Defective sphingosine-1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation

Sphingosine-1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. Sphingosine phosphate receptor 1 (S1P1) agonist, FTY-720 (Gilenya™) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring a S1pr1 gene encoding phosphorylation-deficient receptors [S1P1(S5A)] developed severe experimental autoimmune encephalomyelitis (EAE) due to T helper (TH) 17-mediated autoimmunity in the peripheral immune and nervous system. S1P1 directly activated Janus-like kinase–signal transducer and activator of transcription 3 (JAK-STAT3) pathway via interleukin 6 (IL-6). Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS

Distributed Heat Release Effects on Entropy Generation by Premixed, Laminar Flames

13-C-AJFE-GIT-058This is an open access article published under the Sage Green Open Access policy: https://us.sagepub.com/en-us/nam/posting-to-an-institutional-repository-green-open-access. Please cite this article as: Laksana A, Patki P, John T, Acharya V, Lieuwen T. Distributed heat release effects on entropy generation by premixed, laminar flames. International Journal of Spray and Combustion Dynamics. 2023;0(0). https://doi.org/10.1177/17568277231172887This article studies the generation of entropy disturbances by laminar premixed flames. The total entropy generation equals the integrated ratio of the local heat release rate and the local temperature, namely, 2b(q\u2d9/T)dV . Due to this path dependency, evaluating this integral requires an understanding of how the heat release is distributed in the temperature space. Several studies evaluate the local entropy generation as ( 2bq\u2d9dV)/Tb , where Tb refers to the burned gas temperature, implicitly assuming all the heat release occurs at Tb . Such an approximation is motivated by the high activation energy nature of combustion chemistry. This work evaluates this assumption by comparing it to results from one-dimensional premixed flame calculations for hydrogen, methane, and propane-air flames over a range of pressures, equivalence ratios, and preheat temperatures, quantified via the ratio \u3ba

Delivering medical abortion at scale: a study of the retail market for medical abortion in Madhya Pradesh, India.

BACKGROUND: Medical abortion (mifepristone and misoprostol) has the potential to contribute to reduced maternal mortality but little is known about the provision or quality of advice for medical abortion through the private retail sector. We examined the availability of medical abortion and the practices of pharmacists in India, where abortion has been legal since 1972. METHODS: We interviewed 591 pharmacists in 60 local markets in city, town and rural areas of Madhya Pradesh. One month later, we returned to 359 pharmacists with undercover patients who presented themselves unannounced as genuine customers seeking a medical abortion. RESULTS: Medical abortion was offered to undercover patients by 256 (71.3%) pharmacists and 24 different brands were identified. Two thirds (68.5%) of pharmacists stated that abortion was illegal in India. Only 106 (38.5%) pharmacists asked clients the timing of the last menstrual period and 38 (13.8%) requested to see a doctor's prescription - a legal requirement in India. Only 59 (21.5%) pharmacists correctly advised patients on the gestational limit for medical abortion, 97 (35.3%) provided correct information on how many and when to take the tablets in a combination pack, and 78 (28.4%) gave accurate advice on where to seek care in case of complications. Advice on post-abortion family planning was almost nonexistent. CONCLUSIONS: The retail market for medical abortion is extensive, but the quality of advice given to patients is poor. Although the contribution of medical abortion to women's health in India is poorly understood, there is an urgent need to improve the practices of pharmacists selling medical abortion

Association of vitamin D status with arterial blood pressure and hypertension risk : a mendelian randomisation study

Peer reviewe

A cross-sectional study to test equivalence of low- versus intermediate-flip angle dynamic susceptibility contrast MRI measures of relative cerebral blood volume in patients with high-grade gliomas at 1.5 Tesla field strength

Introduction1.5 Tesla (1.5T) remain a significant field strength for brain imaging worldwide. Recent computer simulations and clinical studies at 3T MRI have suggested that dynamic susceptibility contrast (DSC) MRI using a 30° flip angle (“low-FA”) with model-based leakage correction and no gadolinium-based contrast agent (GBCA) preload provides equivalent relative cerebral blood volume (rCBV) measurements to the reference-standard acquisition using a single-dose GBCA preload with a 60° flip angle (“intermediate-FA”) and model-based leakage correction. However, it remains unclear whether this holds true at 1.5T. The purpose of this study was to test this at 1.5T in human high-grade glioma (HGG) patients.MethodsThis was a single-institution cross-sectional study of patients who had undergone 1.5T MRI for HGG. DSC-MRI consisted of gradient-echo echo-planar imaging (GRE-EPI) with a low-FA without preload (30°/P-); this then subsequently served as a preload for the standard intermediate-FA acquisition (60°/P+). Both normalized (nrCBV) and standardized relative cerebral blood volumes (srCBV) were calculated using model-based leakage correction (C+) with IBNeuro™ software. Whole-enhancing lesion mean and median nrCBV and srCBV from the low- and intermediate-FA methods were compared using the Pearson’s, Spearman’s and intraclass correlation coefficients (ICC).ResultsTwenty-three HGG patients composing a total of 31 scans were analyzed. The Pearson and Spearman correlations and ICCs between the 30°/P-/C+ and 60°/P+/C+ acquisitions demonstrated high correlations for both mean and median nrCBV and srCBV.ConclusionOur study provides preliminary evidence that for HGG patients at 1.5T MRI, a low FA, no preload DSC-MRI acquisition can be an appealing alternative to the reference standard higher FA acquisition that utilizes a preload

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance : a retrospective cohort study

BACKGROUND : Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drugsusceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistancedetermining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all fi rst-line and second-line drugs for tuberculosis. METHODS : Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identifi ed from the drug-resistance scientifi c literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. FINDINGS : We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specifi city (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identifi ed among mutations under selection pressure in non-candidate genes. INTERPRETATION : A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workfl ows, phasing out phenotypic drugsusceptibility testing while reporting drug resistance early.Wellcome Trust, National Institute of Health Research, Medical Research Council, and the European Union.http://www.thelancet.com/infectionhb201