Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, setting, and participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main outcomes and measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR Conclusions and relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial registration: ClinicalTrials.gov Identifier: NCT04364737

COVID-19 Convalescent Plasma Therapy: Long-term Implications

BACKGROUND: The long-term effect of coronavirus disease 2019 (COVID-19) acute treatments on postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is unknown. The CONTAIN-Extend study explores the long-term impact of COVID-19 convalescent plasma (CCP) therapy on postacute sequelae of SARS-CoV-2 infection (PASC) symptoms and general health 18 months following hospitalization. METHODS: The CONTAIN-Extend study examined 281 participants from the original CONTAIN COVID-19 trial (CONTAIN-RCT, NCT04364737) at 18 months post-hospitalization for acute COVID-19. Symptom surveys, global health assessments, and biospecimen collection were performed from November 2021 to October 2022. Multivariable logistic and linear regression estimated associations between the randomization arms and self-reported symptoms and Patient-Reported Outcomes Measurement Information System (PROMIS) scores and adjusted for covariables, including age, sex, race/ethnicity, disease severity, and CONTAIN enrollment quarter and sites. RESULTS: There were no differences in symptoms or PROMIS scores between CCP and placebo (adjusted odds ratio [aOR] of general symptoms, 0.95; 95% CI, 0.54-1.67). However, females (aOR, 3.01; 95% CI, 1.73-5.34), those 45-64 years (aOR, 2.55; 95% CI, 1.14-6.23), and April-June 2020 enrollees (aOR, 2.39; 95% CI, 1.10-5.19) were more likely to report general symptoms and have poorer PROMIS physical health scores than their respective reference groups. Hispanic participants (difference, -3.05; 95% CI, -5.82 to -0.27) and Black participants (-4.48; 95% CI, -7.94 to -1.02) had poorer PROMIS physical health than White participants. CONCLUSIONS: CCP demonstrated no lasting effect on PASC symptoms or overall health in comparison to the placebo. This study underscores the significance of demographic factors, including sex, age, and timing of acute infection, in influencing symptom reporting 18 months after acute hypoxic COVID-19 hospitalization

Association of Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms with Preeclampsia

We tested the hypothesis that angiotensin-converting enzyme (ACE) and angiotensinogen gene polymorphism influence the incidence, development and outcome of preeclampsia. Subjects were recruited from 90 Korean patients with preeclampsia during pregnancy and 98 age-matched controls. After isolation of DNA, polymerase chain reactions (PCR) were carried out to detect polymorphism of the ACE and angiotensinogen. M235T and T174M genotypes of angiotensinogen were determined by digestion with restriction enzyme endonuclease Tth 111-I and NCo I, respectively. The frequency of DD genotype was significantly greater in preeclampsia (0.36) than in controls (0.14) (p<0.05). The frequency of D allele was 0.55 in preeclampsia and 0.40 in controls (p<0.05). There were no differences in the onset of preeclampsia and pregnancy outcomes according to the ACE genotypes. There was no difference in the frequency of a allele of angiotensinogen M235T between the groups (0.79:0.78 in preeclampsia : controls). The frequency of T allele of angiotensinogen T174M gene was slightly increased, but not significantly, in preeclampsia (0.11) than in controls (0.07). In a multivariate analysis, only ACE genotype was associated with the development of preeclampsia (β=0.27, p=0.05). In conclusion, a molecular variant of ACE, but not angiotensinogen, gene is associated with preeclampsia in Korean women

Induction of superoxide by 12-O-tetradecanoylphorbol-13-acetate and thapsigargin, a non-phorbol ester-type tumor promoter, in peritoneal macrophages elicited from SENCAR and B6C3F1 mice: The significance of protein kinase C vs. arachidonic acid-mediated signal transduction pathways

Local production of reactive oxygen intermediates (ROIs) such as superoxide anion by tumor promoter-stimulated inflammatory macrophages (MPs) may contribute significantly to tumor development in classical models of two-stage chemically-induced carcinogenesis in murine skin. It has been suggested that genetic damage in initiated epidermal cells may be potentiated by ROIs generated by tumor promoter-stimulated inflammatory cells. Therefore, an understanding of the signal transduction mechanisms accounting for any observed strain-dependent differences in the stimulation of MPs to produce ROIs by 12-O-tetradecanoylphorbol-13-acetate (TPA) (or other non-TPA-type tumor promoters) may lead to better understanding of the relationship between inflammation and the process of tumor promotion. In the studies reported herein, peritoneal MPs elicited from phorbol ester-sensitive SENCAR mice, demonstrated a dose-dependent release of superoxide anion (4-6 nmol/10\sp6 cells) when stimulated by TPA in vitro; MP superoxide production was significantly inhibited (50-70%) by preincubation with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) (40 uM), a relatively specific protein kinase C (PKC) inhibitor. Alternatively, TPA-stimulated MPs derived from relatively-resistant B6C3F1 mice generated negligible superoxide under the same conditions. A similar strain-dependent induction of superoxide was observed when MPs were stimulated with thapsigargin (TG), a tumor promoter which has been shown to act independently of PKC. TG-stimulated SENCAR MPs released significant superoxide (2-3 nmol/10\sp6 cells) which was not inhibited by H-7; MPs from B6C3F1 mice demonstrated negligible stimulation by TG. Preincubation of SENCAR MPs with dibromoacetophenone (DBAP) (100 uM), an inhibitor of phospholipase A\sb2 (PLA\sb2), completely suppressed the superoxide induced by TPA and TG stimulation. Like TPA, 1-oleoyl-2-acetylglycerol (OAG) (50 uM), a diacylglycerol analogue and PKC activator, also induced significant superoxide from SENCAR MPs. In parallel with the superoxide findings, TPA and TG stimulated significantly greater (\sp3H) -arachidonic acid (AA) release from prelabeled SENCAR MPs (32% and 48% increase, respectively, over unstimulated controls) relative to MPs elicited from B6C3F1 mice. Two-dimensional (2-D) gel electrophoretic analysis indicated that TPA-induced phosphorylation of a 47 kDa protein (a presumed substrate for PKC previously linked to NADPH oxidase activation in guinea pig, and human polymorphonuclear leukocytes (PMNs)) occurred in MPs elicited from both SENCAR and B6C3F1 mice. Therefore, AA production may be a common biochemical pathway by which phorbol and non-phorbol ester-type tumor promoters activate MPs in SENCAR mice; such a response may be permissive for additive (or synergistic) interactions with PKC-driven signal pathways

Atomistic investigation of doping effects on electrocatalytic properties of cobalt oxides for water oxidation

The development of high-performance oxygen evolution reaction (OER) catalysts is crucial to achieve the clean production of hydrogen via water splitting. Recently, Co-based oxides have been intensively investigated as some of the most efficient and cost-effective OER catalysts. In particular, compositional tuning of Co-based oxides via doping or substitution is shown to significantly affect their catalytic activity. Nevertheless, the origin of this enhanced catalytic activity and the reaction mechanism occurring at catalytic active sites remain controversial. Theoretical investigations are performed on the electrocatalytic properties of pristine and transition metal (Fe, Ni, and Mn)-substituted Co oxides using first-principle calculations. A comprehensive evaluation of the doping effects is conducted by considering various oxygen local environments in the crystal structure, which helps elucidate the mechanism behind the doping-induced enhancement of Co-based catalysts. It is demonstrated that the local distortion induced by dopant cations remarkably facilitates the catalysis at a specific site by modulating the hydrogen bonding. In particular, the presence of Jahn-Teller-active Fe(IV) is shown to result in a substantial reduction in the overpotential at the initially inactive catalysis site without compromising the activity of the pristine active sites, supporting previous experimental observations of exceptional OER performance for Fe-containing Co oxides.

An array of metal oxides nanoscale hetero p-n junctions toward designable and highly-selective gas sensors

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An array of metal oxides nanoscale hetero p-n junctions toward designable and highly-selective gas sensors

Nano-helical array of p-NiO/n-SnO2 p-n junctions with well-defined and highly-gas-accessible hetero-interfaces is presented for designable and highly selective gas sensors. The gas sensor having the nanoscale p-n junction sensing layer with a top-and-bottom electrodes configuration was fabricated by conventional photolithography and oblique-angle deposition. The unique device structure enables a predominant modulation in barrier height at the hetero-interfaces, consistent with simulation results, resulting in unusual-yet-promising sensing behaviors upon H-2 and NO2 exposure. Based on our experimental and simulation results, and the ability to fabricate a variety combination of metal oxides heterostructures with a reproducible and controllable way, we believe that it becomes possible to design and realize highly-selective sensor array electronic-noses optimized towards target gases on demand. (C) 2017 Elsevier B.V. All rights reserved.112Nsciescopu

Reversible phase modulation and hydrogen storage in multivalent VO2 epitaxial thin films

Hydrogen, the smallest and the lightest atomic element, is reversibly incorporated into interstitial sites in vanadium dioxide (VO2), a correlated oxide with a 3d(1) electronic configuration, and induces electronic phase modulation. It is widely reported that low hydrogen concentrations stabilize the metallic phase, but the understanding of hydrogen in the high doping regime is limited. Here, we demonstrate that as many as two hydrogen atoms can be incorporated into each VO2 unit cell, and that hydrogen is reversibly absorbed into, and released from, VO2 without destroying its lattice framework. This hydrogenation process allows us to elucidate electronic phase modulation of vanadium oxyhydride, demonstrating two-step insulator (VO2)-metal (HxVO2)-insulator (HVO2) phase modulation during inter-integer d-band filling. Our finding suggests the possibility of reversible and dynamic control of topotactic phase modulation in VO2 and opens up the potential application in proton-based Mottronics and novel hydrogen storage.1155sciescopu

Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonists

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist

Characteristics of Hypoglycemic Diabetic Patients Visiting the Emergency Room

Introduction. Severe hypoglycemia can be life-threatening; therefore, it is important to identify the characteristics of the hypoglycemic patients. The aim of this study is to analyze the type and characteristics of diabetic patients with hypoglycemia who visited an emergency room. Methods. We included diabetic patients with hypoglycemia who visited the emergency room of St. Mary’s Hospital in Seoul from January 2009 to August 2018 in the study. Hypo_S group patients visited the emergency room once whereas Hypo_M group patients visited twice or more. We also compared the incidence of cardiovascular disease between the groups within 5 years after hypoglycemia. Results. A total of 843 patients were included in this study, with a mean age of 71±14 years and average glycated hemoglobin (HbA1c) level of 6.7±1.4%. For patients with hypoglycemia, lower body mass index, lower HbA1c, shorter diabetes duration, and lower glomerular filtration rate have a statistically significant relationship with patient characteristics in the emergency room group (all p<0.001). Hypoglycemia symptoms were most frequently observed between 6:00 and 12:00 am (p<0.001). Cardiovascular diseases within 5 years after discharge were more frequent in the Hypo_S group than in the Hypo_M group; however, there was no statistical significance. The frequency of aneurysms was significantly higher in patients with hypoglycemia than in other patients in the emergency room (p<0.05). Conclusion. Relatively thin older patients with a diabetes duration shorter than 10 years and good blood sugar control showed higher frequency of visits to the emergency room due to hypoglycemia. For these patients, medical staff should always be mindful of their susceptibility to hypoglycemia when prescribing insulin or OHA and educate them on the prevention of hypoglycemia