Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Rare Type of Course and Distribution of an Additional Right Hepatic Artery: A Possible Source of Iatrogenic Injury During Hepato-biliary and Pancreatic Surgeries

Celiac artery shows frequent variations in its branching pattern. Knowledge of its possible variations is useful in gastric, pancreatic and hepato-biliary surgeries. During our dissection classes, we observed a rare variation of the branching pattern of celiac trunk. It divided normally into its three branches; left gastric, splenic and common hepatic arteries. Left gastric and splenic arteries were normal in their course and distribution. The common hepatic artery trifurcated to give hepatic artery proper, gastroduodenal artery and an additional right hepatic artery. The branching pattern of hepatic artery proper and gastroduodenal arteries was normal. The additional right hepatic artery gave origin to a right gastric artery and a large pancreatic branch to the head of the pancreas. It coursed parallel to the bile duct, being on its right side, passed through the Calot’s triangle and entered the right lobe of liver through the fossa for gall bladder. In the Calot’s triangle, it gave a cystic branch to the gall bladder. We discuss the clinical importance of this rare variation in this paper

Methyl Gallate Attenuates Doxorubicin-Induced Cardiotoxicity in Rats by Suppressing Oxidative Stress

Doxorubicin-induced cardiotoxicity is the leading cause of morbidity and mortality among cancer survivors. The present study was aimed to investigate the cardioprotective potential of methyl gallate; an active polyphenolic nutraceutical, against doxorubicin-induced cardiotoxicity in Wistar rats. Twenty-four female Wistar rats (150–200 g) were divided into four groups (n = 6) which consist of normal control (group I), doxorubicin control (group II), test-A (group III), and test-B (group IV). Group III and group IV animals were prophylactically treated with methyl gallate 150 mg/kg/day and 300 mg/kg/day orally, respectively, for seven days. Doxorubicin (25 mg/kg; single dose) was administered through an intraperitoneal route to group II, III, and IV animals on the seventh day to induce acute cardiotoxicity. On the 8th day, besides ECG analysis, serum CK, CK-MB, LDH, AST, MDA, and GSH were assayed. Following gross examination of isolated hearts, histopathological evaluation was performed by light microscopy. A significant (p < 0.05) cardiac injury, as well as oxidative stress, was observed in doxorubicin control rats in comparison to normal control rats. Methyl gallate at both the doses significantly (p < 0.05) reduced doxorubicin-induced ECG changes, dyslipidaemia, and elevation of CK, CK-MB, LDH, AST, MDA and increased GSH level. Methyl gallate reversed the doxorubicin-induced histopathological changes in the heart. The present study revealed that methyl gallate exerts cardioprotection against doxorubicin-induced cardiotoxicity in female Wistar rats by suppressing oxidative stress. Our study opens the perspective to clinical studies for consideration of methyl gallate as a potential chemoprotectant nutraceutical in the combination chemotherapy with doxorubicin to limit its cardiotoxicity

High-Fat Diet Alters the Retinal Pigment Epithelium and Choroidal Transcriptome in the Absence of Gut Microbiota

Relationships between retinal disease, diet, and the gut microbiome have started to emerge. In particular, high-fat diets (HFDs) are associated with the prevalence and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). These effects are thought to be partly mediated by the gut microbiome, which modulates interactions between diet and host homeostasis. Nevertheless, the effects of HFDs on the retina and adjacent retinal pigment epithelium (RPE) and choroid at the transcriptional level, independent of gut microbiota, are not well-understood. In this study, we performed the high-throughput RNA-sequencing of germ-free (GF) mice to explore the transcriptional changes induced by HFD in the RPE/choroid. After filtering and cleaning the data, 649 differentially expressed genes (DEGs) were identified, with 616 genes transcriptionally upregulated and 33 genes downregulated by HFD compared to a normal diet (ND). Enrichment analysis for gene ontology (GO) using the DEGs was performed to analyze over-represented biological processes in the RPE/choroid of GF-HFD mice relative to GF-ND mice. GO analysis revealed the upregulation of processes related to angiogenesis, immune response, and the inflammatory response. Additionally, molecular functions that were altered involved extracellular matrix (ECM) binding, ECM structural constituents, and heparin binding. This study demonstrates novel data showing that HFDs can alter RPE/choroid tissue transcription in the absence of the gut microbiome

Phosphorus(V) Porphyrin-Manganese(II) Terpyridine Conjugates: Synthesis, Spectroscopy, and Photo-Oxidation Studies on a SnO₂ Surface

A major challenge in designing artificial photosynthetic systems is to find a suitable mimic of the highly oxidizing photoactive species P₆₈₀ in photosystem II. High-potential phosphorus­(V) porphyrins have many attractive properties for such a mimic but have not been widely studied. Here, we report the synthesis and photophysical characterization of a novel phosphorus­(V) octaethylporphyrin–oxyphenyl–terpyridine conjugate (PPor-OPh-tpy, <b>1</b>) and its corresponding manganese­(II) complex (PPor-OPh-Mn­(tpy)­Cl₂, <b>2</b>). The X-ray structure of <b>2</b> shows that the Mn­(II) and P­(V) centers are 11.783 Å apart and that the phenoxy linker is not fully conjugated with the terpyridine ligand. The porphyrin fluorescence in <b>1</b> and <b>2</b> is strongly quenched and has a shorter lifetime compared to a reference compound without the terpyridine ligand. This suggests that electron transfer from tpy or Mn­(tpy) to the excited singlet state of the PPor may be occurring. However, femtosecond transient absorbance data show that the rate of relaxation to the ground state in <b>1</b> and <b>2</b> is comparable to the fluorescence lifetimes. Thus, if charge separation is occurring, its lifetime is short. Because both <b>1</b> and <b>2</b> are positively charged, they can be electrostatically deposited onto the surface of negatively charged SnO₂ nanoparticles. Freeze-trapping EPR studies of <b>2</b> electrostatically bound to SnO₂ suggest that excitation of the porphyrin results in electron injection from ¹PPor* into the conduction band of SnO₂ and that the resulting PPor^•+ species acquires enough potential to photo-oxidize the axially bound Mn­(II) (tpy) moiety to Mn­(III) (tpy)

Hermansky-Pudlak Syndrome Type 3 in Ashkenazi Jews and Other Non–Puerto Rican Patients with Hypopigmentation and Platelet Storage-Pool Deficiency

Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non–Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G→A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G→A mutation and for either an 1831+2T→G or a 2621-2A→G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G→A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G→C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS

Absence of Gut Microbiota Is Associated with RPE/Choroid Transcriptomic Changes Related to Age-Related Macular Degeneration Pathobiology and Decreased Choroidal Neovascularization

Studies have begun to reveal significant connections between the gut microbiome and various retinal diseases, including age-related macular degeneration (AMD). As critical supporting tissues of the retina, the retinal pigment epithelium (RPE) and underlying choroid play a critical role in retinal homeostasis and degeneration. However, the relationship between the microbiome and RPE/choroid remains poorly understood, particularly in animal models of AMD. In order to better elucidate this role, we performed high-throughput RNA sequencing of RPE/choroid tissue in germ-free (GF) and specific pathogen-free (SPF) mice. Furthermore, utilizing a specialized laser-induced choroidal neovascularization (CNV) model that we developed, we compared CNV size and inflammatory response between GF and SPF mice. After correction of raw data, 660 differentially expressed genes (DEGs) were identified, including those involved in angiogenesis regulation, scavenger and cytokine receptor activity, and inflammatory response—all of which have been implicated in AMD pathogenesis. Among lasered mice, the GF group showed significantly decreased CNV lesion size and microglial infiltration around CNV compared to the SPF group. Together, these findings provide evidence for a potential gut–RPE/choroidal axis as well as a correlation with neovascular features of AMD

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

Mechanisms governing adaptation of breast cancer to the brain metastatic microenvironment are unclear. Here, the authors use RNA-sequencing and Drosophila screening to identify Rab11b-mediated endosomal recycling as a unique mechanism for adaptation to a challenging metastatic microenvironment, which can be exploited by repurposing statins