Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of subsequent hospitalization and death compared to their non-prescribed peers: population-based matched cohort study.

PURPOSE: To assess the effect of exposure to fluvoxamine around the COVID-19 diagnosis on subsequent hospitalizations and mortality in COVID-19 outpatients in a real-life setting. METHODS: Using nationwide administrative data, we identified adult COVID-19 outpatients diagnosed up to August 15, 2021 and conducted two cohort studies. Study 1 included subjects prescribed fluvoxamine around the index COVID-19 diagnosis (Cohort A), their peers suffering similar psychiatric difficulties but not prescribed fluvoxamine (Cohort B) and those free of psychiatric difficulties/treatments (Cohort C). Study 2 included subjects prescribed fluvoxamine (Cohort Fluvoxamine) and their peers prescribed paroxetine (Cohort Paroxetine). Cohorts were mutually exactly matched and incidence of COVID-19-related hospitalization, 30-day all-cause hospitalization and of COVID-19-related mortality was estimated. RESULTS: Of the 416,030 first-episode outpatients, Study 1 included 1016 Cohort A, 95,984 Cohort B and 275,804 Cohort C patients. Matched Cohort A (n = 749) vs. Cohort B (n = 31,336) relative risks (95%CI/CrI), frequentist and Bayes with skeptical, otpimistic and pesimistic priors, were COVID-related hospitalization 1.37 (0.56-3.33), 1.15 (0.55-2.11), 1.03 (0.56.1.96) and 1.43 (0.63-2.94), respectively; 30-day all-cause hospitalization 1.88 (0.76-4.67), 1.76 (1.39-2.25), 1.76 (1.39-2.24) and 1.86 (1.43-2.38), respectively; COVID-19-related mortality 0.73 (0.35-1.55), 0.93 (0.53-1.76), 0.79 (0.40-1.54) and 0.88 (0.37-2.11), respectively. Matched Cohort A vs. C (866 vs. 222,792) comparison yielded similar estimates, as did the matched Cohort Fluvoxamine vs. Paroxetine comparison in Study 2 (344 of 994 matched to 535 of 1796 patients). CONSLUSION: Outpatients prescribed fluvoxamine around the time of COVID-19 diagnosis were not at a reduced risk of hospitalizations and mortality compared to their non-prescribed peers.

People exposed to proton-pump inhibitors shortly preceding COVID-19 diagnosis are not at an increased risk of subsequent hospitalizations and mortality: A nationwide matched cohort study.

AIMS: To assess whether exposure to proton-pump inhibitors (PPIs) shortly preceding COVID-19 diagnosis affected the risk of subsequent hospitalizations and mortality. METHODS: This population-based study embraced first COVID-19 episodes in adults diagnosed up to 15 August 2021 in Croatia. Patients were classified based on exposure to PPIs and burden of PPI-requiring morbidities as nonusers (no issued prescriptions, no recorded treatment-requiring conditions between 1 January 2019 and COVID-19 diagnosis), possible users (no issued prescriptions, but morbidities present; self-medication possible) and users (≥1 prescription within 3 months prior to the COVID-19 diagnosis; morbidities present). Subsets were mutually exactly matched for pre-COVID-19 characteristics. The contrast between users and possible users informed about the effect of PPIs that is separate of the effect of PPI-requiring conditions. RESULTS: Among 433 609 patients, users and possible users were matched 41 195 (of 55 098) to 17 334 (of 18 170) in the primary and 33 272 to 16 434 in the sensitivity analysis. There was no relevant difference between them regarding mortality (primary: relative risk [RR] = 0.93 [95% confidence interval 0.85-1.02; absolute risk difference [RD] = -0.34% [-0.73, 0.03]; sensitivity: RR = 0.88 [0.78-0.98]; RD = -0.45% [-0.80, -0.11]) or hospitalizations (primary: RR = 1.04 [0.97-1.13]; RD = 0.29% [-0.16, 0.73]; sensitivity: RR = 1.05 [0.97-1.15]; RD = 0.32% [-0.12, 0.75]). The risks of both were slightly higher in possible users or users than in nonusers (absolutely by ~0.4-1.6%) indicating the effect of PPI-requiring morbidities. CONCLUSION: Premorbid exposure to PPIs does not affect the risk of death or hospitalization in adult COVID-19 patients, but PPI-requiring morbidities seemingly slightly increase the risk of both.

A hacked kitchen scale-based system for quantification of grip strength in rodents.

BACKGROUND: Assessment of neuromuscular function is critical for understanding pathophysiological changes related to motor system dysfunction in many rodent disease models. Among methods used for quantification of grip performance in rodents, gauge-based grip strength meters provide the most reliable results, however, such instruments are unaffordable by many laboratories. The present aim was to demonstrate how to build a rodent grip strength apparatus from scratch using a digital kitchen scale, an empty cage, and a microcontroller, with both hardware and software being completely open-source to enable maximal modularity and flexibility of the instrument in concordance with the principles of open-source bioinstrumentation. METHODS: NodeMCU ESP-32S was connected to a hacked digital kitchen scale-based platform and load cell data were acquired using custom open-source scripts. Data were analyzed in R using semi-automatic analysis algorithms implemented in the ratPASTA package. griPASTA system was tested by quantifying muscular rigidity in the rat model of Parkinson's disease (PD) induced by bilateral intrastriatal administration of 6-hydroxydopamine (6-OHDA). RESULTS: In contrast to commercial instruments, the flexibility and modularity of the proposed platform enable collecting raw data and controlling for potential confounding effects on the grip strength. Muscular rigidity is significantly increased in the rat model of PD regardless of the dose used or reboxetine pretreatment. Neither trial speed nor animal weight was recognized as an important confounder. CONCLUSIONS: griPASTA provides a cheap, easy, precise, and reliable way to measure grip strength in rodents using widely available equipment and open-source software.

Publishing of COVID-19 preprints in peer-reviewed journals, preprinting trends, public discussion and quality issues.

COVID-19-related (vs. non-related) articles appear to be more expeditiously processed and published in peer-reviewed journals. We aimed to evaluate: (i) whether COVID-19-related preprints were favored for publication, (ii) preprinting trends and public discussion of the preprints, and (iii) the relationship between the publication topic (COVID-19-related or not) and quality issues. Manuscripts deposited at bioRxiv and medRxiv between January 1 and September 27 2020 were assessed for the probability of publishing in peer-reviewed journals, and those published were evaluated for submission-to-acceptance time. The extent of public discussion was assessed based on Altmetric and Disqus data. The Retraction Watch Database and PubMed were used to explore the retraction of COVID-19 and non-COVID-19 articles and preprints. With adjustment for the preprinting server and number of deposited versions, COVID-19-related preprints were more likely to be published within 120 days since the deposition of the first version (OR = 1.96, 95% CI: 1.80-2.14) as well as over the entire observed period (OR = 1.39, 95% CI: 1.31-1.48). Submission-to-acceptance was by 35.85 days (95% CI: 32.25-39.45) shorter for COVID-19 articles. Public discussion of preprints was modest and COVID-19 articles were overrepresented in the pool of retracted articles in 2020. Current data suggest a preference for publication of COVID-19-related preprints over the observed period. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11192-021-04249-7.

Nitrocellulose redox permanganometry: A simple method for reductive capacity assessment.

We propose a rapid, simple, and robust method for measurement of the reductive capacity of liquid and solid biological samples based on potassium permanganate reduction followed by trapping of manganese dioxide precipitate on a nitrocellulose membrane. Moreover, we discuss how nitrocellulose redox permanganometry (NRP) can be used for high-throughput analysis of biological samples and present HistoNRP, its modification used for detailed analysis of reductive capacity spatial distribution in tissue with preserved anatomical relations.•NRP is a rapid, cost-effective, and simple method for reductive capacity assessment•NRP is compatible with a high-throughput screening of solid and liquid biological samples•HistoNRP exploits passive diffusion slice print blotting for reductive capacity spatial analysis.

Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis.

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.

Is Galactose a Hormetic Sugar? An Exploratory Study of the Rat Hippocampal Redox Regulatory Network.

SCOPE: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer's disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN). METHODS AND RESULTS: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg-1 ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1. CONCLUSION: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.

5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.

BACKGROUND: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA. METHODS: Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0. RESULTS: AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage. CONCLUSION: AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.

The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion.

Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.