TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate.

BACKGROUND: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). OBJECTIVE: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. DATA SOURCES: Scientific databases and clinical trial registry platforms. STUDY ELIGIBILITY CRITERIA, INTERVENTIONS, AND PARTICIPANTS: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. METHODS OF DATA SYNTHESIS AND RISK-OF-BIAS ASSESSMENT: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. RESULTS: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

Confirmation bias emerges from an approximation to Bayesian reasoning.

Confirmation bias is defined as searching for and assimilating information in a way that favours existing beliefs. We show that confirmation bias emerges as a natural consequence of boundedly rational belief updating by presenting the BIASR model (Bayesian updating with an Independence Approximation and Source Reliability). In this model, an individual's beliefs about a hypothesis and the source reliability form a Bayesian network. Upon receiving information, an individual simultaneously updates beliefs about the hypothesis in question and the reliability of the information source. If the individual updates rationally then this introduces numerous dependencies between beliefs, the tracking of which represents an unrealistic demand on memory. We propose that human cognition overcomes this memory limitation by assuming independence between beliefs, evidence for which is provided in prior research. We show how a Bayesian belief updating model incorporating this independence approximation generates many types of confirmation bias, including biased evaluation, biased assimilation, attitude polarisation, belief perseverance and confirmation bias in the selection of sources.

How cognitive selection affects language change.

Like biological species, words in language must compete to survive. Previously, it has been shown that language changes in response to cognitive constraints and over time becomes more learnable. Here, we use two complementary research paradigms to demonstrate how the survival of existing word forms can be predicted by psycholinguistic properties that impact language production. In the first study, we analyzed the survival of words in the context of interpersonal communication. We analyzed data from a large-scale serial-reproduction experiment in which stories were passed down along a transmission chain over multiple participants. The results show that words that are acquired earlier in life, more concrete, more arousing, and more emotional are more likely to survive retellings. We reason that the same trend might scale up to language evolution over multiple generations of natural language users. If that is the case, the same set of psycholinguistic properties should also account for the change of word frequency in natural language corpora over historical time. That is what we found in two large historical-language corpora (Study 2): Early acquisition, concreteness, and high arousal all predict increasing word frequency over the past 200 y. However, the two studies diverge with respect to the impact of word valence and word length, which we take up in the discussion. By bridging micro-level behavioral preferences and macro-level language patterns, our investigation sheds light on the cognitive mechanisms underlying word competition.

Simvastatin in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

When fairness is not enough: The disproportionate contributions of the poor in a collective action problem.

Many of our most pressing challenges, from combating climate change to dealing with pandemics, are collective action problems: situations in which individual and collective interests conflict with each other. In such situations, people face a dilemma about making individually costly but collectively beneficial contributions to the common good. Understanding which factors influence people's willingness to make these contributions is vital for the design of policies and institutions that support the attainment of collective goals. In this study, we investigate how inequalities, and different causes of inequalities, impact individual-level behavior and group-level outcomes. First, we find that what people judged to be fair was not enough to solve the collective action problem: if they acted according to what they thought was fair, they would collectively fail. Second, the level of wealth (rich vs. poor) altered what was judged to be a fair contribution to the public good more than the cause of wealth (merit vs. luck vs. uncertain). Contributions during the game reflected these fairness judgments, with poorer individuals consistently contributing a higher proportion of their wealth than richer participants, which further increased inequality-particularly in successful groups. Finally, the cause of one's wealth was largely irrelevant, mattering most only when it was uncertain, as opposed to resulting from merit or luck. We discuss implications for policymakers and international climate change negotiations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Skin-to-deltoid-muscle distance at three recommended sites for intramuscular vaccination in a population with obesity: an observational study.

AIM: Worldwide, immunisation guidelines variably locate the deltoid injection site based on anatomical landmarks. This may influence the skin-to-deltoid-muscle distance and therefore the needle length required to achieve intramuscular injection. Obesity is associated with increased skin-to-deltoid-muscle distance, but it is unknown whether the injection site location chosen in individuals with obesity impacts the needle length required for intramuscular injection. The aim of the study was to estimate the differences in skin-to-deltoid-muscle distance between three different vaccine injection sites recommended by the national guidelines of the United States of America (USA), Australia and New Zealand, in obese adults. The study also explored i) the associations between skin-to-deltoid-muscle distance across the three recommended sites with sex, body mass index (BMI), and arm circumference, and ii) the proportion of participants with a skin-to-deltoid-muscle distance >20 millimetres (mm), in whom the standard 25mm needle length would not ensure deposition of vaccine within the deltoid muscle. METHOD: Non-interventional cross-sectional study in a single site, non-clinical setting in Wellington, New Zealand. Forty participants (29 females), aged ≥18 years, with obesity (BMI>30 kilograms [km]/m[[2]]). Measurements included distance from acromion to injection sites, BMI, arm circumference, and skin-to-deltoid-muscle distance measured by ultrasound at each recommended injection site. RESULTS: Mean (SD) skin-to-deltoid-muscle distances for USA, Australia and New Zealand sites were 13.96mm (4.54), 17.94mm (6.08) and 20.26mm (5.91) respectively, with a mean (95% confidence interval) for the distance between Australia minus New Zealand -2.7mm (-3.5 to -1.9), P<0.001; and USA minus New Zealand -7.6 mm (-8.5 to -6.7); P<0.001. Skin-to-deltoid-muscle distance was greater in females and was positively associated with BMI and arm circumference. The proportions with a skin-to-deltoid-muscle distance >20 mm were 45%, 40% and 15% for the New Zealand, Australia and USA sites respectively. However, the sample size was relatively small, limiting interpretation in specific sub-groups. CONCLUSION: There were marked differences in the skin-to-deltoid-muscle distance between the three recommended injection sites studied. When choosing the required needle length to achieve intramuscular vaccination in obese vaccine recipients, consideration needs to be given to the injection site location, sex, BMI and/or arm circumference, as these factors all influence the skin-to-deltoid-muscle distance. A standard needle length of 25mm may be insufficient to ensure deposition of vaccine into the deltoid muscle in a substantive proportion of adults with obesity. Research is urgently required to determine anthropometric measurement cut-points that can be used to enable appropriate needle length selection to ensure intramuscular vaccination.

When should a longer needle be used for intramuscular injection in obese patients? A combined analysis of New Zealand data.

AIM: To estimate thresholds for Body Mass Index (BMI) and arm circumference above which a longer needle is needed to ensure intramuscular (IM) delivery of a vaccine in the deltoid muscle at the site recommended by New Zealand (NZ) immunization guidelines. METHODS: A combined analysis of two studies, including 442 adults, with measurements of arm circumference, BMI and skin to deltoid muscle distance (SDMD) at the NZ immunization guideline-recommended IM injection site. Receiver Operator Characteristic curves identified arm circumference and BMI cut-points that gave 100% sensitivity for SDMD thresholds. These thresholds were: SDMD of 20 mm, accounting for a minimal penetration of 5 mm into muscle with the standard needle; and 25 mm, which is the length of a standard needle for IM injection, representing the depth this can reach. RESULTS: Cut-point values for arm circumference, at which a longer needle would be required, were higher for males than females: 35 cm versus 30 cm for the 20 mm cut-point, and 40 cm versus 36.7 cm for the 25 mm cut-point respectively. The BMI cut-points were also higher for male than females: 24.6 kg/m2 versus 23.7 kg/m2 for the 20 mm cut-point, and 38.2 kg/m2 vs 31.6 kg/m2 for the 25 mm cut-point respectively. CONCLUSION: Arm circumference and BMI cut-points provide practical measures from which to choose a needle length that increases the chance of successful IM vaccination. Based on our data, an arm circumference of 35 cm for men and 30 cm for women should prompt selection of a longer needle to ensure intramuscular injection at the deltoid site. Thresholds for the different skin to deltoid sites proposed internationally should be determined to enable successful IM vaccination in clinical practice beyond NZ.

Quantifying the retention of emotions across story retellings.

Story retelling is a fundamental medium for the transmission of information between individuals and among social groups. Besides conveying factual information, stories also contain affective information. Though natural language processing techniques have advanced considerably in recent years, the extent to which machines can be trained to identify and track emotions across retellings is unknown. This study leverages the powerful RoBERTa model, based on a transformer architecture, to derive emotion-rich story embeddings from a unique dataset of 25,728 story retellings. The initial stories were centered around five emotional events (joy, sadness, embarrassment, risk, and disgust-though the stories did not contain these emotion words) and three intensities (high, medium, and low). Our results indicate (1) that RoBERTa can identify emotions in stories it was not trained on, (2) that the five emotions and their intensities are preserved when they are transmitted in the form of retellings, (3) that the emotions in stories are increasingly well-preserved as they experience additional retellings, and (4) that among the five emotions, risk and disgust are least well-preserved, compared with joy, sadness, and embarrassment. This work is a first step toward quantifying situation-driven emotions with machines.

What variables should inform needle length choice for deltoid intramuscular injection? A systematic review.

OBJECTIVES: (1) Assess the distribution of skin-to-deltoid-muscle distance (SDMD) at the deltoid intramuscular (IM) injection site; (2) its relationship with demographic and anthropometric variables and (3) Consider the findings in relation to clinical guidance on IM injection, such as COVID-19 vaccines. DESIGN: Systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL and SCOPUS between June and July 2021 with no publication date limit. ELIGIBILITY CRITERIA: Studies reporting measurements of the SDMD in living adults aged 16 years and older, at the deltoid IM injection site, published in English were considered. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed each stage of screening, data extraction and quality assessments using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross sectional studies. RESULTS: 16 105 papers were identified, of which 11 studies were suitable for review, representing 1414 participants. Heterogeneity in the definition of the deltoid IM injection site, locations measured and methods of measurement precluded meta-analysis. Evidence from ultrasound SDMD measurements demonstrated some patients in all but 'underweight' body mass index (BMI) categories, may require needles longer than 25 mm for successful IM injection. Calliper measurements overestimated SDMD compared with ultrasound. Female sex, higher BMI categories and greater weight in women were associated with greater SDMD. CONCLUSIONS: The reviewed evidence was insufficient to inform definitive needle length 'cut points' for IM injection based on demographic or anthropomorphic variables. Contemporary clinical guidance currently based on this evidence, including the site of injection and choice of needle length, may result in subcutaneous administration in a small proportion of recipients, particularly if obese or of female sex. PROSPERO REGISTRATION NUMBER: CRD42021264625.

Therapeutic advances in COVID-19.

Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin-angiotensin-aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens.