utilize TPNH as cofactor. The 20α-HSD has a pH optimum of 6.2 and a Km of approximately 7 μM. Unlike placental preparations, the 105,000 × g supernatant fraction prepared from human skin has more 20α-HSD than 17β-hydroxy-steroid dehydrogenase activity. This soluble skin enzyme acting on steroid hormones is distinct from previously reported particulate enzymes

RNA interference of gonadotropin-inhibitory hormone gene induces arousal in songbirds.

Gonadotropin-inhibitory hormone (GnIH) was originally identified in quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. However, GnIH neuronal fibers do not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting it has multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we investigated the effect of RNA interference (RNAi) of the GnIH gene on the behavior of white-crowned sparrows, a highly social songbird species. Administration of small interfering RNA against GnIH precursor mRNA into the third ventricle of male and female birds reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. GnIH RNAi further enhanced song production of short duration in male birds when they were challenged by playbacks of novel male songs. These behaviors resembled those of breeding birds during territorial defense. The overall results suggest that GnIH gene silencing induces arousal. In addition, the activities of male and female birds were negatively correlated with GnIH mRNA expression in the paraventricular nucleus. Density of GnIH neuronal fibers in the ventral tegmental area was decreased by GnIH RNAi treatment in female birds, and the number of gonadotropin-releasing hormone neurons that received close appositions of GnIH neuronal fiber terminals was negatively correlated with the activity of male birds. In summary, GnIH may decrease arousal level resulting in the inhibition of specific motivated behavior such as in reproductive contexts

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study

© 2021 Elsevier Inc. Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19

Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0

Multiscale Modeling of Superior Cavopulmonary Circulation: Hemi-Fontan and Bidirectional Glenn Are Equivalent

Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis

Antibiotic Prescribing Patterns in Paediatric Primary Care in Italy: Findings from 2012–2018

Comprehensive data are needed to monitor antibiotic prescribing and inform stewardship. We aimed to evaluate the current antibiotic prescribing patterns, including treatment switching and prolongation, in the paediatric primary care setting in Italy. This database study assessed antibiotic prescriptions retrieved from Pedianet, a paediatric primary care database, from 1 January 2012 to 31 December 2018. Descriptive analyses were stratified by diagnosis class, calendar year, and children’s age. Generalized linear Poisson regression was used to assess variation in the prescriptions. In total, 505,927 antibiotic prescriptions were included. From 2012 to 2018, the number of antibiotics per child decreased significantly by 4% yearly from 0.79 in 2012 to 0.62 in 2018. Amoxicillin prescriptions decreased with increasing children’s age, while macrolides and third-generation cephalosporins had the opposite trend. Prescriptions were associated with a diagnosis of upper respiratory infection in 23% of cases, followed by pharyngitis (21%), bronchitis and bronchiolitis (12%), and acute otitis media (12%). Eight percent of treatment episodes were prolonged or switched class, mostly represented by co-amoxiclav, macrolides, and third-generation cephalosporins. Our findings report an overall decrease in antibiotic prescriptions, but pre-schoolers are still receiving more than one antibiotic yearly, and broad-spectrum antibiotics prescription rates remain the highest

Machine learning applications on neonatal sepsis treatment: a scoping review.

INTRODUCTION: Neonatal sepsis is a major cause of health loss and mortality worldwide. Without proper treatment, neonatal sepsis can quickly develop into multisystem organ failure. However, the signs of neonatal sepsis are non-specific, and treatment is labour-intensive and expensive. Moreover, antimicrobial resistance is a significant threat globally, and it has been reported that over 70% of neonatal bloodstream infections are resistant to first-line antibiotic treatment. Machine learning is a potential tool to aid clinicians in diagnosing infections and in determining the most appropriate empiric antibiotic treatment, as has been demonstrated for adult populations. This review aimed to present the application of machine learning on neonatal sepsis treatment. METHODS: PubMed, Embase, and Scopus were searched for studies published in English focusing on neonatal sepsis, antibiotics, and machine learning. RESULTS: There were 18 studies included in this scoping review. Three studies focused on using machine learning in antibiotic treatment for bloodstream infections, one focused on predicting in-hospital mortality associated with neonatal sepsis, and the remaining studies focused on developing machine learning prediction models to diagnose possible sepsis cases. Gestational age, C-reactive protein levels, and white blood cell count were important predictors to diagnose neonatal sepsis. Age, weight, and days from hospital admission to blood sample taken were important to predict antibiotic-resistant infections. The best-performing machine learning models were random forest and neural networks. CONCLUSION: Despite the threat antimicrobial resistance poses, there was a lack of studies focusing on the use of machine learning for aiding empirical antibiotic treatment for neonatal sepsis

Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study

Objective To evaluate resting heart rate as an independent predictor of cardiovascular risk in women

Flexible and Stretchable Self-Powered Multi-Sensors Based on the N-Type Thermoelectric Response of Polyurethane/Na-x(Ni-ett)(n) Composites

Flexible and stretchable electronic devices have a broad range of potential uses, from biomedicine, soft robotics, and health monitoring to the internet‐of‐things. Unfortunately, finding a robust and reliable power source remains challenging, particularly in off‐the‐grid and maintenance‐free applications. A sought‐after development overcome this challenge is the development of autonomous, self‐powered devices. A potential solution is reported exploiting a promising n‐type thermoelectric compound, poly nickel‐ethenetetrathiolates (Na_{x}(Ni‐ett)_{n}). Highly stretchable n‐type composite films are obtained by combining Nax(Ni‐ett)n with commercial polyurethane (Lycra). As high as 50 wt% Na_{x}(Ni‐ett)_{n} content composite film can withstand deformations of ≈500% and show conductivities of ≈10^{-2} S cm^{-1} and Seebeck coefficients of approx. −40 µV K^{-1}. These novel materials can be easily synthesized on a large scale with continuous processes. When subjected to a small temperature difference (<20 °C), the films generate sufficient thermopower to be used for sensing strain (gauge factor ≈20) and visible light (sensitivity factor ≈36% (kW m^{-2})^{-1}), independent of humidity (sensitivity factor ≈0.1 (%RH)^{-1}. As a proof‐of‐concept, a wearable self‐powered sensor is demonstrated by using n‐type Na_{x}(Ni‐ett)_{n}/Lycra and PEDOT:PSS/Lycra elements, connected in series by hot pressing, without employing any metal connections, hence preserving good mechanical ductility and ease of processing

Antibiotic Prescription Patterns in the Paediatric Primary Care Setting before and after the COVID-19 Pandemic in Italy: An Analysis Using the AWaRe Metrics.

The containment measures following COVID-19 pandemic drastically reduced airway infections, but they also limited the access of patients to healthcare services. We aimed to assess the antibiotic prescription patterns in the Italian paediatric primary care setting before and after the containment measures implementation. For this retrospective analysis, we used a population database, Pedianet, collecting data of patients aged 0-14 years enrolled with family paediatricians (FP) from March 2019 to March 2021. Antibiotic prescriptions were classified according to WHO AWaRe classification. An interrupted time series evaluating the impact of the containment measures implementation on the monthly antibiotic index, on the access to watch index, and on the amoxicillin to co-amoxiclav index stratified by diagnosis was performed. Overall, 121,304 antibiotic prescriptions were retrieved from 134 FP, for a total of 162,260 children. From March 2020, the antibiotic index dropped by more than 80% for respiratory infections. The Access to Watch trend did not change after the containment measures, reflecting the propensity to prescribe more broad-spectrum antibiotics for respiratory infections even during the pandemic. Similarly, co-amoxiclav was prescribed more often than amoxicillin alone for all the diagnoses, with a significant variation in the trend slope for upper respiratory tract infections prescriptions