Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion.

Introduction: Neural tube defects (NTDs) are among the most debilitating and common developmental defects in humans. The induction of NTDs has been attributed to abnormal folic acid (vitamin B9) metabolism, Wnt and BMP signaling, excess retinoic acid (RA), dietary components, environmental factors, and many others. In the present study we show that reduced RA signaling, including alcohol exposure, induces NTDs. Methods: Xenopus embryos were exposed to pharmacological RA biosynthesis inhibitors to study the induction of NTDs. Embryos were treated with DEAB, citral, or ethanol, all of which inhibit the biosynthesis of RA, or injected to overexpress Cyp26a1 to reduce RA. NTD induction was studied using neural plate and notochord markers together with morphological analysis. Expression of the neuroectodermal regulatory network and cell proliferation were analyzed to understand the morphological malformations of the neural plate. Results: Reducing RA signaling levels using retinaldehyde dehydrogenase inhibitors (ethanol, DEAB, and citral) or Cyp26a1-driven degradation efficiently induce NTDs. These NTDs can be rescued by providing precursors of RA. We mapped this RA requirement to early gastrula stages during the induction of neural plate precursors. This reduced RA signaling results in abnormal expression of neural network genes, including the neural plate stem cell maintenance genes, geminin, and foxd4l1.1. This abnormal expression of neural network genes results in increased proliferation of neural precursors giving rise to an expanded neural plate. Conclusion: We show that RA signaling is required for neural tube closure during embryogenesis. RA signaling plays a very early role in the regulation of proliferation and differentiation of the neural plate soon after the induction of neural progenitors during gastrulation. RA signaling disruption leads to the induction of NTDs through the mis regulation of the early neuroectodermal network, leading to increased proliferation resulting in the expansion of the neural plate. Ethanol exposure induces NTDs through this mechanism involving reduced RA levels.

Non-vertical cultural transmission, assortment and the evolution of cooperation.

Cultural evolution of cooperation under vertical and non-vertical cultural transmission is studied, and conditions are found for fixation and coexistence of cooperation and defection. The evolution of cooperation is facilitated by its horizontal transmission and by an association between social interactions and horizontal transmission. The effect of oblique transmission depends on the horizontal transmission bias. Stable polymorphism of cooperation and defection can occur, and when it does, reduced association between social interactions and horizontal transmission evolves, which leads to a decreased frequency of cooperation and lower population mean fitness. The deterministic conditions are compared to outcomes of stochastic simulations of structured populations. Parallels are drawn with Hamilton's rule incorporating relatedness and assortment.

Beneficial effect of awake prone position in hypoxaemic patients with COVID-19: case reports and literature review.

We hereby present two case reports of moderate coronavirus disease patients, suffering from profound hypoxaemia, further deteriorating later on. A schedule pre-planned awake prone position manoeuvres were executed during their hospital stay. Following this, the patients' saturation improved, later to be weaned from oxygen support. Paucity of evidence and data regarding this topic led us to review the concept of awake prone position.

Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center.

BACKGROUND: In February 2020, the World Health Organisation designated the name COVID-19 for a clinical condition caused by a virus identified as a cause for a cluster of pneumonia cases in Wuhan, China. The virus subsequently spread worldwide, causing havoc to medical systems and paralyzing global economies. The first COVID-19 patient in Israel was diagnosed on 27 February 2020. OBJECTIVES: To present our findings and experiences as the first and largest center for COVID-19 patients in Israel. METHODS: The current analysis included all COVID-19 patients treated in Sheba Medical Center from February 2020 to April 2020. Clinical, laboratory, and epidemiological data gathered during their hospitalization are presented. RESULTS: Our 162 patient cohort included mostly adult (mean age of 52 ± 20 years) males (65%). Patients classified as severe COVID-19 were significantly older and had higher prevalence of arterial hypertension and diabetes. They also had significantly higher white blood cell counts, absolute neutrophil counts, and lactate dehydrogenase. Low folic acid blood levels were more common amongst severe patients (18.2 vs. 12.9 vs. 9.8, P = 0.014). The rate of immune compromised patients (12%) in our cohort was also higher than in the general population. The rate of deterioration from moderate to severe disease was high: 9% necessitated non-invasive oxygenation and 15% were intubated and mechanically ventilated. The mortality rate was 3.1. CONCLUSIONS: COVID-19 patients present a challenge for healthcare professionals and the whole medical system. We hope our findings will assist other providers and institutions in their care for these patients.

["STILL IS NOT ENOUGH" - WHAT IS THE DIFFERENTIAL DIAGNOSIS AND THE WORKUP WHEN THE FERRITIN LEVEL IS EXTREMELY HIGH?]

INTRODUCTION: In this case-report, a young female patient presented with a systemic inflammatory disease, accompanied by an extremely elevated ferritin blood level (Hyperferritinemia).The combination of high fever with extremely elevated ferritin level is considered to be a medical emergency being associated with the following four life threating conditions: Adult-onset Still's disease, catastrophic antiphospholipid syndrome, septic shock and macrophage activating syndrome. These conditions were recently bundled under the umbrella term of Hyperferritinemia Syndrome. During the patient's hospitalization, after empiric board spectrum antibiotics did not appear to improve the patient's condition, she was diagnosed with Adult-onset Still's disease and treated with steroids and methotrexate, resulting in gradual clinical improvement. This patient exemplifies a diagnostic challenge, recurring in the patients' milieu of internal medicine departments. Therefore, we discuss the differential diagnosis of Hyperferritinemia syndrome and treatment options for refectory adult's Still disease.

A Stroke in the Young with Surprising Recovery.

INTRODUCTION: The differential diagnosis of stroke in a comparatively young adult should always include cardiovascular aetiologies as well as central nervous system infection. CASE PRESENTATION: A 56-year-old man, with no significant medical history, presented with headache, nausea and vomiting, and right hemiparesis. Routine stroke investigation was initiated, while CNS infection was also sought. Diagnoses of HIV infection, neurosyphilis, HCV and HBV were established. Targeted therapy resulted in prompt clinical improvement. CONCLUSION: This case highlights the importance of considering CNS infection as a cause of neurological deficits in parallel with other investigations in cases of stroke in a comparatively young adult. LEARNING POINTS: The differential diagnosis should be wide for all patients presenting with stroke.Neurosyphilis should be included in the differential diagnosis of stroke in the young and middle-aged.Newly diagnosed HIV patients should be screened for other, sexually transmitted coinfection.

The Impact of Entropy and Solution Density on Selected SAT Heuristics.

We present a new characterization of propositional formulas called entropy, which approximates the freedom we have in assigning the variables. Like several other such measures (e.g., back-door and back-door-key variables), it is computationally expensive to compute. Nevertheless, for small and medium-size satisfiable formulas, it enables us to study the effect of this freedom on the impact of various SAT heuristics, following up on a recent study by C. Oh (Oh, SAT'15, LNCS 9340, 307-323). Oh's findings were that the expected success of various heuristics depends on whether the input formula is satisfiable or not. With entropy, and also with the measure of solution density, we are able to refine these findings for the case of satisfiable formulas. Specifically, we found empirically that satisfiable formulas with small entropy "behave" similarly to unsatisfiable formulas.