A coarse-grain force field based on quantum mechanics (CGq FF) for molecular dynamics simulation of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles

In order to provide the means to predict from molecular dynamics (MD) simulations the structures of copolymer-based micelles in solution, we developed coarse grain force field (CGq FF) parameters for poly(ethylene glycol) (PEG) and for poly(ε-caprolactone) (PCL). A key advance here is the use of quantum mechanics to train the parameters describing the non-bonded (NB) interactions between the CG beads. The functional forms are the same as the MARTINI CG FF so standard MD codes can be used. Our CGq FF describes well the experimentally observed properties for the polymer–air and polymer–water interfaces, indicating the accuracy of the NB interactions. The structural properties (density, radius of gyration (R_g), and end-to-end distance (h)) match both experiment and all atom (AA) simulations. We illustrate the application of this CGq FF by following the formation of a spherical micelle from 250 chains of PEG₂₃-b-PCL₉ diblock copolymer, each block with molecular weight of 1000 Daltons (10 500 beads, corresponding to 123 250 atoms), in a water box with 119 139 water beads (426 553 water molecules)

Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Hyperbolic cones for casual diffeomorphisms

This paper begins with introducing a new class of diffeomorphisms on pseudo-Riemannian manifolds which are called casual diffeomorphisms. We deduce a new pseudo-Riemannian metric via a casual diffeomorphism. We introduce a class of cones for a diffeomorphism, and we prove the existence of such cones for each p in a hyperbolic set of a casual diffeomorphism. As an example we find a hyperbolic casual diffeomorphism on a Schwarzschild pseudo-Riemannian manifold, and show that the whole manifold is a hyperbolic set for it

Rupture of Splenic Aneurysm: A Rare Case Report

Although, trauma is the most cause of spleen rupture, spontaneous rupture of the splenic aneurism is a rare problem which causes a massive bleeding inside the abdomen, and ultimately reduces blood pressure, shock, and death. Here we reported a rare rupture of splenic aneurysm in pregnant woman with abdominal pain and reduced blood pressure. Splenectomy was performed after the stabilization. This problem is a life-threatening condition during the pregnancy and surgical intervention is the best treatment option

Competition of Triticale (Triticosecale wittmack) Lines with Wild Oat (Avena fatua) and its Different Densities

To study competitive effects of different densities of wild oat (Avena fatua) with triticale lines an experiment was conducted at Research Station of Islamic Azad University, Tabriz Branch, Tabriz, Iran during 2011-2012 with 3 replications. Treatments were 19 triticale lines and 6 densities of wild oat (0, 40, 80, 120, 160 and 200 plants m-2). Results indicated that effects of wild oat densities on thousand seed weight and seed yield of triticale lines were significant at 1% probability level. Also, tiller number per plant and biological yield of triticale lines were affected by the weed densities. While, wild oat traits under study were not affected by triticale lines. Hexaploid lines of triticale could tolerate 40 weed plants m-2 without any significant reduction in1000 seed weight. Wild oat density of 120 and higher plants m-2 had negative effect on seed yield of hexaploid lines of triticale

Evaluating the tabriz health complex model, lessons to learn

Background and Objectives: One of the decentralized models that has been formed based on universal health coverage is the model of health complexes in Tabriz. This study was conducted to evaluate the model.   Methods: This case study was conducted in 2017. Beside observation, 28 individuals, including informed experts in the field of establishment of health complexes in Tabriz University of Medical Sciences, were purposefully selected and semi-structured interviews were also conducted. To analyze the interviews and the results of observations, the framework analysis was used based on the components of the Primary Care Evaluation Tool (PCET) model.   Results: The strengths of the health complex model are decentralized planning, strengthening the private sector participation, have more appropriate methods for assessing the performance of the health team, creating a sense of delivering effective services in providers, using electronic information registration system, using the prospective payment method, strengthening the referral system, enhancing service continuity, and facilitating financial and geographical access, especially in marginalized areas. However, there are some problems such as lack of some facilities and equipment, lack of some workforces and high workload, financial instability, and lack of insurance organizations cooperation with the plan.   Conclusion: The health complex model has improved organizational, financial, and geographic access to health services. It seems that if the resources are more stable and by cooperation of basic insurances, the results of this project will be better