Intensivist physician-to-patient ratios and mortality in the intensive care unit.

PURPOSE: A high daily census may hinder the ability of physicians to deliver quality care in the intensive care unit (ICU). We sought to determine the relationship between intensivist-to-patient ratios and mortality among ICU patients. METHODS: We performed a retrospective cohort study of intensivist-to-patient ratios in 29 ICUs in 10 hospitals in the United States from 2018 to 2020. We used meta-data from progress notes in the electronic health record to determine an intensivist-specific caseload for each ICU day. We then fit a multivariable proportional hazards model with time-varying covariates to estimate the relationship between the daily intensivist-to-patient ratio and ICU mortality at 28 days. RESULTS: The final analysis included 51,656 patients, 210,698 patient days, and 248 intensivist physicians. The average caseload per day was 11.8 (standard deviation: 5.7). There was no association between the intensivist-to-patient ratio and mortality (hazard ratio for each additional patient: 0.987, 95% confidence interval: 0.968-1.007, p = 0.2). This relationship persisted when we defined the ratio as caseload over the sample-wide average (hazard ratio: 0.907, 95% confidence interval: 0.763-1.077, p = 0.26) and cumulative days with a caseload over the sample-wide average (hazard ratio: 0.991, 95% confidence interval: 0.966-1.018, p = 0.52). The relationship was not modified by the presence of physicians-in-training, nurse practitioners, and physician assistants (p value for interaction term: 0.14). CONCLUSIONS: Mortality for ICU patients appears resistant to high intensivist caseloads. These results may not generalize to ICUs organized differently than those in this sample, such as ICUs outside the United States.

Digital Health Solutions for Weight Loss and Obesity: A Narrative Review.

Personal exercise programmes have long been used and prescribed for weight loss and the improvement of quality of life in obese patients. While individualised programmes are usually the preferred option, they can be more costly and challenging to deliver in person. A move to digital programmes with a wider reach has commenced, and demand has increased due to the SARS-CoV-2 pandemic. In this review, we evaluate the current status of digital exercise programme delivery and its evolution over the past decade, with a focus on personalisation. We used specific keywords to search for articles that met our predetermined inclusion and exclusion criteria in order to provide valuable evidence and insights for future research. We identified 55 studies in total in four key areas of focus, from the more recent development of apps and personal digital assistants to web-based programmes and text or phone call interventions. In summary, we observed that apps may be useful for a low-intensity approach and can improve adherence to programmes through self-monitoring, but they are not always developed in an evidence-based manner. Engagement and adherence are important determinants of weight loss and subsequent weight maintenance. Generally, professional support is required to achieve weight loss goals.

Harmonization of maternal balanced energy-protein supplementation studies for individual participant data (IPD) meta-analyses - finding and creating similarities in variables and data collection.

BACKGROUND: Public health and clinical recommendations are established from systematic reviews and retrospective meta-analyses combining effect sizes, traditionally, from aggregate data and more recently, using individual participant data (IPD) of published studies. However, trials often have outcomes and other meta-data that are not defined and collected in a standardized way, making meta-analysis problematic. IPD meta-analysis can only partially fix the limitations of traditional, retrospective, aggregate meta-analysis; prospective meta-analysis further reduces the problems. METHODS: We developed an initiative including seven clinical intervention studies of balanced energy-protein (BEP) supplementation during pregnancy and/or lactation that are being conducted (or recently concluded) in Burkina Faso, Ethiopia, India, Nepal, and Pakistan to test the effect of BEP on infant and maternal outcomes. These studies were commissioned after an expert consultation that designed recommendations for a BEP product for use among pregnant and lactating women in low- and middle-income countries. The initiative goal is to harmonize variables across studies to facilitate IPD meta-analyses on closely aligned data, commonly called prospective meta-analysis. Our objective here is to describe the process of harmonizing variable definitions and prioritizing research questions. A two-day workshop of investigators, content experts, and advisors was held in February 2020 and harmonization activities continued thereafter. Efforts included a range of activities from examining protocols and data collection plans to discussing best practices within field constraints. Prior to harmonization, there were many similar outcomes and variables across studies, such as newborn anthropometry, gestational age, and stillbirth, however, definitions and protocols differed. As well, some measurements were being conducted in several but not all studies, such as food insecurity. Through the harmonization process, we came to consensus on important shared variables, particularly outcomes, added new measurements, and improved protocols across studies. DISCUSSION: We have fostered extensive communication between investigators from different studies, and importantly, created a large set of harmonized variable definitions within a prospective meta-analysis framework. We expect this initiative will improve reporting within each study in addition to providing opportunities for a series of IPD meta-analyses.

Human ACE2 expression, a major tropism determinant for SARS-CoV-2, is regulated by upstream and intragenic elements.

Angiotensin-converting enzyme 2 (ACE2), part of the renin-angiotensin system (RAS), serves as an entry point for SARS-CoV-2, leading to viral proliferation in permissive cell types. Using mouse lines in which the Ace2 locus has been humanized by syntenic replacement, we show that regulation of basal and interferon induced ACE2 expression, relative expression levels of different ACE2 transcripts, and sexual dimorphism in ACE2 expression are unique to each species, differ between tissues, and are determined by both intragenic and upstream promoter elements. Our results indicate that the higher levels of expression of ACE2 observed in the lungs of mice relative to humans may reflect the fact that the mouse promoter drives expression of ACE2 in populous airway club cells while the human promoter drives expression in alveolar type 2 (AT2) cells. In contrast to transgenic mice in which human ACE2 is expressed in ciliated cells under the control of the human FOXJ1 promoter, mice expressing ACE2 in club cells under the control of the endogenous Ace2 promoter show a robust immune response after infection with SARS-CoV-2, leading to rapid clearance of the virus. This supports a model in which differential expression of ACE2 determines which cell types in the lung are infected, and this in turn modulates the host response and outcome of COVID-19.

The political polarization of COVID-19 treatments among physicians and laypeople in the United States.

In the United States, liberals and conservatives disagree about facts. To what extent does expertise attenuate these disagreements? To study this question, we compare the polarization of beliefs about COVID-19 treatments among laypeople and critical care physicians. We find that political ideology predicts both groups' beliefs about a range of COVID-19 treatments. These associations persist after controlling for a rich set of covariates, including local politics. We study two potential explanations: a) that partisans are exposed to different information and b) that they interpret the same information in different ways, finding evidence for both. Polarization is driven by preferences for partisan cable news but not by exposure to scientific research. Using a set of embedded experiments, we demonstrate that partisans perceive scientific evidence differently when it pertains to a politicized treatment (ivermectin), relative to when the treatment is not identified. These results highlight the extent to which political ideology is increasingly relevant for understanding beliefs, even among expert decision makers such as physicians.

The race that stopped a nation: lessons from Australia's Covid vaccine failures

Australia handled many aspects of the Covid-19 pandemic very well. The international border was closed early, contract tracing regimes were implemented quickly, and targeted lockdowns helped keep case and death rates per capita to relatively low levels. Yet in mid-2021, Australia's vaccine rollout was the slowest in the OECD. We estimate that an optimal vaccine rollout could have saved lives and averted at least A$31 billion in economic damage. The policy errors reflected a failure to heed basic economic concepts of portfolio diversification, option value, and dynamic optimization. We conclude with some policy lessons concerning pandemic preparedness for Australia and other countries.

Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology.

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.

Severe Pediatric COVID-19 Pneumonia Treated With Adjuvant Anakinra.

BACKGROUND AND OBJECTIVES: To compare previous hemophagocytic lymphohistiocytosis criteria with adult coronavirus disease 2019 (COVID-19)-associated hyperinflammatory syndrome (cHIS) criteria for the diagnosis of hyperinflammation in pediatric patients with COVID-19. The secondary objective was to assess treatment response to intravenous (IV) anakinra in these patients. METHODS: This case series included children admitted to the PICU for COVID-19 pneumonia with hyperinflammation and treated with IV anakinra between July 2020 to April 2021. Hyperinflammatory criteria were determined for each patient. Clinical course, chest imaging, and inflammatory marker trends were assessed pre- and post-anakinra treatment. RESULTS: All patients had a cHIS criteria score of ≥5. Two patients met 2004-hemophagocytic lymphohistiocytosis criteria. Only the patient that required extracorporeal membrane oxygenation met the H-Score cut-off value. All but one patient had a decrease in their inflammatory markers and improvement in clinical status with early initiation of adjunctive IV anakinra. CONCLUSIONS: In this case series, adult cHIS criteria were successfully used to identify pediatric COVID-19 patients with hyperinflammation. Ferritin levels decreased after the early initiation of IV anakinra.

COVID-19-associated necrotizing encephalopathy presenting without active respiratory symptoms: a case report with histopathology.

Acute necrotizing encephalopathy (ANE) is a rare complication of coronavirus disease 2019 (COVID-19) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The condition is typically diagnosed based on characteristic neuroimaging findings in the context of active viral respiratory symptoms. We present a rare case of COVID-19-associated ANE presenting with expressive aphasia and encephalopathy in the absence of active respiratory symptoms. Initial evaluation revealed bilateral thalamic lesions and a mild neutrophilic-predominant pleocytosis on cerebrospinal fluid analysis, the latter of which has not been described in previously published cases. Presence of these atypical features prompted extensive diagnostic evaluation. Metagenomic next-generation sequencing on cerebrospinal fluid did not detect the presence of pathogenic nucleic acids. Thalamic biopsy revealed perivascular neutrophilic inflammation suggestive of small vessel vasculitis with surrounding hemorrhage and necrosis. Ultimately, the diagnosis was made following detection of SARS-CoV-2 serologies and after exclusion of alternative etiologies. The patient was successfully treated with a short course of high-dose methylprednisolone with favorable outcome.

Willingness to Treat with Therapies of Unknown Effectiveness in Severe COVID-19: A Survey of Intensivist Physicians.

Rationale: Little is known about how physicians develop their beliefs about new treatments or update their beliefs in the face of new clinical evidence. These issues are particularly salient in the context of the coronavirus disease (COVID-19) pandemic, which created rapid demand for novel therapies in the absence of robust evidence. Objectives: To identify psychological traits associated with physicians' willingness to treat with unproven therapies and willingness to update their treatment preferences in the setting of new evidence in the context of COVID-19. Methods: We administered a longitudinal e-mail survey to United States physicians board certified in intensive care medicine in April and May 2020 (phase one) and October and November 2020 (phase two). We assessed five psychological traits potentially related to evidence uptake: need for cognition, evidence skepticism, need for closure, risk tolerance, and research engagement. We then examined the relationship between these traits and physician preferences for pharmacological treatment for a hypothetical patient with severe COVID-19 pneumonia. Results: There were 592 responses to the phase one survey, conducted prior to publication of trial data. At this time physicians were most willing to treat with macrolide antibiotics (50.5%), followed by antimalaria agents (36.1%), corticosteroids (24.5%), antiretroviral agents (22.6%), and angiotensin inhibitors (4.4%). Greater evidence skepticism (relative risk [RR], 1.40; 95% confidence interval [CI], 1.30-1.52; P < 0.001), greater need for closure (RR, 1.19; 95% CI, 1.06-1.34; P = 0.003), and greater risk tolerance (RR, 1.17; 95% CI, 1.08-1.26; P < 0.001) were associated with an increased willingness to treat, whereas greater need for cognition (RR, 0.85; 95% CI, 0.75-0.96, P = 0.010) and greater research engagement (RR, 0.91; 95% CI, 0.88-0.95; P < 0.0001) were associated with decreased willingness to treat. In phase two, most physicians updated their beliefs after publication of trial data about antimalarial agents and corticosteroids. Physicians with greater evidence skepticism were more likely to persist in their beliefs. Conclusions: Psychological traits associated with clinical decisions in the setting of uncertain evidence may provide insight into strategies to better align clinical practice with published evidence.

A Nonadaptive Combinatorial Group Testing Strategy to Facilitate Health Care Worker Screening during the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Outbreak.

Routine testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in health care workers (HCWs) is critical. Group testing strategies to increase capacity facilitate mass population testing but do not prioritize turnaround time, an important consideration for HCW screening. We propose a nonadaptive combinatorial (NAC) group testing strategy to increase throughput while facilitating rapid turnaround. NAC matrices were constructed for sample sizes of 700, 350, and 250. Matrix performance was tested by simulation under different SARS-CoV-2 prevalence scenarios of 0.1% to 10%. NAC matrices were compared versus Dorfman sequential (DS) group testing approaches. NAC matrices performed well at low prevalence levels, with an average of 97% of samples resolved after a single round of testing via the n = 700 matrix at a prevalence of 1%. In simulations of low to medium (0.1% to 3%) prevalence, all NAC matrices were superior to the DS strategy, measured by fewer repeated tests required. At very high prevalence levels (10%), the DS matrix was marginally superior, although both group testing approaches performed poorly at high prevalence levels. This strategy maximizes the proportion of samples resolved after a single round of testing, allowing prompt return of results to HCWs. This methodology may allow laboratories to adapt their testing scheme based on required throughput and the current population prevalence, facilitating a data-driven testing strategy.