Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

"I Didn't Realize How Hard It Was Going to Be Just Transitioning Back into Life": A Qualitative Exploration of Outcomes for Survivors of Pediatric Septic Shock.

Recovery following pediatric critical illness is multifaceted and complex. While most critically ill children survive, many experience morbidities in physical, emotional, cognitive, and social function. We aimed to deeply explore and describe the multidimensional impact of pediatric septic shock for affected children and their families at the granular level using exploratory qualitative methodology. We performed semistructured telephone interviews of adolescents and caregivers of children admitted with community-acquired septic shock to two tertiary pediatric intensive care units in the United States. Interviews were conducted within two years of hospital admission, and were recorded, transcribed, and analyzed using thematic analysis. Two adolescents and 10 caregivers were interviewed. Participants described meaningful and long-lasting outcomes of septic shock on multiple dimensions of their lives. The adolescents and caregivers described substantial negative consequences on physical health and function which resulted in increased medical complexity and heightened caregiver vigilance. The physical impact led to substantial psychosocial consequences for both the child and family, including social isolation. Most caregivers expressed that septic shock was transformational in their lives, with some caregivers describing posttraumatic growth. This preliminary study provides a novel, granular view of the multidimensional impact of septic shock in pediatric patients and their families. Exploring these experiences through qualitative methodology provides greater insight into important patient and family outcomes. Deeper understanding of these outcomes may support the development of meaningful interventions to improve quality of life for children and their families following critical illness.

Pilot Evaluation of Perioperative High Dose Rate Brachytherapy in Head Neck Cancers.

Perioperative high dose rate brachytherapy involves insertion of brachytherapy catheter over the tumor bed during surgical removal of disease followed by radiation in the postoperative period. It has applications in radiotherapy dose escalation or reirradiation and for extending the surgical margins. We report here initial results of treatment in five cases of locally advanced head and neck cancers.

Attorney demands for protected psychological test information: Is access necessary for cross examination or does it lead to misinformation? An interorganizational* position paper.

Objective: Some attorneys claim that to adequately cross examine neuropsychological experts, they require direct access to protected test information, rather than having test data analyzed by retained neuropsychological experts. The objective of this paper is to critically examine whether direct access to protected test materials by attorneys is indeed necessary, appropriate, and useful to the trier-of-fact. Method: Examples are provided of the types of nonscientific misinformation that occur when attorneys, who lack adequate training in testing, attempt to independently interpret neurocognitive/psychological test data. Results: Release of protected test information to attorneys introduces inaccurate information to the trier of fact, and jeopardizes future use of tests because non-psychologists are not ethically bound to protect test content. Conclusion: The public policy underlying the right of attorneys to seek possibly relevant documents should not outweigh the damage to tests and resultant misinformation that arise when protected test information is released directly to attorneys. The solution recommended by neuropsychological/psychological organizations and test publishers is to have protected psychological test information exchanged directly and only between clinical psychologist/neuropsychologist experts.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

A copper metal-organic framework-based electrochemical sensor for identification of glutathione in pharmaceutical samples.

The construction of a new electrochemical sensing platform based on a copper metal-organic framework (Cu-MOF) heterostructure is described in this paper. Drop-casting Cu-MOF suspension onto the electrode surface primed the sensor for glutathione detection. The composition and morphology of the Cu-MOF heterostructure were investigated using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), X-ray diffraction spectroscopy (XRD), Fourier transform infrared spectroscopy (FT-IR), and UV-visible spectroscopy. The Cu-MOF heterostructure can identify glutathione (GSH) with an enhanced sensitivity of 0.0437 µA µM-1 at the detection limit (LOD; 0.1 ± 0.005 µM) and a large dynamic range of 0.1-20 µM. Boosting the conductivity and surface area enhances electron transport and promotes redox processes. The constructed sensors were also adequately selective against interference from other contaminants in a similar potential window. Furthermore, the Cu-MOF heterostructure has outstanding selectivity, long-term stability, and repeatability, and the given sensors have demonstrated their capacity to detect GSH with high accuracy (recovery range = 98.2-100.8%) in pharmaceutical samples.

Acoustic and language-specific sources for phonemic abstraction from speech.

Spoken language comprehension requires abstraction of linguistic information from speech, but the interaction between auditory and linguistic processing of speech remains poorly understood. Here, we investigate the nature of this abstraction using neural responses recorded intracranially while participants listened to conversational English speech. Capitalizing on multiple, language-specific patterns where phonological and acoustic information diverge, we demonstrate the causal efficacy of the phoneme as a unit of analysis and dissociate the unique contributions of phonemic and spectrographic information to neural responses. Quantitive higher-order response models also reveal that unique contributions of phonological information are carried in the covariance structure of the stimulus-response relationship. This suggests that linguistic abstraction is shaped by neurobiological mechanisms that involve integration across multiple spectro-temporal features and prior phonological information. These results link speech acoustics to phonology and morphosyntax, substantiating predictions about abstractness in linguistic theory and providing evidence for the acoustic features that support that abstraction.

Chagas Disease Diagnostic Practices at Four Major Hospital Systems in California and Texas.

BACKGROUND: Chagas disease (CD) is a parasitic disease that affects ∼300 000 people living in the United States. CD leads to cardiac and/or gastrointestinal disease in up to 30% of untreated people. However, end-organ damage can be prevented with early diagnosis and antiparasitic therapy. METHODS: We reviewed electronic health records of patients who underwent testing for CD at four hospital systems in California and Texas between 2016 and 2020. Descriptive analyses were performed as a needs assessment for improving CD diagnosis. RESULTS: In total, 470 patients were tested for CD. Cardiac indications made up more than half (60%) of all testing, and the most frequently cited cardiac condition was heart failure. Fewer than 1% of tests were ordered by obstetric and gynecologic services. Fewer than half (47%) of patients had confirmatory testing performed at the Centers for Disease Control and Prevention. DISCUSSION: Four major hospitals systems in California and Texas demonstrated low overall rates of CD diagnostic testing, testing primarily among older patients with end-organ damage, and incomplete confirmatory testing. This suggests missed opportunities to diagnose CD in at-risk individuals early in the course of infection when antiparasitic treatment can reduce the risk of disease progression and prevent vertical transmission.

Recent Advances on Electrochemical Sensors for Detection of Contaminants of Emerging Concern (CECs).

Contaminants of Emerging Concern (CECs), a new category of contaminants currently in the limelight, are a major issue of global concern. The pervasive nature of CECs and their harmful effects, such as cancer, reproductive disorders, neurotoxicity, etc., make the situation alarming. The perilous nature of CECs lies in the fact that even very small concentrations of CECs can cause great impacts on living beings. They also have a nature of bioaccumulation. Thus, there is a great need to have efficient sensors for the detection of CECs to ensure a safe living environment. Electrochemical sensors are an efficient platform for CEC detection as they are highly selective, sensitive, stable, reproducible, and prompt, and can detect very low concentrations of the analyte. Major classes of CECs are pharmaceuticals, illicit drugs, personal care products, endocrine disruptors, newly registered pesticides, and disinfection by-products. This review focusses on CECs, including their sources and pathways, health effects caused by them, and electrochemical sensors as reported in the literature under each category for the detection of major CECs.

Risk Factors for Radiotherapy Failure in the Treatment of Spinal Metastases.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To build a predictive model for risk factors for failure of radiation therapy, hypothesizing a higher SINS would correlate with failure. METHODS: Patients with spinal metastasis being treated with radiation at a tertiary care academic center between September 2014 and October 2018 were identified. The primary outcome measure was radiation therapy failure as defined by persistent pain, need for re-irradiation, or surgical intervention. Risk factors were primary tumor type, Karnofsky and ECOG scores, time to treatment, biologically effective dose (BED) calculations using α/ß ratio = 10, and radiation modality. A logistic regression was used to construct a prediction model for radiation therapy failure. RESULTS: One hundred and seventy patients were included. Median follow up was 91.5 days. Forty-three patients failed radiation therapy. Of those patients, 10 required repeat radiation and 7 underwent surgery. Thirty-six patients reported no pain relief, including some that required re-irradiation and surgery. Total SINS score for those who failed reduction therapy was <7 for 27 patients (62.8%), between 7-12 for 14 patients (32.6%), and >12 for 2 patients (4.6%). In the final prediction model, BED (OR .451 for BED > 43 compared to BED ≤ 43; P = .174), Karnofksy score (OR .736 for every 10 unit increase in Karnofksy score; P = .008), and gender (OR 2.147 for male compared to female; P = .053) are associated with risk of radiation failure (AUC .695). A statistically significant association between SINS score and radiation therapy failure was not found. CONCLUSIONS: In the multivariable model, BED ≤ 43, lower Karnofksy score, and male gender are predictive for radiotherapy failure. SINS score was among the candidate risk factors included in multivariable model building procedure, but it was not selected in the final model. LEVEL OF EVIDENCE: Prognostic level III.

Detection of Environmentally Harmful Malathion Pesticides Using a Bimetallic Oxide of CuO Nanoparticles Dispersed over a 3D ZnO Nanoflower.

Super-sensitive malathion detection was achieved using a nonenzymatic electrochemical sensor based on a CuO/ZnO-modified glassy carbon electrode (GCE). Due to the high affinity between the Cu element and the sulfur groups in malathion, the developed CuO-ZnO/GCE sensor may bond malathion with ease, inhibiting the redox signal of the Cu element when malathion is present. In addition to significantly increasing the ability of electron transfer, the addition of 3D-flower-like ZnO enhances active sites of the sensor interface for the high affinity of malathion, giving the CuO-ZnO/GCE composite an exceptional level of sensitivity and selectivity. This enzyme-free CuO-ZnO/GCE malathion sensor demonstrates outstanding stability and excellent detection performance under optimal operating conditions with a wide linear range of malathion from 0 to 200 nM and a low detection limit of 1.367 nM. A promising alternative technique for organophosphorus pesticide (OP) determination is offered by the analytical performance of the proposed sensor, and this method can be quickly and sensitively applied to samples that have been contaminated with these pesticides.

Association of Sex and Age with Mortality and Health-Related Quality of Life in Children with Septic Shock: A Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

Introduction: Sepsis is more common in males than females, but whether outcomes differ by sex in various pediatric age groups is unclear. The Life After Pediatric Sepsis Evaluation (LAPSE) was a multicenter prospective cohort study that evaluated health-related quality of life (HRQL) in children after community-acquired septic shock. In this secondary analysis, we evaluated whether male children are at increased risk of mortality or long-term decline in HRQL than female children by age group. Methods: Children (1 month-18 years) with community-acquired septic shock were recruited from 12 pediatric intensive care units in the U.S. Data included sex, age group (<1 year, 1-<13 years, 13-18 years), acute illness severity (acute organ dysfunction and inflammation), and longitudinal assessments of HRQL and mortality. Persistent decline in HRQL was defined as a 10% decrease in HRQL comparing baseline to 3 months following admission. Male and female children were stratified by age group and compared to evaluate the difference in the composite outcome of death or persistent decline in HRQL using the Cochran-Mantel-Haenszel test. Results: Of 389 children, 54.2% (n = 211) were male. Overall, 10% (21/211) of males and 12% (22/178) of females died by 3 months (p = 0.454). Among children with follow-up data, 41% (57/138) of males and 44% (48/108) of females died or had persistent decline in HRQL at 3 months (p = 0.636), with no observed difference by sex when stratified by age group. There was no significant difference in acute illness severity between males and females overall or stratified by age group. Conclusions: In this secondary analysis of the LAPSE cohort, HRQL, and mortality were not different between male and female children when stratified by age group. There were no significant differences by sex across multiple measures of illness severity or treatment intensity.

Photocatalytic CO2 Conversion into Solar Fuels Using Carbon-Based Materials-A Review.

Carbon materials with elusive 0D, 1D, 2D, and 3D nanostructures and high surface area provide certain emerging applications in electrocatalytic and photocatalytic CO2 utilization. Since carbon possesses high electrical conductivity, it expels the photogenerated electrons from the catalytic surface and can tune the photocatalytic activity in the visible-light region. However, the photocatalytic efficiency of pristine carbon is comparatively low due to the high recombination of photogenerated carriers. Thus, supporting carbon materials, such as graphene, CNTs (Carbon nanotubes), g-C3N4, MWCNs (Multiwall carbon nanotubes), conducting polymers, and its other simpler forms like activated carbon, nanofibers, nanosheets, and nanoparticles, are usually combined with other metal and non-metal nanocomposites to increase the CO2 absorption and conversion. In addition, carbon-based materials with transition metals and organometallic complexes are also commonly used as photocatalysts for CO2 reduction. This review focuses on developing efficient carbon-based nanomaterials for the photoconversion of CO2 into solar fuels. It is concluded that MWCNs are one of the most used materials as supporting materials for CO2 reduction. Due to the multi-layered morphology, multiple reflections will occur within the layers, thus enhancing light harvesting. In particular, stacked nanostructured hollow sphere morphologies can also help the metal doping from corroding.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

BACKGROUND: Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). METHODS: A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. RESULTS: The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1ß, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CONCLUSIONS: CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial.

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

The facilitating role of phycospheric heterotrophic bacteria in cyanobacterial phosphonate availability and Microcystis bloom maintenance.

BACKGROUND: Phosphonates are the main components in the global phosphorus redox cycle. Little is known about phosphonate metabolism in freshwater ecosystems, although rapid consumption of phosphonates has been observed frequently. Cyanobacteria are often the dominant primary producers in freshwaters; yet, only a few strains of cyanobacteria encode phosphonate-degrading (C-P lyase) gene clusters. The phycosphere is defined as the microenvironment in which extensive phytoplankton and heterotrophic bacteria interactions occur. It has been demonstrated that phytoplankton may recruit phycospheric bacteria based on their own needs. Therefore, the establishment of a phycospheric community rich in phosphonate-degrading-bacteria likely facilitates cyanobacterial proliferation, especially in waters with scarce phosphorus. We characterized the distribution of heterotrophic phosphonate-degrading bacteria in field Microcystis bloom samples and in laboratory cyanobacteria "phycospheres" by qPCR and metagenomic analyses. The role of phosphonate-degrading phycospheric bacteria in cyanobacterial proliferation was determined through coculturing of heterotrophic bacteria with an axenic Microcystis aeruginosa strain and by metatranscriptomic analysis using field Microcystis aggregate samples. RESULTS: Abundant bacteria that carry C-P lyase clusters were identified in plankton samples from freshwater Lakes Dianchi and Taihu during Microcystis bloom periods. Metagenomic analysis of 162 non-axenic laboratory strains of cyanobacteria (consortia cultures containing heterotrophic bacteria) showed that 20% (128/647) of high-quality bins from eighty of these consortia encode intact C-P lyase clusters, with an abundance ranging up to nearly 13%. Phycospheric bacterial phosphonate catabolism genes were expressed continually across bloom seasons, as demonstrated through metatranscriptomic analysis using sixteen field Microcystis aggregate samples. Coculturing experiments revealed that although Microcystis cultures did not catabolize methylphosphonate when axenic, they demonstrated sustained growth when cocultured with phosphonate-utilizing phycospheric bacteria in medium containing methylphosphonate as the sole source of phosphorus. CONCLUSIONS: The recruitment of heterotrophic phosphonate-degrading phycospheric bacteria by cyanobacteria is a hedge against phosphorus scarcity by facilitating phosphonate availability. Cyanobacterial consortia are likely primary contributors to aquatic phosphonate mineralization, thereby facilitating sustained cyanobacterial growth, and even bloom maintenance, in phosphate-deficient waters. Video Abstract.

Change in Functional Status During Hospital Admission and Long-Term Health-Related Quality of Life Among Pediatric Septic Shock Survivors.

OBJECTIVES: To investigate whether change in functional status from pre-hospitalization baseline to hospital discharge is associated with long-term health-related quality of life (HRQL) among children surviving septic shock. DESIGN: Secondary analysis of Life After Pediatric Sepsis Evaluation (LAPSE), a prospective cohort study of children with community-acquired septic shock, enrolled from January 2014 to June 2017. SETTING: Twelve U.S. academic PICUs. PATIENTS: Children, 1 month to 18 years, who survived to hospital discharge and had follow-up data for HRQL at 3 and/or 12 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional Status Scale (FSS) was assessed around enrollment to ascertain baseline status (pre-hospitalization) and at 28 days or hospital discharge. Two measures of HRQL were utilized: children with significant development delay were measured with the Functional Status II-R (FSII-R); typically, developing children were measured with the Pediatric Quality of Life Inventory (PedsQL). Each group was analyzed separately with multivariable regression modeling to determine the association between change in FSS from baseline to day 28 and HRQL at 3 and 12 months from PICU admission. Of the original 389 LAPSE participants, 224 (58%) are included. Among children with developmental delay ( n = 88), worsened FSS was associated with lower FSII-R at 3 months from PICU admission (-2.02; 95% CI, -3.34 to -0.0.71; p = 0.003), but not 12 months. Among developmentally typical children ( n = 136), worsened FSS was associated with lower PedsQL at both 3 and 12 months. Developmentally typical children with a neurologic insult during the PICU stay had the largest decrement in PedsQL at 12 months (-14.04 mo; 95% CI, -22.15 to -5.94 mo; p < 0.001). However, worsened FSS remained associated with poor HRQL-PedsQL at 3 and 12 months, after controlling for neurologic events (both p < 0.001). CONCLUSIONS: Change in FSS during hospitalization for septic shock is associated with long-term reductions in HRQL and could serve as a useful tool for identifying children at risk for this sequela.

A cost analysis of MR-guided laser interstitial thermal therapy for adult refractory epilepsy.

OBJECTIVE: MR-guided laser interstitial thermal therapy (LITT) is used increasingly for refractory epilepsy. The goal of this investigation is to directly compare cost and short-term adverse outcomes for adult refractory epilepsy treated with temporal lobectomy and LITT, as well as to identify risk factors for increased costs and adverse outcomes. METHODS: The National Inpatient Sample (NIS) was queried for patients who received LITT between 2012 and 2019. Patients with adult refractory epilepsy were identified. Multivariable mixed-effects models were used to analyze predictors of cost, length of stay (LOS), and complications. RESULTS: LITT was associated with reduced LOS and overall cost relative to temporal lobectomy, with a statistical trend toward lower incidence of postoperative complications. High-volume surgical epilepsy centers had lower LOS overall. Longer LOS was a significant driver of increased cost for LITT, and higher comorbidity was associated with non-routine discharge. SIGNIFICANCE: LITT is an affordable alternative to temporal lobectomy for adult refractory epilepsy with an insignificant reduction in inpatient complications. Patients may benefit from expanded access to this treatment modality for both its reduced LOS and lower cost.