Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis.

BACKGROUND: HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology. METHODS: We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672. FINDINGS: We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21-0·29), with moderate heterogeneity (Q=132·3, p<0·0001, I2=64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08-0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24-0·53]) and men who have sex with men (0·30 [0·33-0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14-0·31]), post-partum transmission (0·18 [0·03-0·57]), pre-partum transmission (0·17 [0·08-0·33]), and intra-partum transmission (0·27 [0·14-0·45]). INTERPRETATION: We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes. FUNDING: Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant.

First dose COVID-19 vaccine coverage amongst adolescents and children in England: an analysis of 3.21 million patients' primary care records in situ using OpenSAFELY

Background: The coronavirus disease 2019 (COVID-19) vaccination programme in England was extended to include all adolescents and children by April 2022. The aim of this paper is to describe trends and variation in vaccine coverage in different clinical and demographic groups amongst adolescents and children in England. Methods: : With the approval of NHS England, a cohort study was conducted of 3.21 million children and adolescents' records in general practice in England, in situ and within the infrastructure of the electronic health record software vendor TPP using OpenSAFELY. Vaccine coverage across various demographic (sex, deprivation index and ethnicity) and clinical (risk status) populations is described. Results: : Coverage is higher amongst adolescents than it is amongst children, with 53.5% adolescents and 10.8% children having received their first dose of the COVID-19 vaccine. Within those groups, coverage varies by ethnicity, deprivation index and risk status;there is no evidence of variation by sex. Conclusion: First dose COVID-19 vaccine coverage is shown to vary amongst various demographic and clinical groups of children and adolescents.

Detecting Tweets Containing Cannabidiol-Related COVID-19 Misinformation Using Transformer Language Models and Warning Letters From Food and Drug Administration: Content Analysis and Identification.

Background: COVID-19 has introduced yet another opportunity to web-based sellers of loosely regulated substances, such as cannabidiol (CBD), to promote sales under false pretenses of curing the disease. Therefore, it has become necessary to innovate ways to identify such instances of misinformation. Objective: We sought to identify COVID-19 misinformation as it relates to the sales or promotion of CBD and used transformer-based language models to identify tweets semantically similar to quotes taken from known instances of misinformation. In this case, the known misinformation was the publicly available Warning Letters from Food and Drug Administration (FDA). Methods: We collected tweets using CBD- and COVID-19-related terms. Using a previously trained model, we extracted the tweets indicating commercialization and sales of CBD and annotated those containing COVID-19 misinformation according to the FDA definitions. We encoded the collection of tweets and misinformation quotes into sentence vectors and then calculated the cosine similarity between each quote and each tweet. This allowed us to establish a threshold to identify tweets that were making false claims regarding CBD and COVID-19 while minimizing the instances of false positives. Results: We demonstrated that by using quotes taken from Warning Letters issued by FDA to perpetrators of similar misinformation, we can identify semantically similar tweets that also contain misinformation. This was accomplished by identifying a cosine distance threshold between the sentence vectors of the Warning Letters and tweets. Conclusions: This research shows that commercial CBD or COVID-19 misinformation can potentially be identified and curbed using transformer-based language models and known prior instances of misinformation. Our approach functions without the need for labeled data, potentially reducing the time at which misinformation can be identified. Our approach shows promise in that it is easily adapted to identify other forms of misinformation related to loosely regulated substances.

Emerging Paradigms in Type 2 Immunity.

A principal purpose of type 2 immunity was thought to be defense against large parasites, but it also functions in the restoration of homeostasis, such as toxin clearance following snake bites. In other cases, like allergy, the type 2 T helper (Th2) cytokines and cells present in the environment are detrimental and cause diseases. In recent years, the recognition of cell heterogeneity within Th2-associated cell populations has revealed specific functions of cells with a particular phenotype or gene signature. In addition, here we discuss the recent data regarding heterogeneity of type 2 immunity-related cells, as well as their newly identified role in a variety of processes ranging from involvement in respiratory viral infections [especially in the context of the recent COVID-19 (coronavirus disease 2019) pandemic] to control of cancer development or of metabolic homeostasis.

Patient, Family Member and Physician Perspectives and Experiences with AML Treatment Decision-Making.

INTRODUCTION: Treatment decisions in older adults with acute myeloid leukemia (AML) are challenging, particularly for those who are not candidates for intensive chemotherapy (IC), and the trade-offs patients, their families and physicians consider when choosing a treatment option are not well understood. This qualitative research explored the value of extending survival and the treatment decision-making process from a multi-stakeholder perspective. METHODS: Overall, 28 patients with AML (≥ 65 years old, unsuitable for IC), 25 of their relatives and 10 independent physicians from the US, UK and Canada took part in one-on-one, 60-minute qualitative interviews. RESULTS: Across all stakeholders, improved health-related quality of life (HRQoL), extended survival and relief of AML symptoms were recognized as most important in AML treatment decision-making. However, extending survival in 'good health' was more important than extending survival alone, particularly because of the extra time it gives patients and their relatives together, and allows patients to achieve important goals. Patients' limited understanding of available treatment options, paired with incorrect perceptions of treatment side effects, impacted their involvement in the treatment decision-making process. Patients and physicians perceived physicians to have the most influence in the decision-making process despite their priorities not always aligning. CONCLUSION: These findings illustrate the importance of having structured discussions which explicitly assess patients' goals and their understanding and expectations of treatments and also the need for patient friendly resources about the lived experience of AML and available treatment options. These measures will help to ensure that patients are fully involved in the shared decision-making process.

Getting Serious About People Over Profit: Addressing Burnout by Establishing Meaning and Connection

Interventions to promote healthy sleep may reduce physician burnout susceptibility.5 An extensive study of physicians reported sleep-related impairment in 40% of attending physicians and 51% of house staff physicians.6 There was large correlation between sleeprelated impairment and interpersonal disengagement, work exhaustion, and overall burnout.6 After adjustment for other variables, high sleep impairment levels increased the odds of self-reporting a clinically significant medical error by 96%.6 Besides medical errors, sleep-related impairment and occupational distress have also been associated with unsolicited patient complaints. Activities that enhance social supports (e.g., peer support programs and Balint groups) and add meaning to work (e.g., professional development time, mentorship, time to develop connections with patients, etc.) are likely to provide some benefit, as they support physicians' capacity to maintain perspective, sense of purpose, and enhance sense of control over their situation.9,10 One study showed such a group normalized struggles, reduced isolation, and provided new strategies for navigating challenging interactions.11 In another study, self-facilitated physician small-group meetings improved burnout, symptoms of depression, and job satisfaction.12 Although rates of burnout among physicians have grown, physicians are resilient when compared to other occupational groups. A recent review found the rate of burnout among nurses working in hospitals ranged widely from 5% to 50%, based on specialty differences and geographical regions.14 More specifically, the review indicated the overall prevalence of emotional exhaustion was 34.1%, of depersonalization 12.6%, and of lack of personal accomplishment 15.2%.15 This same review took COVID-19 into account and noted nurse burnout risk factors as younger age, decreased social support, low family and colleague readiness to cope with COVID-19 outbreak, increased perceived threat of COVID-19, longer working time in quarantine areas, working in a high-risk environment, working in hospitals with inadequate and insufficient material and human resources, increased workload, and lower level of specialized training regarding COVID-19.15 Burnout has many consequences in nurses. Emotional exhaustion is negatively associated with the quality and safety of care, patient satisfaction, nurses' organizational commitment, and productivity.14 Nurse burnout has been a significant factor in predicting medication-associated errors.16 Protective factors in nurses include belief in readiness to cope with COVID-19 outbreaks, willingness to participate in frontline work, prior training and experience in COVID-19 patients' management, safe practices, and increased social support.15 Empathy and nursing organizational climate have been found to be protective against burnout, suggesting this could be targeted in managerial interventions.17 Nursing surveys of three types of work engagement (i.e., vigor, dedication, and absorption) and resiliency suggested some protection from burnout.18 Mindfulness-based interventions could potentially have a protective effect for burnout in nurses.19 (See Table 2 for an overview of how burnout impacts feelings about careers in nurses and physicians.) COVID-19 PANDEMIC AS ACCELERANT TO THE BURN Healthcare workers were already hurting before 2020 and the start of the COVID-19 pandemic.

Development of humanized ACE2 mouse and rat models for COVID‐19 research

To date (17 November 2021), there has been more than 254 million confirmed cases of COVID‐19, and more than 5 million death globally (World Health Organization. https://covid19.who.int/). The virus causing COVID‐19 is called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2). SARS‐CoV‐2 infects host cells by the binding of its spike protein to the cellular surface protein angiotensin‐converting enzyme 2 (ACE2). The predicted 29 amino acid residues of ACE2 that interact with SARS‐CoV‐2 spike protein receptor binding domain (RBD) vary between human ACE2 and mouse or rat ACE2. Therefore, wildtype mice and rats show lower SARS‐CoV‐2 infection rate and mild symptoms compared to what is seen in humans. Small animal models that recapitulate human COVID‐19 disease are urgently needed for better understanding the transmission and therapeutic measurement. Currently, scientists use either mouse‐adapted SAS‐CoV‐2 (SAS‐CoV‐2 MA) models or random transgenic mouse models that artificially express human ACE2 under the control of cytokeratin 18 promoter or a constitutive promoter. SAS‐CoV‐2 MA may not completely reflect all aspects of the original human‐tropic SAS‐CoV‐2 and the current transgenic human ACE2 mouse models typically have high mortality rate caused by neuroinvasion and encephalitis due to very high human ACE2 expression. To overcome these limitations, we have developed humanized ACE2 mouse and rat models using CRISPR‐Cas9. Specifically, we inserted a ~3kb human ACE2 cDNA cassette into the mouse and rat Ace2 gene loci to ensure that human ACE2 expression is under the control of rodent Ace2 promoter and regulatory elements, while simultaneously disabling the rodent Ace2 gene. To accomplish this, CRISPR gRNAs targeting close to the translation initiation site of Ace2 were screened in cultured mouse and rat cells. Then CRISPR/Cas9 complex and donor DNA were subsequently microinjected into one‐cell stage embryos which were subsequently implanted into pseudo pregnant females. Resulting pups were screened for correct knockin by junction PCR and insert PCR, and the PCR products were Sanger sequenced. Targeted Locus Amplification (TLA) further confirmed the integration sites and transgene sequence. RT‐qPCR and Western blot analysis data showed that, in our models, human ACE2 is expressed in tissues expressing endogenous Ace2 (such as lung, kidney, and GI tract), while rodent endogenous Ace2 is absent from these tissues. Further breeding data indicated that both hemizygous and homozygous humanized ACE2 animals appear to be normal and fertile. Most importantly, animals displayed symptoms after infection with SARS‐CoV‐2. In summary, these data suggest that our humanized ACE2 models can be valuable for COVID‐19 research.

Overstated Claims of Efficacy and Safety. Comment On: "Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect Against Viral Infections". Nutrients 2020, 12, 1181.

Calder et al [...].

Polymeric and lipid nanoparticles for delivery of self-amplifying RNA vaccines.

Self-amplifying RNA (saRNA) is a next-generation vaccine platform, but like all nucleic acids, requires a delivery vehicle to promote cellular uptake and protect the saRNA from degradation. To date, delivery platforms for saRNA have included lipid nanoparticles (LNP), polyplexes and cationic nanoemulsions; of these LNP are the most clinically advanced with the recent FDA approval of COVID-19 based-modified mRNA vaccines. While the effect of RNA on vaccine immunogenicity is well studied, the role of biomaterials in saRNA vaccine effectiveness is under investigated. Here, we tested saRNA formulated with either pABOL, a bioreducible polymer, or LNP, and characterized the protein expression and vaccine immunogenicity of both platforms. We observed that pABOL-formulated saRNA resulted in a higher magnitude of protein expression, but that the LNP formulations were overall more immunogenic. Furthermore, we observed that both the helper phospholipid and route of administration (intramuscular versus intranasal) of LNP impacted the vaccine immunogenicity of two model antigens (influenza hemagglutinin and SARS-CoV-2 spike protein). We observed that LNP administered intramuscularly, but not pABOL or LNP administered intranasally, resulted in increased acute interleukin-6 expression after vaccination. Overall, these results indicate that delivery systems and routes of administration may fulfill different delivery niches within the field of saRNA genetic medicines.

Initial prehospital Rapid Emergency Medicine Score (REMS) to predict outcomes for COVID-19 patients.

OBJECTIVE: The Rapid Emergency Medicine Score (REMS) has not been widely studied for use in predicting outcomes of COVID-19 patients encountered in the prehospital setting. This study aimed to determine whether the first prehospital REMS could predict emergency department and hospital dispositions for COVID-19 patients transported by emergency medical services. METHODS: This retrospective study used linked prehospital and hospital records from the ESO Data Collaborative for all 911-initiated transports of patients with hospital COVID-19 diagnoses from July 1 to December 31, 2020. We calculated REMS with the first recorded prehospital values for each component. We calculated area under the receiver operating curve (AUROC) for emergency department (ED) mortality, ED discharge, hospital mortality, and hospital length of stay (LOS). We determined optimal REMS cut-points using test characteristic curves. RESULTS: Among 13,830 included COVID-19 patients, median REMS was 6 (interquartile range [IQR]: 5-9). ED mortality was <1% (n = 80). REMS ≥9 predicted ED death (AUROC 0.79). One-quarter of patients (n = 3,419) were discharged from the ED with an optimal REMS cut-point of ≤5 (AUROC 0.72). Eighteen percent (n = 1,742) of admitted patients died. REMS ≥8 optimally predicted hospital mortality (AUROC 0.72). Median hospital LOS was 8.3 days (IQR: 4.1-14.8 days). REMS ≥7 predicted hospitalizations ≥3 days (AUROC 0.62). CONCLUSION: Initial prehospital REMS was modestly predictive of ED and hospital dispositions for patients with COVID-19. Prediction was stronger for outcomes more proximate to the first set of emergency medical services (EMS) vital signs. These findings highlight the potential value of first prehospital REMS for risk stratification of individual patients and system surveillance for resource planning related to COVID-19.

Comparison of four high-throughput, automated immunoassays for the detection of SARS-CoV-2 antibodies.

BACKGROUND: A number of immunoassays have been developed to measure antibodies specific to SARS-CoV-2. More data is required on their comparability, particularly among those with milder infections and in the general practice population. The aim of this study was to compare four high-throughput automated anti-SARS-CoV-2 assays using samples collected from hospitalized patients and healthcare workers with confirmed SARS-CoV-2 infection. In addition, we collected general practice samples to compare antibody results and determine seroprevalence. METHODS: Samples were collected from 57 hospitalized patients and nine healthcare workers at 14 days and at 28 days following confirmed SARS-CoV-2 infection. Samples were also collected from 225 patients presenting to general practice. Four assays were used: Abbott Architect IgG, Beckman Coulter DxI 800 IgG, Roche Cobas e801 total antibody and Siemens Advia Centaur XPT total antibody. RESULTS: All four assays showed concordance at 14 days in 83.9% of hospitalized patients and in 66.7% of healthcare workers. All four assays showed concordance at 28 days in 88.4% of hospitalized patients and 77.8% of healthcare workers. The sensitivity to detect recent infection was higher for the IgG assays than the total assays. All four assays showed concordance of 95.1% in the general practice population. Seroprevalence ranged from 4.9 to 5.8% depending on the assay used. CONCLUSIONS: All four assays showed excellent comparability, but it may be possible to obtain a negative result for any of the anti-SARS-CoV-2 assays in patients with confirmed previous SARS-CoV-2 infection. An equivocal range would be useful for all anti-SARS-CoV-2 assays.

The Impact of COVID-19 on Rural Food Supply and Demand in Australia: Utilising Group Model Building to Identify Retailer and Customer Perspectives.

Prior to the 2020 outbreak of COVID-19, 70% of Australians' food purchases were from supermarkets. Rural communities experience challenges accessing healthy food, which drives health inequalities. This study explores the impact of COVID-19 on food supply and purchasing behaviour in a rural supermarket. Group model building workshops explored food supply experiences during COVID-19 in a rural Australian community with one supermarket. We asked three supermarket retailers "What are the current drivers of food supply into this supermarket environment?" and, separately, 33 customers: "What are the current drivers of purchases in this supermarket environment?" Causal loop diagrams were co-created with participants in real time with themes drawn afterwards from coded transcripts. Retailers' experience of COVID-19 included 'empty shelves' attributed to media and government messaging, product unavailability, and community fear. Customers reported fear of contracting COVID-19, unavailability of food, and government restrictions resulting in cooking more meals at home, as influences on purchasing behaviour. Supermarket management and customers demonstrated adaptability and resilience to normalise demand and combat reduced supply.

The Impact of Telemedicine Adoption on a Multidisciplinary Bariatric Surgery Practice During the COVID-19 Pandemic.

OBJECTIVE: This study aims to show how full-time telemedicine adoption has impacted patient visit volume and attendance in a comprehensive metabolic and weight loss center. SUMMARY BACKGROUND DATA: Elective surgical practices have been profoundly impacted by the global COVID-19 pandemic, leading to a rapid increase in the utilization of telemedicine. The abrupt initiation of audio-video telehealth visits for all providers of a multidisciplinary clinic on March 19 2020 provided unique circumstances to assess the impact of telemedicine. METHODS: Data from the clinical booking system (new patient and follow-up visits) for all clinical provider types of the multidisciplinary metabolic center from the pre-telehealth, post-telehealth, and a 2019 comparative period were retrospectively reviewed and compared. The primary outcome is the change in patient visit volume for all clinical providers from before to after the initiation of telemedicine for both new patient, and follow-up visits. RESULTS: There were a total of 506 visits (162 new patient visits, and 344 follow-ups) in the pre-telehealth period, versus 413 visits (77 new patient visits, and 336 follow-ups) during the post-telehealth period. After telehealth implementation, new visits for surgeons decreased by 75%. Although follow-up visits decreased by 55.06% for surgeons, there was an increase by 27.36% for advanced practitioners. When surgeons were separated from other practitioners, their follow-up visit rate decrease by 55.06%, compared to a 16.08% increase for the group of all other practitioners (P < 0.0001). Dietitians experienced higher rates of absenteeism with new patient visits (10.00% vs 31.42%, P = 0.0128), whereas bariatricians experienced a decrease in follow-up visit absenteeism (33.33% vs 0%, P = 0.0093). CONCLUSIONS: Although new patient visit volume fell across the board, follow-up visits increased for certain nonsurgical providers. This provides a template for adoption of a multidisciplinary telehealth clinic in a post-pandemic world.

How Do We Combat Bogus Medicines in the Age of the COVID-19 Pandemic?

The COVID-19 pandemic has brought concurrent challenges. The increased incidence of fake and falsified product distribution is one of these problems with tremendous impact, especially in low- and middle-income countries. Up to a tenth of medicines including antibiotics and antimalarial drugs in the African market are considered falsified. Pandemics make this worse by creating an ecosystem of confusion, distraction, and vulnerability stemming from the pandemic as health systems become more stressed and the workload of individuals increased. These environments create opportunities for substandard and falsified medicines to be more easily introduced into the marketplace by unscrupulous operators. In this work we discuss some of the challenges with fake or falsified product distribution in the context of COVID-19 and proposed strategies to best manage this problem.

COVID-19 Preliminary Case Series: Characteristics of EMS Encounters with Linked Hospital Diagnoses.

BACKGROUND: Few studies have examined the prehospital presentation, assessment, or treatment of patients diagnosed with coronavirus disease 2019 (COVID-19). The objective of this preliminary report is to describe prehospital encounters for patients with a COVID-19 hospital diagnosis and/or COVID-19 EMS suspicion versus those with neither a hospital diagnosis nor EMS suspicion of the disease. METHODS: This case series evaluated electronic patient care records from EMS agencies participating in a large national bi-directional data exchange. All records for 9-1-1 responses between March 1 and April 19, 2020, resulting in transport to a hospital, with at least one ICD-10 outcome returned via the data exchange were included. Hospital ICD-10 codes used to determine COVID-19 diagnoses included B97.2, B97.21, B97.29, B34.2, and U07.1. COVID-19 EMS suspicion was defined as a documented EMS primary or secondary impression of COVID-19, or indication of COVID-19 suspicion in the prehospital free-text narrative. Comparisons were stratified by COVID-19 hospital diagnosis and COVID-19 EMS suspicion. Descriptive and comparative statistics are presented. RESULTS: There were 84,540 EMS patient records with linked hospital ICD-10 codes included. Of those, 814 (1%) patients had a COVID-19 hospital diagnosis. Overall, COVID-19 EMS suspicion was documented for 3,204 (4%) patients. A COVID-19 EMS suspicion was documented for 636 (78%) of hospital diagnosed COVID-19 patients. Those with COVID-19 hospital diagnoses were more likely to present with tachycardia, tachypnea, hypoxia, and fever during the EMS encounter. EMS responses for patients diagnosed with COVID-19 were also more likely to originate from a skilled nursing/assisted living facility. EMS PPE (eye protection, mask, or gown) use was more frequently documented on records of patients who had hospital diagnosed COVID-19. CONCLUSION: In this large sample of prehospital encounters, EMS COVID-19 suspicion demonstrated sensitivity of 78% and positive predictive value of 20% compared with hospital ICD-10 codes. These data indicate that EMS suspicion alone is insufficient to determine appropriate utilization of PPE.