A TERTIARY CENTER'S EXPERIENCE COMPARING THE USUAL PRITCHARD REGIME WITH A LOW DOSE MAGNESIUM SULPHATE REGIME FOR SEVERE PREECLAMPSIA AND ECLAMPSIA: A CROSS-SECTIONAL STUDY.

Background The study's objective was to ascertain whether skipping the intravenous (IV) loading dosage of magnesium sulphate would have an equivalent effect to the conventional loading dose (intramuscular + intravenous) in eclampsia for the purpose of preventing convulsions.  Methods Patients were randomly assigned to two groups. Group A (modified Pritchard protocol) received an IM loading dose of MgSo4 and a 12-hour maintenance dose instead of IV.  Group B got the standard Pritchard regimen, including IV and IM loading doses and 24-hour maintenance dosages. To see if the adapted Pritchard protocol performed as well as the original.  Results The two regimens had similar age, parity, gestational age at presentation, and birthing methods. Participants in groups A and B with pre-eclampsia (PE) or eclampsia achieved the therapeutic range of MgSo4 after an hour after loading dose, with group A having a lower toxicity risk (because the IV dose was missed). Recurrent convulsions occurred in 5 (19.6%) of group A and 9 (29.4%) of group B of 62 eclampsia patients. Both groups of severe PE women had no seizures after MgSO4 loading.  Conclusions Given the reduced propensity for MgSo4 toxicity, the 12-hour maintenance dose and the reduced loading dose regimen—which do not include the IV loading dose—of MgSo4 are as effective as the full loading dose and the 24-hour maintenance regimen in the standard Pritchard regimen in managing convulsion and preventing recurrent convulsion in eclampsia and severe pre-eclampsia.  Recommendations According to the study, the revised Pritchard protocol for eclampsia proposes lowering IV MgSo4 infusion. Maintenance with lower loading dosages for 12 hours and IV loading doses for 24 hours prevents seizures. Since MgSo4 is less toxic, it can prevent and cure convulsions in eclampsia and severe pre-eclampsia. Clinical use and evaluation of this improved approach may improve at-risk pregnancy care

Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy.

During the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human