title: The Challenges of Episodic Office-based Blood Pressure Measurement for the Management of Hypertension

abstract:
ImportanceClinicians use blood pressure (BP) readings obtained during clinical encounters to detect hypertension and determine the adequacy of treatment. Variations in office-based BP measurements may obscure a hypertension diagnosis or overwhelm a signal of treatment response.

ObjectivesTo quantify visit-to-visit variability (VVV) in BP values and its association with patient factors in real-world practice.

Design, Setting and, ParticipantsRetrospective cohort analysis of adult patients (age [≥]18 years) with at least two outpatient visits in the Yale-New Haven Health System between January 1, 2014 to October 31, 2018.

Main Outcome and MeasuresPatient-level measures of VVV included standard deviation (SD) and coefficient of variation (CV) of a given patients BP across visits. We introduced a metric to determine the VVV between any two visits (dyad) to characterize the BP information that clinicians have as they formulate their recommendations. Dyad-level measures of VVV included difference, absolute difference, standardized difference, and absolute standardized difference between the two visits of a dyad.

ResultsThe study population included 537,245 adults, with a total of 7,721,864 BP measurements. The mean age was 53.4 years (SD of 19.0), 60.4% were women, 69.4% were non-Hispanic White, and 18.1% with hypertension treatment. At the patient level, the mean intra-individual SD and CV were 10.6 mmHg and 0.08 mmHg. At the dyad level, the mean difference, absolute difference, standardized difference, and absolute standardized difference were -0.7 mmHg, 11.6 mmHg, 0 mmHg, and 0.09 mmHg, respectively. Given the observed VVV, if an antihypertensive medication truly reduced a patients SBP by 10 mmHg (the average BP-lowering effect reported in previous review), clinicians would expect to observe a reduction of SBP < 5mm Hg at the next visit 36.9% of the time. In the multivariable linear regression model, only 2% of the variance in absolute standardized difference was attributable to patient characteristics.

Conclusions and RelevanceThe large VVV poses challenges for diagnosis, treatment, and monitoring of patients with hypertension based on BP readings in outpatient settings, supporting recent guidelines recommending home BP monitoring and ambulatory BP monitoring as out-of-office alternatives to establish diagnosis of hypertension and BP control.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat is the visit-to-visit variability (VVV) in blood pressure (BP) values and its association with patient factors in real-world practice?

FindingsIn this retrospective cohort analysis that included 537,245 adults and 7,721,864 office-based BP measurements from a large health system, marked VVV was observed in BP values and the median absolute change between two consecutive visits was about 12 mmHg. The VVV was not significantly associated with patient demographic and clinical characteristics.

MeaningThe large VVV poses challenges for diagnosis, treatment, and monitoring of patients with hypertension based on BP readings in outpatient settings, supporting recent guidelines recommending home BP monitoring and ambulatory BP monitoring as out-of-office alternatives to establish a new diagnosis of hypertension and BP control.


title: Trends in Awareness, Antihypertensive Medication Use and Blood Pressure Control by Race and Ethnicity Among Adults with Hypertension in the United States: A National Health and Nutrition Examination Analysis from 2011 to 2018

abstract:
ObjectiveTo examine United States (US) trends in racial/ethnic differences in hypertension awareness and antihypertensive medication use, and whether these differences help explain racial/ethnic differences in hypertension control among adults from 2011 to 2018.

DesignPopulation-based study.

SettingNational Health and Nutrition Examination Survey (NHANES), 2011-2018.

ParticipantsA nationally representative sample of US adults aged 18 years or older.

Main outcome measuresHypertension awareness was defined as self-reported physician diagnosis of hypertension. Antihypertensive treatment was based on self-reported use of antihypertensive agents. Blood pressure (BP) control was measured systolic BP <140 mmHg and diastolic BP <90 mmHg.

ResultsThis study included 8,095 adults with hypertension from NHANES 2011-2018. During the study period, age-adjusted hypertension awareness declined from 84.0% (95% confidence interval 79.5 to 86.2) to 77.5% (74.0 to 80.5), hypertension treatment declined from 77.3% (73.4 to 81.1) to 71.4% (69.0 to 73.8) and control rates declined from 51.9% (47.1 to 56.7) to 43.1% (39.7 to 46.5). These declines were consistent for Black, Hispanic, and White individuals, but the three outcomes increased or did not change for Asian individuals. Compared with White individuals, Black individuals did not have a significantly different awareness (odds ratio:1.20 [0.96 to 1.45]) and overall treatment rate (1.04 [0.84 to 1.25]), but received more antihypertensive medications if treated (1.41 [1.27 to 1.56]), and had a lower BP control rate (0.72 [0.61 to 0.83]); Asian and Hispanic individuals had significantly lower awareness rates (0.69 [0.52 to 0.85] and 0.74 [0.59 to 0.89], respectively), overall treatment rates (0.72 [0.57 to 0.88] and 0.69 [0.55 to 0.82]), received fewer medications if treated (0.60 [0.50 to 0.72] and 0.86 [0.75 to 0.96]), and had lower BP control rates (0.66 [0.54 to 0.79] and 0.69 [0.57 to 0.81]). The racial/ethnic differences in awareness, treatment, and BP control persisted over the study period and were consistent across age, sex, and income strata. Lower awareness and treatment were associated with lower BP control in Asian and Hispanic individuals, but not in Black individuals.

ConclusionsHypertension awareness, treatment, and control declined from 2011-2018, and this decline was consistent for Black, Hispanic, and White individuals. BP control was worse for Asian, Black, and Hispanic individuals than for White individuals over the entire study period; this was explained partly by differences in awareness and treatment for Asian and Hispanic individuals, but not for Black individuals.

What this Paper AddsO_ST_ABSSection 1: What is already known on this subject?C_ST_ABSHypertension control rate has declined in the United States (US) since 2013, and this decline is more pronounced in Black and Hispanic communities.

Section 2: What this study addsOur study shows that hypertension awareness, treatment, and control in the US have worsened from 2011 to 2018, and this trend was consistent for Black, Hispanic, and White individuals. Compared with White individuals, Black individuals had similar awareness and overall treatment rates, received more antihypertensive medications if treated, but had a lower control rate; Asian and Hispanic individuals had significantly lower awareness rates, overall treatment rates, received fewer medications if treated, and had lower control rates. Lower awareness and treatment were associated with lower BP control in Asian and Hispanic individuals, but not in Black individuals. These findings highlight the need for interventions to improve awareness and treatment among Asian and Hispanic individuals, and more investigation into the downstream factors that may contribute to the poor hypertension control among Black individuals.

category: cardiovascular medicine


title: Using routine emergency department data for syndromic surveillance of acute respiratory illness before and during the COVID-19 pandemic in Germany, week 10-2017 and 10-2021

abstract:
BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic expanded the need for timely information on acute respiratory illness on the population level.

AimWe explored the potential of routine emergency department data for syndromic surveillance of acute respiratory illness in Germany.

MethodsWe included routine attendance data from emergency departments who continuously transferred data between week 10-2017 and 10-2021, with ICD-10 codes available for >75% of the attendances. Case definitions for acute respiratory illness (ARI), severe ARI (SARI), influenza-like illness (ILI), respiratory syncytial virus disease (RSV) and COVID-19 were based on a combination of ICD-10 codes, and/or chief complaints, sometimes combined with information on hospitalisation and age.

ResultsWe included 1,372,958 attendances from eight emergency departments. The number of attendances dropped in March 2020, increased during summer, and declined again during the resurge of COVID-19 cases in autumn and winter of 2020/2021. A pattern of seasonality of acute respiratory infections could be observed. By using different case definitions (i.e. for ARI, SARI, ILI, RSV) both the annual influenza seasons in the years 2017-2020 and the dynamics of the COVID-19 pandemic in 2020-2021 were apparent. The absence of the 2020/2021 flu season was visible, parallel to the resurge of COVID-19 cases. The percentage SARI among ARI cases peaked in April-May 2020 (17%) and November 2020-January 2021 (14%).

ConclusionSyndromic surveillance using routine emergency department data has the potential to monitor the trends, timing, duration, magnitude and severity of illness caused by respiratory viruses, including both influenza and SARS-CoV-2.

category: epidemiology


title: Using routine emergency department data for syndromic surveillance of acute respiratory illness in Germany, week 10-2017 and 10-2021


title: Using routine emergency department data for syndromic surveillance of acute respiratory illness in Germany, week 10-2017 to 10-2021


title: Predictors of Adolescent Engagement and Outcomes: A cross-sectional study using the Togetherall (formerly Big White Wall) digital mental health platform

abstract:
Online mental health platforms can improve access to, and use of, mental health support for young people who may find it difficult to engage with face-to-face delivery.

We modelled engagement and change in anxiety and depression symptoms in adolescent users of the Togetherall (formerly "Big White Wall") anonymous digital mental health peer-support platform.

A cross-sectional study assessed online activity data from members of Togetherall in UK adolescents referred from mental health services (N=606). Baseline demographics, depression, anxiety, and usage statistics were assessed. Symptom levels among participants who chose to take validated anxiety and depression measures were measured. And participant characteristics were used to predict engagement.

Mean number of logins for adolescent members was higher for older adolescents, and for a longer duration than younger adolescents. Mean number of logins and usage time was higher in female adolescents than males. For the total sample, 47.9% of users accessed more than one course, and 27% accessed at least one self-help resource. Gender and age predicted number of joined courses. Greater accessed self-help materials predicted reduced anxiety symptoms. Members mean baseline symptom levels were: GAD-7 between 13.63 and 14.79; PHQ-9 between 16.8 and 18.58.

Data were derived from a naturalistic design and modelling of multiple symptom scores should be interpreted with caution.

Findings show that adolescents readily engage with an anonymous online platform for common mental disorder, with scope for tailored pathways for different symptom profiles. Members benefit from engagement with Togetherall materials and courses.

category: psychiatry and clinical psychology


title: The social media response to twice-weekly mass asymptomatic testing in England

abstract:
BackgroundFrom 9th April 2021, everyone in England has been encouraged to take two COVID-19 tests per week. This is the first time that national mass asymptomatic testing has been introduced in the UK and the effectiveness of the policy depends on uptake with testing and willingness to self-isolate following a positive test result. This paper examines attitudes towards twice-weekly testing, as well as barriers and facilitators to engaging in testing.

MethodsBetween 5th April and 28th May 2021 we searched Twitter, Facebook, and online news articles with publicly available comment sections to identify comments relating to twice-weekly testing. We identified 5783 comments which were then analysed using a framework analysis.

ResultsWe identified nine main themes. Five themes related to barriers to engaging in testing: low perceived risk from COVID-19; mistrust in the government; concern about taking a test; perceived ineffectiveness of twice-weekly testing policy; and perceived negative impact of twice-weekly testing policy. Four themes related to facilitators to engaging in testing: wanting to protect others; positive perceptions of tests; a desire to return to normal; and perceived efficacy for reducing asymptomatic transmission.

ConclusionsOverall, the comments identified indicated predominately negative attitudes towards the twice weekly testing policy. Several recommendations can be made to improve engagement with twice weekly testing, including: 1) communicate openly and honestly about the purpose of testing; 2) provide information about the accuracy of tests; 3) provide financial support for those required to self-isolate, and; 4) emphasise accessibility of testing.

category: public and global health


title: Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection

abstract: The majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.

category: sexual and reproductive health


title: Seroresponse to SARS-CoV-2 vaccines among maintenance dialysis patients

abstract:
ImportanceVaccines against SARS-CoV-2 are highly effective in the general population; however, their efficacy may be diminished in maintenance dialysis patients, a population particularly vulnerable to COVID-19 infection and morbidity.

ObjectiveWe assessed vaccine response in a national sample of maintenance dialysis patients and identified predictors of response.

DesignRetrospective cohort study

Setting130 Dialysis Clinic, Inc (DCI) facilities

ParticipantsMaintenance dialysis patients without known prior COVID-19 or a positive baseline antibody titer

Exposure(s)Vaccine type and clinical characteristics

Main Outcome(s)Using a semi-quantitative assay for antibodies against SARS-CoV-2 spike antigen, vaccine response was defined as at least one titer [≥]1 U/L between 14 and 74 days after completion of a SARS-CoV-2 vaccine series. Regression analysis was used to identify characteristics associated with response.

ResultsAmong 1528 patients, 437 received BNT162b2/Pfizer vaccine, 766 received mRNA-1273/Moderna, and 325 received Ad26.COV2.S/Janssen. Serologic response differed significantly by vaccine type: 381/437 (87%) among BNT162b2/Pfizer recipients, 736/766 (96%) among mRNA-1273/Moderna recipients, and 119/325 (37%) among Ad26.COV2.S/Janssen recipients. Vaccine type, older age, immune-modulating medication, history of transplantation, and lower serum albumin were associated with vaccine non-response.

Conclusions and RelevanceSerologic response to mRNA vaccines is robust among maintenance dialysis patients. Future research should evaluate durability of this response, correlation between seroresponse and protection from COVID-19, and the role of the AD26.COV2.S/Janssen vaccine in this vulnerable population.

category: nephrology


title: Tissue damage detected by quantitative gradient echo MRI correlates with clinical progression in non-relapsing progressive MS

abstract:
BackgroundImaging biomarkers of progressive MS are needed. Quantitative gradient recalled echo (qGRE) MRI technique allows evaluation of tissue damage associated with microstructural damage in multiple sclerosis (MS).

ObjectiveTo evaluate qGRE-derived R2t* as an imaging biomarker of MS disease progression as compared to atrophy and lesion burden.

MethodsTwenty-three non-relapsing progressive MS (PMS), twenty-two relapsing-remitting MS (RRMS) and eighteen healthy control participants were imaged with qGRE at 3T. PMS subjects were imaged and neurologically assessed every nine months over five sessions. In each imaging session, lesion burden, atrophy and R2t* in cortical grey matter (GM), deep GM, normal-appearing white matter (NAWM) were measured.

ResultsR2t* reductions correlated with neurological impairment cross-sectionally and longitudinally. PMS patients with clinically defined disease progression showed significantly faster decrease of R2t* in NAWM and deep GM compared with the clinically stable PMS group. Importantly, tissue damage measured by R2t* outperformed lesion burden and atrophy as a biomarker of progression during the study period.

ConclusionClinical impairment and progression correlated with accumulating R2t*-defined microstructural tissue damage in deep GM and NAWM. qGRE-derived R2t* is a potential imaging biomarker of MS progression.

category: neurology


title: Using Natural Language Processing to Classify Serious Illness Communication with Oncology Patients

abstract: One core measure of healthcare quality set forth by the Institute of Medicine is whether care decisions match patient goals. High-quality "serious illness communication" about patient goals and prognosis is required to support patient-centered decision-making, however current methods are not sensitive enough to measure the quality of this communication or determine whether care delivered matches patient priorities. Natural language processing (NLP) offers an efficient method for identification and evaluation of documented serious illness communication, which could serve as the basis for future quality metrics in oncology and other forms of serious illness. In this study, we trained NLP algorithms to identify and characterize serious illness communication with oncology patients.

category: health informatics


title: Linking Free Text Documentation of Functioning and Disability to the ICF with Natural Language Processing

abstract:
BackgroundInvaluable information on patient functioning and the complex interactions that define it is recorded in free text portions of the Electronic Health Record (EHR). Leveraging this information to improve clinical decision-making and conduct research requires natural language processing (NLP) technologies to identify and organize the information recorded in clinical documentation.

MethodsWe used NLP methods to analyze information about patient functioning recorded in two collections of clinical documents pertaining to claims for federal disability benefits from the U.S. Social Security Administration (SSA). We grounded our analysis in the International Classification of Functioning, Disability and Health (ICF), and used the ICFs Activities and Participation domain to classify information about functioning in three key areas: Mobility, Self-Care, and Domestic Life. After annotating functional status information in our datasets through expert clinical review, we trained machine learning-based NLP models to automatically assign ICF categories to mentions of functional activity.

ResultsWe found that rich and diverse information on patient functioning was documented in the free text records. Annotation of 289 documents for Mobility information yielded 2,455 mentions of Mobility activities and 3,176 specific actions corresponding to 13 ICF-based categories. Annotation of 329 documents for Self-Care and Domestic Life information yielded 3,990 activity mentions and 4,665 specific actions corresponding to 16 ICF-based categories. NLP systems for automated ICF coding achieved over 80% macro-averaged F-measure on both datasets, indicating strong performance across all ICF categories used.

ConclusionsNLP can help to navigate the tradeoff between flexible and expressive clinical documentation of functioning and standardizable data for comparability and learning. The ICF has practical limitations for classifying functional status information in clinical documentation, but presents a valuable framework for organizing the information recorded in health records about patient functioning. This study advances the development of robust, ICF-based NLP technologies to analyze information on patient functioning, and has significant implications for NLP-powered analysis of functional status information in disability benefits management, clinical care, and research.


title: Reduced serum neutralization capacity against SARS-CoV-2 variants in a multiplex ACE2 RBD competition assay

abstract: As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.

category: infectious diseases


title: COVID-19 patient serum less potently inhibits ACE2-RBD binding for various SARS-CoV-2 RBD mutants


title: Effect of familiarity with COVID-19 infection--history of infection or close contact--on outing behaviors when a state of emergency is declared

abstract:
BackgroundRestricting the movement of the public to gathering places and limiting close physical contact are effective measures against COVID-19 infection. In Japan, states of emergency have been declared in specific prefectures to reduce public movement and control COVID-19 transmission. We investigated how COVID-19 infection related experiences including people with a history of infection, people with a history of close contact, and people whose acquaintances have been infected, affected self-restraint related to outing behaviors during the second state of emergency in Japan.

MethodsA prospective cohort study was conducted among workers aged 20-65 years using data from an internet survey. The baseline survey was conducted on December 22-25, 2020, and a follow-up survey was on February 18-19, 2021. There were 19,941 participants who completed both surveys and were included in the final analysis. We identified eight outing behaviors: (1) eating out (4 people or fewer); (2) eating out (5 people or more); (3) gathering with friends and colleagues; (4) day trip; (5) overnight trip (excluding visiting home); (6) visiting home; (7) shopping for daily necessities; and (8) shopping for other than daily necessities. We set self-restraint regarding each outing behavior after the second state of emergency was declared in January 2021 as the dependent variable, and COVID-19 infection related experiences as independent variables. Odds ratios were estimated using multilevel logistic regression analyses.

ResultsSignificant differences by COVID-19 infection related experiences were identified: compared to people without COVID-19 related experiences, people with a history of COVID-19 were less likely self-restraint from most outing behaviors. People whose acquaintance had been diagnosed with COVID-19 were significantly more likely to refrain from most outing behaviors. There was no significant difference in any outing behaviors for people with a history of close contact only.

ConclusionsTo maximize the effect of a state of emergency, health authorities should disseminate information for each person in the target population, taking into account potential differences related to the COVID-19 infection related experiences.


title: Effect of COVID-19 infection related experiences on outing behaviors when a state of emergency is declared: a cohort study


title: Inhaled nitric oxide use in COVID19-induced hypoxemic respiratory failure.

abstract:
IntroductionNitric Oxide (NO) is an endogenous vasodilator that is synthesized by the vascular endothelium. Due to its vasodilatory effect and short half-life, the use of NO as an exogenous inhaled medication (iNO) to target the pulmonary vasculature, in conditions with increased pulmonary vascular resistance, has been studied.

The use of iNO in patients with ARDS secondary to COVID-19 has therapeutic importance in improving oxygenation. It also has potential anti-viral, anti-inflammatory, and anti-thrombotic properties.

Herein, we want to share our experience of use of iNO in hypoxemic respiratory failure secondary to COVID 19 pneumonia. We hypothesized that iNO may be beneficial at preventing intubation, decreasing invasive mechanical ventilation duration, and consequently improve outcomes including hospital mortality.

MethodsThis is a descriptive hypothesis generating study of patients admitted for COVID-19 pneumonia who received iNO for hypoxemic respiratory failure, at a single tertiary care center. We collected information on patient demographics, co-morbidities, iNO treatment, need for intubation, arterial blood gas analysis, laboratory values, hospital length of stay, and mortality. Patients were divided into two groups based on the timing of iNO administration: group 1 - "pre-intubation" (i.e. iNO started at least 1 day prior to endotracheal intubation, if any) and group 2 - "post-intubation" (i.e. iNO started on the same day as or after endotracheal intubation and mechanical ventilation).

ResultA total of 45 (group 1, n=26 [57.8%] vs group2, n=19 [42.2%]) COVID 19 patients who had iNO use. The mean time from hospital admission to iNO administration(days) in group 1 was 2.1 ({+/-}1.8) vs 4.2 ({+/-}5.9) in group 2. The mean hospital length of stay from the beginning of iNO treatment until discharge or death was 18.3 vs 26.2 days, with 8 deaths (30.8%) vs 9 deaths (47.4%) in group 1 vs group 2, respectively.

DiscussionOur study is unable to demonstrate comparably outcomes benefit of iNO. Although there was a trend towards decreased need for invasive mechanical ventilation in group 1[Only 11 (42.3%) patients were intubated out of 26 who received iNO early after hospital admission (2.3 days)], no statistical significance could be achieved because of small sample size.

Our study demonstrated that iNO administration pre-intubation did not appear harmful and appears to be safe, complementary to HFNC, signalling the domain where systematic investigation is required to confirm or not the potential for iNO to improve patient outcomes in the management of COVID 19-induced hypoxemic respiratory failure.

ConclusionThis study showcases the potential benefit of early pre-intubation use of iNO in COVID patients with hypoxemic respiratory failure. This study could conclusively form the basis for a prospective trial and could have a tremendous impact in improving patient outcomes.

HighlightsO_LIInhaled nitric oxide can be used in the treatment COVID 19 induced hypoxemic respiratory failure.
C_LIO_LIInhaled nitric oxide use can lower the burden on overwhelmed medical system.
C_LIO_LIInhaled nitric oxide use may lower the need for intubation and subsequent invasive mechanical ventilation.
C_LI

category: intensive care and critical care medicine


title: A prospective study of the protective effect of SARS-CoV-2-specific antibodies and T cells in Moscow residents

abstract: Rapid spread of COVID-19 pandemic made a substantial share of the world population immunised by SARS-CoV-2 antigens. Infection induces the development of virus-specific antibodies and T cells. Ample evidence on the antibody-mediated protection is contrasted by the elusive role of T cells in preventing infection. To explore the impact of T cells and to quantify the protective levels of the immune responses we conducted a large prospective study: 5,340 Moscow residents were evaluated for the antibody and cellular immune responses to SARS-CoV-2 and monitored for COVID-19 up to 300 days. The antibody and cellular responses were tightly interconnected, their magnitude inversely correlated with infection probability. Similar maximal level of protection was reached by individuals positive for both types of responses and by individuals with antibodies alone. Meanwhile, T cells in the absence of antibodies provided an intermediate level of protection. The real-world data on the protective effects of T cells have important implications for T cell immunology and development of the strategies to fight the pandemic.


title: SARS-CoV-2 specific T cells and antibodies in COVID-19 protection: a prospective study


title: Can a vaccine-led approach end the NSW outbreak in 100 days, or at least substantially reduce morbidity and mortality?

abstract:
Background and AimsThe New South Wales (NSW) COVID-19 outbreak is at 478 daily cases on August 16, 2021.

Our aims were to:

O_LIestimate the time required to reach [≤]5 cases per day under three lockdown strengths (weak, moderate, strong), and four vaccination rollouts: (a) per the original plan, (b) prioritizing essential workers, (c) b plus rapid vaccination of 25% of <60-year-olds with AstraZeneca (AZ25), and (d) b plus rapid vaccination of 50% of <60-year-olds with AstraZeneca (AZ50).
C_LIO_LIestimate the number of cases, hospitalizations, and deaths in the 100 days after 1/August for the 12 scenarios.
C_LI

MethodsAn agent-based model was adapted to NSW and the Delta variant. Hospitalization and mortality rates for unvaccinated COVID-19 infections were doubled given the virulence of Delta.

ResultsThe business-as-usual rollout fully vaccinates 50%, 70% and 80% of >16-year-olds by 10/Oct, 21/Nov, and 28/Dec, respectively. This reduced to 1/Oct, 30/Oct, and 22/Nov for the fastest (AZ50) rollout.

A strong lockdown with a rapid vaccine rollout was the fastest to reach [≤]5 cases (14-day average), with a median of 78 days (90% Uncertainty interval 61 - 103) or 18/Oct, compared to 207 days (166 - 254) or 24/Feb for a weak lockdown with no rollout acceleration. Increased lockdown strength had more impact than rollout acceleration.

Under the AZ25 vaccination scenario, there were 1,440 (90% UI 262 - 10,600 deaths in the first 100 days of cases under a weak lockdown, compared to 71 (90% UI 26 - 178) under a strong lockdown scenario.

ConclusionNSW will likely achieve 70% vaccination of >16-year-olds before reaching [≤]5 daily cases. Accelerating the vaccine rollout is important for the medium-term, but in the short-term increased restriction strength was more effective at reducing caseload (and subsequently mortality and hospitalisation) than accelerating the vaccine rollout.

O_TEXTBOXSignificance of Study

"The known" NSW is facing a Delta-variant COVID-19 outbreak, with a vaccination-led strategy for controlling the outbreak. Despite the increased infectivity and virulence of the Delta-variant, little contemporaneous modelling exists. We, therefore, model several restrictions and vaccination scenarios.

"The new" NSW will likely achieve 70% vaccination of >16-year-olds before daily cases are [≤]5. Increased lockdown strength was more effective at reducing cases than accelerating the vaccine rollout.

"The implications" Accelerating the vaccine rollout is important in the medium-term, but in the short-term strong public health and social restrictions (including lockdown) are more effective at reining in cases.

C_TEXTBOX


title: A composite endpoint for acceptability evaluation of oral drug formulations in the pediatric population

abstract:
IntroductionA medicines acceptability is likely to have significant impact on pediatric compliance. EMA and FDA guidance on this topic ask for investigation of acceptability. Although palatability and deglutition are denoted as elements of acceptability, the impact of both on acceptability remains unclear as an unambiguous definition of acceptability is lacking. Actually, globally applied standards for acceptability definition, testing methodology and assessment criteria do not exist. A definition of acceptability establishing a composite endpoint that combines deglutition and palatability in different age groups is presented here.

MethodsThis composite acceptability endpoint is based on validated assessment methods for deglutition and palatability in children of different age groups with different galenic placebo formulations, in line with criteria EMA proposed for assessing acceptability in children from newborn to 18 years. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films and syrup were used to investigate the validity, expediency and applicability of the suggested composite acceptability assessment tool.

ResultsThe new composite endpoint is highly suitable and efficient to distinguish preferences of oral formulations: Mini-tablets and oblong tablets were significantly better accepted than syrup and orodispersible film.

ConclusionSince the suggested acceptability criterion takes both deglutition and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined, valid approach, which particularly meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as an easy, standardized method to assess and compare acceptability of pediatric formulations with active substances.

category: pediatrics


title: Gut microbiota signatures associate with prostate cancer risk

abstract:
BackgroundProstate cancer (PC) is the most common cancer in men worldwide. The incidence of PC varies significantly geographically, which might result e.g. from genetic factors and local discrepancies in screening policies, but also from differences in lifestyle such as diet. Novel environmental factor, namely gut microbiota (GM) has been recently associated with many pathological processes including tumor progression within human body but its role in PC is disputable.

MethodsWithin a clinical prospective single center trial, the GM profiles were assessed from 181 men with clinical suspicion of PC utilizing 16S rRNA gene sequencing (Illumina). Sequences were assigned to operational taxonomic units (OTUs) after which differential abundance analysis, - and {beta}-diversities, and predictive functional (PICRUST) analysis were performed. Further, plasma steroid hormone levels correlated to predicted microbiota functions.

ResultsPC was diagnosed in 60% (108/181). Apart for less smoking among subjects with PC, there were no life-style differences between the groups. The GM profiles of men with PC differed significantly from those without cancer, e.g. Prevotella 9, members of family Erysipelotrichaceae and potentially pathogenic Escherichia-Shigella were increased, and e.g. Jonquetella, Moryella, Anaeroglobus, Corynebacterium and CAG-352 were reduced in PC cases. Predictive functional analyses revealed increased 5--reductase activity (5-AR), copper absorption and retinal metabolism as functional results of different microbiota. Plasma testosterone negatively correlated with predicted microbial 5-AR activity (Wilcoxon rank sum p=0.057) and in a subgroup of men taking 5-AR inhibitors (n=17), plasma estrone (p=0.027), and estradiol (p=0.054) levels were higher in men with predicted increased microbial 5-AR function.

ConclusionsCertain bacterial and functional features within GM composition are associated with PC risk and altered androgen, copper and retinol metabolism are potential mechanisms. Findings could explain the previously reported association of life-style effects and geographical differences observed in PC.

Trial registration numberNCT02241122

category: urology


title: Virtual Delivery of Simulation Education to Undergraduate Medical Students During the COVID-19 Pandemic

abstract:
BackgroundThe COVID-19 pandemic has restricted in-person clinical training for medical students. Simulation-based teaching is a promising tool to introduce learners to the clinical environment. MacSim is a student-led simulation workshop for learners to develop clinical competencies. The objective of this study was to assess the impacts of MacSim and participants perspectives regarding simulation-based teaching.

MethodsA comprehensive simulation, representative of a virtual care scenario, was delivered to 42 pre-clerkship medical students via video conferencing. In pairs, participants obtained histories and carried out management plans for simulated patients. Participants were surveyed and interviewed. Survey data were analyzed using the Wilcoxon signed-ranks test. Interview transcript data were thematically analyzed.

ResultsPost-simulation, participants (n=24) felt more prepared to make clinical decisions, collaborate, and communicate in a virtual setting. 92% of respondents agreed MacSim was a valuable learning experience and 96% agreed more simulation-based learning should be integrated into curricula. Emergent themes from interviews (n=12) included: 1) value of simulation fidelity, 2) value of physician feedback, and 3) effectiveness of MacSim in improving virtual clinical skills.

ConclusionSimulation-based teaching is of importance and educational value to medical students. It may play an increasingly prevalent role in education as virtual care is likely to become more prevalent.

category: medical education


title: Intention to receive a COVID-19 vaccine by HIV status among a population-based sample of women and gender diverse individuals in British Columbia, Canada

abstract:
IntroductionCOVID-19 vaccination is recommended for people living with HIV (PLWH), among whom social inequities and co-morbidities may drive risks of COVID-19 infection and outcome severity. Among a provincial (British Columbia) sample, we determined the prevalence of COVID-19 vaccine intention by HIV status and assessed socio-demographic, vaccine hesitancy, and psychological predictors of vaccine intention.

MethodsIndividuals (25-69y) recruited from province-wide research cohorts completed an online survey examining COVID-19 impacts (August/2020-March/2021). Among women and gender diverse participants, we compared intention to receive a recommended COVID-19 vaccine (Very likely/Likely vs Neutral/Unlikely/Very Unlikely) by self-reported HIV status. Logistic regression models assessed the independent effect of HIV status and other factors on vaccine intention.

ResultsOf 5,588 participants, 69 (1.2%) were PLWH, of whom 79.7% were on antiretroviral therapy. Intention to vaccinate was significantly lower among PLWH compared to participants not living with HIV (65.2% vs 79.6%; OR: 0.44; 95%CI: 0.32-0.60). However, this association was attenuated after adjustment for social disparities (aOR:0.85; 95%CI: 0.48-1.55). Among PLWH, those with greater vaccine confidence, positive attitudes towards the COVID-19 vaccine, and more strongly influenced by direct and indirect social norms to vaccinate had significantly higher odds of vaccine intention.

DiscussionTailored messaging is needed to build vaccine confidence, address questions about vaccine benefits, and support informed vaccination decision-making to promote COVID-19 vaccine uptake among women and gender diverse PLWH.

category: hiv aids


title: Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

abstract:
BackgroundImmune protection following either vaccination or infection with SARS-CoV-2 decreases over time.

ObjectiveTo determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals.

MethodsAntibody titers were measured between January 31, 2021, and July 31, 2021 in two mutually exclusive groups: i) vaccinated individuals who received two doses of BNT162b2 vaccine and had no history of previous infection with COVID-19 and ii) SARS-CoV-2 convalescents who had not received the vaccine.

ResultsA total of 2,653 individuals fully vaccinated by two doses of vaccine during the study period and 4,361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8-5644.6]) after the second vaccination, than in convalescent individuals (median 355.3 AU/mL IQR [141.2-998.7]; p<0.001). In vaccinated subjects, antibody titers decreased by up to 40% each subsequent month while in convalescents they decreased by less than 5% per month. Six months after BNT162b2 vaccination 16.1% subjects had antibody levels below the seropositivity threshold of <50 AU/mL, while only 10.8% of convalescent patients were below <50 AU/mL threshold after 9 months from SARS-CoV-2 infection.

ConclusionsThis study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.

FundingThis research was internally funded by Leumit Health Services (LHS) and was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Impact statementLarge scale study display the kinetics of SARS-CoV-2 IgG antibodies present in individuals vaccinated with two doses of mRNA vaccine vs. unvaccinated patients who had recovered from the disease: initial levels of antibody are much higher in vaccinated patients, but decrease faster.


title: Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs

abstract:
BackgroundThe SARS-CoV-2 Delta variant (B.1.617.2), initially identified in India, has become predominant in several countries, including Portugal. Few studies have compared the effectiveness of mRNA vaccines against Delta versus Alpha variant of concern (VOC) and estimated variant-specific viral loads in vaccine infection breakthroughs cases. In the context of Delta dominance, this information is critical to inform decision-makers regarding the planning of restrictions and vaccination roll-out.

MethodsWe developed a case-case study to compare mRNA vaccines effectiveness against Delta (B.1.617.2) versus Alpha (B.1.1.7) variants. We used RT-PCR positive cases notified to the National Surveillance System between 17th of May and 4th of July 2021 (week 20 to 26) and information about demographics and vaccination status through the electronic vaccination register. Whole-genome sequencing (WGS) or spike (S) gene target failure (SGTF) data were used to classify SARS-CoV-2 variants. The odds of vaccinated individuals to become infected (odds of vaccine infection breakthrough) in Delta cases compared to Alpha SARS-CoV-2 cases was estimated by conditional logistic regression adjusted for age group, sex, and matched by the week of diagnosis. As a surrogate of viral load, mean RT-PCR Ct values were stratified and compared between vaccine status and VOC.

ResultsOf the 2 097 SARS-CoV-2 RT-PCR positive cases included in the analysis, 966 (46.1%) were classified with WGS and 1131 (53.9%) with SGTF. Individuals infected with the Delta variant were more frequently vaccinated 162 (12%) than individuals infected with the Alpha variant 38 (5%). We report a statistically significant higher odds of vaccine infection breakthrough for partial (OR=1.70; CI95% 1.18 to 2.47) and complete vaccination (OR=1.96; CI95% 1.22 to 3.14) in the Delta cases when compared to the Alpha cases, suggesting lower mRNA vaccine effectiveness against Delta cases. On our secondary analysis, we observed lower mean Ct values for the Delta VOC cases versus Alpha, regardless the vaccination status. Additionally, the Delta variant cases revealed a Ct-value mean increase of 2.24 (CI95% 0.85 to 3.64) between unvaccinated and fully vaccinated breakthrough cases contrasting with 4.49 (CI95% 2.07 to 6.91) in the Alpha VOC, suggesting a lower impact of vaccine on viral load of Delta cases.

ConclusionsWe found significantly higher odds of vaccine infection breakthrough in Delta cases when compared to Alpha cases, suggesting lower effectiveness of the mRNA vaccines in preventing infection with the Delta variant. Additionally, the vaccine breakthrough cases are estimated to be of higher mean Ct values, suggesting higher infectiousness with the Delta variant infection. These findings can help decision-makers weigh on the application or lifting of control measures and adjusting vaccine roll-out depending on the predominance of the Delta variant and the coverage of partial and complete mRNA vaccination.


title: Disability-adjusted life years (DALYs) due to the direct health impact of COVID-19 in India, 2020

abstract: COVID-19 has affected all countries. Its containment represents a unique challenge for India due to a large population (>1.38 billion) across a wide range of population densities. Assessment of the COVID-19 disease burden is required to put the disease impact into context and support future pandemic policy development. Here, we present the national-level burden of COVID-19 in India in 2020 that accounts for differences across urban and rural regions and across age groups. Disability-adjusted life years (DALY) due to COVID-19 were estimated in the Indian population in 2020, comprised of years of life lost (YLL) and years lived with disability (YLD). Scenario analyses were conducted to account for excess deaths not recorded in the official data and for reported COVID-19 deaths. The direct impact of COVID-19 in 2020 in India was responsible for 14,106,060 (95% uncertainty interval [UI] 14,030,129-14,213,231) DALYs, consisting of 99.2% (95% UI 98.47-99.64%) YLLs and 0.80% (95% UI 0.36-1.53) YLDs. DALYs were higher in urban (56%; 95% UI 56-57%) than rural areas (44%; 95% UI 43.4-43.6) and in males (64%) than females (36%). In absolute terms, the highest DALYs occurred in the 51-60-year-old age group (28%) but the highest DALYs per 100,000 persons were estimated for the 71-80 year old age group (5,481; 95% UI 5,464-5,500 years). There were 4,823,791 (95% UI 4,760,908-4,924,307) DALYs after considering reported COVID-19 deaths only. The DALY estimations have direct and immediate implications not only for public policy in India, but also internationally given that India represents one sixth of the worlds population.


title: Discovery Of 42 Genome-Wide Significant Loci Associated With Dyslexia

abstract: Reading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia [1, 2], which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70% [3, 4], yet no convincing genetic markers have been found due to limited study power [5]. Here, we present a genome-wide association study representing a 20-fold increase in sample size from prior work, with 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls. We identified 42 independent genome-wide significant loci: 17 are in genes linked to or pleiotropic with cognitive ability/educational attainment; 25 are novel and may be more specifically associated with dyslexia. Twenty-three loci (12 novel) were validated in independent cohorts of Chinese and European ancestry. We confirmed a similar genetic aetiology of dyslexia between sexes, and found genetic covariance with many traits, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Causal analyses revealed a directional effect of dyslexia on attention deficit hyperactivity disorder and bidirectional effects on socio-educational traits but these relationships require further investigation. Dyslexia polygenic scores explained up to 6% of variance in reading traits in independent cohorts, and might in future enable earlier identification and remediation of dyslexia.


title: Assessment of inter-laboratory differences in SARS-CoV-2 consensus genome assemblies between public health laboratories in Australia

abstract: Whole-genome sequencing of viral isolates is critical for informing transmission patterns and ongoing evolution of pathogens, especially during a pandemic. However, when genomes have low variability in the early stages of a pandemic, the impact of technical and/or sequencing errors increases. We quantitatively assessed inter-laboratory differences in consensus genome assemblies of 72 matched SARS-CoV-2-positive specimens sequenced at different laboratories in Sydney, Australia. Raw sequence data were assembled using two different bioinformatics pipelines in parallel, and resulting consensus genomes were compared to detect laboratory-specific differences. Matched genome sequences were predominantly concordant, with a median pairwise identity of 99.997%. Identified differences were predominantly driven by ambiguous site content. Ignoring these produced differences in only 2.3% (5/216) of pairwise comparisons, each differing by a single nucleotide. Matched samples were assigned the same Pango lineage in 98.2% (212/216) of pairwise comparisons, and were mostly assigned to the same phylogenetic clade. However, epidemiological inference based only on single nucleotide variant distances may lead to significant differences in the number of defined clusters if variant allele frequency thresholds for consensus genome generation differ between laboratories. These results underscore the need for a unified, best-practices approach to bioinformatics between laboratories working on a common outbreak problem.


title: Interpreting Wastewater SARS-CoV-2 Results using Bayesian Analysis

abstract: Wastewater surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven a practical complement to clinical data for assessing community-scale infection trends. Clinical assays, such as the CDC-promulgated N1, N2, and N3 have been used to detect and quantify viral RNA in wastewater but, to date, have not included estimates of reliability of true positive or true negative. Bayes Theorem was applied to estimate Type I and Type II error rates for detections of the virus in wastewater. Conditional probabilities of true positive or true negative were investigated when one assay was used, or multiple assays were run concurrently. Cumulative probability analysis was used to assess the likelihood of true SARS-CoV-2 detection using multiple samples. Results demonstrate highly reliable positive (>0.86 for priors >0.25) and negative (>0.80 for priors = 0.50) results using a single assay. Using N1 and N2 concurrently caused greater reliability (>0.99 for priors <0.05) when results concurred but generated potentially counterintuitive interpretations when results were discordant. Regional wastewater surveillance data was investigated as a means of setting prior probabilities. Probability of true detection with a single marker was investigated using cumulative probability across all combinations of positive and negative results for a set of three samples. Findings using a low (0.11) and uniformed (0.50) initial prior resulted in high probabilities of detection (>0.95) even when a set of samples included one or two negative results, demonstrating the influence of high sensitivity and specificity values. Analyses presented here provide a practical framework for understanding analytical results generated by wastewater surveillance programs.


title: Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): Statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial

abstract:
The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The CLARITY trial is a multi-centre, randomised controlled Bayesian adaptive trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here we describe the statistical analysis plan for the trial, and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at Day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.

Trial registrationClinicalTrials.gov, NCT04394117. Registered on 19 May 2020.

https://clinicaltrials.gov/ct2/show/NCT04394117

Clinical Trial Registry of India: CTRI/2020/07/026831

Version and revisionsVersion 1.0. No revisions.

category: respiratory medicine


title: Dynamics of SARS-CoV-2 exposure in Malawian blood donors: a retrospective seroprevalence analysis between January 2020 and February 2021

abstract:
BackgroundAs at end of July 2021, the COVID-19 pandemic has been less severe in sub-Saharan Africa than elsewhere. In Malawi, there have been two subsequent epidemic waves. We therefore aimed to describe the dynamics of SARS-CoV-2 exposure in Malawi.

MethodsWe measured the seroprevalence of anti-SARS-CoV-2 antibodies among randomly selected blood donor sera in Malawi from January 2020 to February 2021. In a subset, we also assesed in vitro neutralisation against the original variant (D614G WT) and the Beta variant.

FindingsA total of 3586 samples were selected from the blood donor database, of which 2685 (74.9%) were male and 3132 (87.3%) were aged 20-49 years. Of the total, 469 (13.1%) were seropositive. Seropositivity was highest in October 2020 (15.7%) and February 2021 (49.7%) reflecting the two epidemic waves. Unlike the first wave, both urban and rural areas had high seropositivity by February 2021, Balaka (rural, 37.5%), Blantyre (urban, 54.8%), Lilongwe (urban, 54.5%) and Mzuzu (urban, 57.5%). First wave sera showed potent in vitro neutralisation activity against the original variant (78%[7/9]) but not the Beta variant (22% [2/9]). Second wave sera potently neutralised the Beta variant (73% [8/11]).

InterpretationThe findings confirm extensive SARS-CoV-2 exposure in Malawi over two epidemic waves with likely poor cross-protection to reinfection from the first on the second wave. Since prior exposure augments COVID-19 vaccine immunity, prioritising administration of the first dose in high SARS-CoV-2 exposure settings could maximise the benefit of the limited available vaccines in Malawi and the region.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on August 16, 2021, with no language restrictions, for titles and abstracts published between Jan 1, 2020, and August 16, 2021, using the search terms: "SARS-CoV-2 seroprevalence in Africa"[Title/Abstract]) OR "SARS-CoV-2 seroprevalence in blood donors" [Title/Abstract] OR "SARS-CoV-2 seroprevalence in Malawi", and found 15 records. There are limited SARS-CoV-2 seroprevalence studies in sub Saharan Africa, however the few that are available report high seroprevalence than can be deduced from the respective national reported COVID-19 cases and deaths. Only two published SARS-CoV-2 serosurveys were done on blood donors, from Kenya and Madagascar. Blood donor serosurveys have been recommended by the WHO as an important tool for assessing the spread of SARS-CoV-2 and estimating the burden of COVID-19 pandemic.

Added value of this studyUnlike previous SARS-CoV-2 blood donor serosurveys in African populations that were conducted for a maximum period of 9 months, our study covers a full year from January 2020 to February 2021, capturing potential introduction of SARS-CoV-2 into Malawi as well as the two epidemic waves. This study provides evidence against the speculation that SARS-CoV-2 had been circulating more widely in sub-Saharan Africa before the first detected cases. It also provides supporting evidence suggesting that the Beta variant was the likely driver of the second wave that resulted in high SARS-CoV-2 seropositivity in January to February 2021 in Malawi.

Implications of all the available evidenceOur results show extensive community transmission of SARS-CoV-2 in Malawi as reflected in the blood donors serosurvey, with almost half the sample population being seropositive for anti-SARS-CoV-2 antibodies by February 2021. This has implications for COVID-19 vaccination policy in sub-Saharan Africa (SSA), where there are limited available vaccine doses. Considering that prior exposure to SARS-CoV-2 augments COVID-19 vaccine immunity, strategies to maximise administration of the first vaccine dose, while waiting for more vaccines to become available, could maximise the benefits of the limited available vaccines in high SARS-CoV-2 exposure settings in SSA such as Malawi.


title: Studies on the level of neutralizing antibodies produced by inactivated COVID-19 vaccines in the real world

abstract:
BackgroundAlthough effective vaccines have been developed against COVID-19, the level of neutralizing antibodies (Nabs) induced after vaccination in the real world is still unknown. To evaluate the level and persistence of NAbs induced by two inactivated COVID-19 vaccines in China.

Methods and findingsSerum samples were collected from 1,335 people aged 18 and over who were vaccinated with COVID-19 inactivated vaccine in Peking University Peoples Hospital from January 19 to June 23, 2021, for detection of COVID-19 antibodies. The WHO standard of SARS-CoV-2 NAbs was detected. The coefficients of variation between the detection results and the true values of the NAbs detected by the WHO standard were all lower than the WHO international standard 3% after the dilution of the original and the dilution of the theoretical concentrations of 500 IU/mL, 250 IU/mL, 125 IU/mL, 72.5 IU/mL, 36.25 IU/mL and 18.125 IU/mL. On day 11-70, the positive rate of NAbs against COVID-19 was 82% to 100%; From day 71 to 332, the positive rate of NAbs decreased to 27%. The level of NAbs was significantly higher at 3-8 Weeks than at 0-3 Weeks. There was a high linear correlation between NAbs and IgG antibodies in 1335 vaccinated patients. NAbs levels were decreased in 31 of 38 people (81.6%) at two time points after the second dose of vaccine. There was no significant difference in age between the group with increased and decreased neutralizing antibody levels ({chi}2 =-0.034, P>0.05). The positive rate of NAbs in the two-dose vaccine group (77.3%) was significantly higher than that in the one-dose group (18.1%), with statistical difference ({chi}2=312.590, P<0.001). A total of 206 people who were 11-70 days after receiving the second dose were tested and divided into three groups: 18-40 years old, 41-60 years old and >60 years old. The positive rates of NAbs in three groups (18-40 years old, 41-60 years old and >60 years old) were 95.14%, 78.43% and 81.8%, respectively. The positive rate of NAbs was significantly higher in 18-40 years old than in 41-60 years old ({chi}2=12.547, P <0.01). The titer of NAbs in 18-40 years old group was significantly higher than that in 41-60 years old group (t=-0.222, P <0.01). The positive rate of NAbs in male group (89.32%) was lower than in female (91.26%), but there was no significant difference ({chi}2=0.222, P >0.05).

ConclusionsThe positive rate of NAbs was the highest from 10 to 70 days after the second dose of vaccine, and the positive rate gradually decreased as time went by. There was a high linear correlation between COVID-19 NAbs and IgM/IgG antibodies in vaccinators, suggesting that in cases where NAbs cannot be detected, IgM/IgG antibodies can be detected instead. The level of NAbs produced after vaccination was affected by age, but not by gender. The highest levels of NAbs were produced between shots 21 to 56 days apart, suggesting that 21 to 56 days between shots is suitable for vaccination.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIAt present, the inactivated vaccines that have been approved to market in China have passed clinical trials to prove their effectiveness and safety. But the level of neutralizing antibodies induced by vaccination in the real world remains unclear.
C_LIO_LISerological testing for neutralizing antibodies against COVID-19 is important for assessing vaccine and treatment responses and comparing multiple drug candidates. We assessed the levels of neutralizing antibodies produced in populations receiving inactivated vaccines and assessed the persistence of these vaccines in producing COVID-19 neutralizing antibodies in healthy adults.
C_LI

What did the researchers do and find?O_LIWe collected serum samples from 1,335 people aged 18 and above who had received COVID-19 vaccine in Peking University Peoples Hospital, and divided them into two groups according to one dose of inactivated vaccine and two doses of inactivated vaccine.
C_LIO_LIOur study found that the positive rate of NAbs was 66.2% in adults who received one or two doses of inactivated vaccine and 77.3% in adults who received two doses of inactivated vaccine in the real world.
C_LIO_LIFrom 11 to 70 days after the second dose of vaccine, the positive rate of neutralizing antibodies against COVID-19 was 82-100%; On days 71-332, the positive rate of neutralizing antibodies decreased to 27%.
C_LIO_LIThe titer and the positive rate of NAbs in 18-40 years old group were significantly higher than that in 41-60 years old group.
C_LI

What do these findings mean?O_LIWhat is novel is we observed that in the real world, the positive rate of neutralization antibody was the highest at 10 to 70 days after the second vaccination, and with the extension of the vaccination time, the positive rate of antibody gradually decreased. Therefore, we recommend that the third dose of vaccine be administered at day 61 to day 70 for COVID-19 neutralizing antibodies levels.
C_LIO_LIWe observed that there was a high linear correlation between COVID-19 neutralization antibodies and COVID-19 IgM/IgG antibodies in vaccinators, suggesting that in cases where NAbs cannot be detected, COVID-19 IgM/IgG antibodies can be detected instead.
C_LIO_LIIn our manuscript, we found that the titer and positive rate of neutralizing antibodies in 18-40 years old group were higher than those in 41-60 years old group. The level of neutralizing antibodies produced after vaccination was affected by age, but not by gender.
C_LIO_LIWe also observed that the highest levels of NAbs were produced between shots 21 to 35 days apart, suggesting that 21 to 35 days between shots is suitable for vaccination.
C_LI


title: Intraspecies strain exclusion, antibiotic pretreatment, and donor selection control microbiota engraftment after fecal transplantation

abstract: Fecal microbiota transplantation (FMT) is both a promising therapeutic approach to treat microbiota-associated pathologies and an experimental tool to establish a causal role of microbiome dysbiosis in human pathologies. Although clearly efficacious in resolving recurrent Clostridioides difficile infection (rCDI), the therapeutic value of FMT in other pathologies is not yet established, and our mechanistic and ecological understanding of how FMT alters the microbiome in patients is incomplete. Here, we assembled the most comprehensive FMT trial microbiota dataset to date, including new and previously generated fecal metagenomes from FMT trials in rCDI, inflammatory bowel disease (IBD), metabolic syndrome (MetS), drug-resistant pathogen colonization (MDR), and resistance to immune checkpoint inhibitor anti-tumor therapy (ICI). We characterized post-FMT microbiota assembly in the recipients by establishing the origin of the detected strains, and we identified the clinical and ecological factors that determine the engraftment of donor strains. Our findings showed little coexistence of donor and recipient strains and linked the magnitude of donor strain engraftment to dysbiosis of the recipient microbiome. Dysbiosis and strain engraftment were low in pathologies other than rCDI but could be enhanced through pretreatment with antibiotics and lavage. Using generalized linear mixed-effects models, we demonstrate that both ecological (low recipient and high donor [a]-diversity and relative species abundance) and clinical (antibiotic pretreatment, bowel lavage, multiple rounds of FMT) variables are associated with increased donor microbiota engraftment, and that donor strain engraftment events are predictable for individual patients and strains. Overall donor strain engraftment was not linked to FMT outcome in IBD patients but was higher in ICI patients that responded to immunotherapy after FMT. Our findings provide an ecological framework for post-FMT microbiota assembly that can predict donor strain engraftment and determine its importance for clinical outcomes, informing more targeted and personalized approaches to increase the therapeutic benefits of FMTs.

category: gastroenterology


title: Modeling SARS-CoV-2 transmission at a winter destination resort region with high outside visitation

abstract: Travel destinations, particularly large resorts in otherwise small communities, risk infectious disease outbreaks from an influx of visitors who may import infections during peak seasons. The COVID-19 pandemic highlighted this risk in the context of global travel and has raised questions about appropriate interventions to curb the potential spread of infectious disease at tourist destinations. In Colorado, the initial outbreaks of SARS-CoV-2 in the state occurred in ski communities, leading to large economic losses from closures and visitor restrictions. In this study, we modeled SARS-CoV-2 transmission during the 2020-21 season in a ski region of Colorado to determine optimal combinations of intervention strategies that would keep the region below a predetermined threshold of SARS-CoV-2 infection density. This analysis used an age-stratified, deterministic SEIR compartmental model of disease transmission, calibrated to cellphone-based mobility data, to simulate infection trajectories during the winter ski season. Under three national infection levels corresponding to high, medium, and low viral importation risk, we estimated the potential impact of interventions including policy and behavior changes, visitor restriction strategies, and case investigation/contact tracing, in order to quantify the relative and absolute impacts of these interventions in the context of the COVID-19 pandemic. Our results suggest that, in the context of low viral importation risk, case investigation/contact tracing and policy and behavior changes may be sufficient to stay below predetermined infection thresholds without visitor restrictions. However, if viral importation risk is high, visitor restrictions and/or screening for infected visitors would be needed to avoid lockdown-like control scenarios and large outbreaks in tourist communities. These findings provide important guidance to tourist destinations for balancing policy impact in future infectious disease outbreaks.


title: Effects of the Mindfulness-Based Blood Pressure Reduction (MB-BP) Program on Depression and Neural Structural Connectivity

abstract: Hypertension-related illnesses are a leading cause of disability and death in the United States, where 46% of adults have hypertension and only half have it controlled. It is critical to reduce hypertension, and either new classes of interventions are required, or we need to develop enhanced approaches to improve medical regimen adherence. The Mindfulness-Based Blood Pressure Reduction program (MB-BP) is showing novel mechanisms and early evidence of efficacy, but the neural correlates are unknown. The objectives of this study were to identify structural neural correlates of MB-BP using diffusion tensor magnetic resonance imaging (DTI) and assess potential correlations with key clinical outcomes. In a subset of participants from a larger randomized controlled trial, MB-BP participants exhibited increased interoception and decreased depressive symptoms compared to controls. Analyses of DTI data revealed significant group differences in several white matter neural tracts associated with the limbic system and/or hypertension. Specific changes in neural structural connectivity were significantly associated with measures of blood pressure, depression anxiety and symptoms, mindfulness, and emotional regulation. It is concluded that MB-BP has extensive and substantial effects on brain structural connectivity which could mediate beneficial changes in depression, interoceptive awareness, blood pressure, and related measures in individuals with hypertension.


title: Interventions designed to improve vaccination uptake: Scoping review of systematic reviews and meta-analyses - protocol (version 1)

abstract:
BackgroundVaccine uptake varies substantially, and resources to promote the uptake of vaccines differ widely by country and income level. As a result, immunization rates are often suboptimal. There is a need to understand what works, particularly in low- and middle-income countries and other settings where resources are scarce.

MethodsWe plan to conduct a scoping review of interventions designed to increase vaccination uptake

We will include systematic reviews and meta-analyses of interventional studies that address the question of vaccine uptake. We will search the following electronic databases: MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, Epistemonikos, Google Scholar, LILACs and TRIP database (which covers guidelines and the grey literature) until 01 July 2021 and hand-search the reference lists of included articles. We will include systematic reviews that comprise studies of all ages if they report quantitative data on the impact on vaccine uptake. To assess the quality, we will use a modified AMSTAR score and ate the quality of the evidence in included reviews using the "Grade of Recommendations Assessment, Development and Evaluation" (GRADE).

Expected resultsWe intend to present the evidence using summary tables to present the evidence stratified by vaccine coverage, the specific population, e.g., children, adolescents and older adults, and by setting, e.g. healthcare, community. We will also present when low middle-income subgroups are reported.


title: Dynamics of gut microbiome - mediated bile acid metabolism in progression to islet autoimmunity

abstract: Previous studies suggest that the human gut microbiome is dysregulated in islet autoimmunity, preceding the clinical onset of type 1 diabetes (T1D). The microbiota of the gut plays an important role in the regulation of bile acid (BA) metabolism. However, not much is known about the regulation of BAs during progression to T1D. Here, we analyzed BAs in a longitudinal series of serum (n= 333) and stool (n= 304) samples, collected at 3, 6, 12, 18, 24 and 36 months of age, from children who developed a single islet autoantibody (P1Ab), multiple islet autoantibodies (P2Ab), and controls (CTRs) who remained autoantibody (AAb) negative during the follow-up. In addition, we analyzed the stool microbiome by shotgun metagenomics in a subgroup of these children (n=111). Factor analysis showed that age had the strongest impact on BA and microbiome profiles. We found that, at an early age, the systemic BA (including taurine and glycine conjugates) and microbial secondary BA pathways were altered in the P2Ab group as compared to the P1Ab or CTR groups. Our findings thus suggest that dysregulated BA metabolism in early life may contribute to the risk and pathogenesis of T1D.

category: endocrinology


title: Assessing physical and environmental predictors of bovine Schistosoma japonicum infection in rural China

abstract: In China, bovines are believed to be the most common animal source of human schistosomiasis infections, though little is known about what factors promote bovine infections. The current body of literature features inconsistent, and sometimes contradictory results, and to date, few studies have looked beyond physical characteristics to identify the broader environmental conditions that predict bovine schistosomiasis. Because schistosomiasis is a sanitation-related, water-borne disease transmitted by many animals, we hypothesized that several environmental factors - such as the lack of improved sanitation systems, or participation in agricultural production that is water-intensive - could promote schistosomiasis infection in bovines. Using data collected as a part of a repeat cross-sectional study conducted in rural villages in Sichuan, China from 2007 to 2016, we used a Random Forests, machine learning approach to identify the best physical and environmental predictors of bovine S. japonicum infection. Candidate predictors included: 1) physical/biological characteristics of bovines, 2) human sources of environmental schistosomes, 3) socio-economic indicators, 4) animal reservoirs, and 5) agricultural practices. The density of bovines in a village and agricultural practices such as the area of rice and dry summer crops planted and the use of night soil as an agricultural fertilizer, were among the top predictors of bovine S. japonicum infection in all collection years. Additionally, human infection prevalence, pig ownership and bovine age were found to be strong predictors of bovine infection in at least one year. Our findings highlight that presumptively treating bovines in villages with high bovine density or human infection prevalence may help to interrupt transmission. Furthermore, village-level predictors were stronger predictors of bovine infection than household-level predictors, suggesting future investigations may need to apply a broad ecological lens to identify potential underlying sources of persistent transmission.

category: occupational and environmental health


title: Predictors of bovine Schistosoma japonicum infection in rural China


title: CORONAVIRUS DISEASE 2019 IN A TERTIARY PEDIATRIC CENTER IN PORTUGAL

abstract:
ObjectivesDescribe the demographic, clinical, laboratory, and imaging features of SARS-CoV-2 infected children at a tertiary pediatric center in Portugal during the first 6 months of the COVID-19 pandemic.

DesignSingle center, descriptive study of pediatric patients, who had a confirmed SARS-CoV-2 infection from March 7 to September 20, 2020.

SettingTertiary Pediatric referral center.

Patients18 years or younger.

Main outcome measuresIncidence, mortality, age of infection, clinical characteristics, treatment prescribed and outcome.

ResultsA total of 300 patients were included with a median age of 5 years (IQR 1-11) and in 67% a contact was identified (co-habitant in 52.7%). 56 (18.7%) had pre-existing medical conditions. A mode of three days mediated symptom appearance to diagnose. The most common symptoms were fever (55.7%), cough (38.3%), and nasal congestion (24%). 23% of the patients were admitted due to complications related to COVID-19 and 2% required intensive care. We used drugs with antiviral activity in 9% of the patients, immunomodulatory medication with corticosteroids in 3.3%, and intravenous immunoglobulin in 1.7%. Two (0.6%) children died and 2.3% reported short-term sequelae.

ConclusionsCOVID-19 is usually a mild disease in children, but a small proportion of patients develop severe and critical disease. Fatal outcomes were rare overall and exclusive of severe previous medical conditions. Suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging. Our data also reflect the uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed.


title: Anticipating the hospital burden of future COVID-19 epidemic waves

abstract: Forecasting SARS-CoV-2 epidemic trends with confidence more than a few weeks ahead is almost impossible as these entirely depend on political decisions. We address this problem by investigating the consequences for the health system of an epidemic wave of a given size. This approach yields semi-quantitative results that depend on the proportion of the population already infected and vaccinated. We introduce the COVimpact software, which allows users to visualise estimated numbers of ICU admissions, deaths, and infections stratified by age class at the French departmental, regional, or national level caused by the wave. We illustrate the usefulness of our approach by showing that for France, even with a 95% vaccination coverage, the current vaccine efficiency against the delta variant would make a large epidemic wave infecting 25% of the population difficult to sustain for the current hospital bed occupancy capacity. Overall, using the final epidemic wave size and ignoring detailed epidemiological dynamics yields valuable and practical insights to optimise public health response to epidemics.

category: epidemiology


title: SafeSwab, a sample collection and dispensing device for near-patient testing

abstract:
BackgroundThe COVID-19 pandemic has accelerated the pace of innovation around virtual care visits and testing technology. Here we present the SafeSwab (Safe Health Systems, Los Angeles, CA), an integrated, universal sample collection and dispensing device that is designed to minimize user error and enable rapid testing in a point of care or self-testing format.

MethodsThe SafeSwab was used with the Safe Health Systems HealthCheck digital health application to enable self-testing by patients using lateral flow tests for SARS-CoV-2 antigen or for antibodies against SARS-CoV-2.

ResultsPatients (n=74) using the SafeSwab produced a valid rapid test result in 96% of attempts, and 96% of patients felt confident that they had collected a good sample. The Safe HealthCheck app has an integrated image analysis algorithm, AutoAdapt LFA, that interprets a picture of a rapid test result, and the algorithm interpreted the result correctly 100% of the time.

ConclusionThe SafeSwab was found to be versatile and easy to use for both self-collected nasal sampling as well as fingerstick blood sampling. The use of Safe Health Systems HealthCheck app allows an integrated solution for patient instruction and test interpretation


title: Reduced T cell and antibody responses to inactivated coronavirus vaccine among males and individuals above 55 years old

abstract:
BackgroundCoronaVac is an inactivated SARS-CoV-2 vaccine that has been rolled out in several low and middle-income countries including Brazil, where it was the mainstay of the first wave of immunization of health care workers and the elderly population. We aimed to assess the T cell and antibody responses of vaccinees as compared to convalescent subjects.

MethodsWe detected IgG against SARS-CoV-2 antigens, neutralizing antibodies against the original SARS-CoV-2 strain, and used SARS-CoV-2 peptides to detect IFN-g and IL-2 specific T cell responses in a cohort of CoronaVac vaccinees (N=101) and convalescent (N=72) individuals.

FindingsAmong vaccinees, 95% displayed T cell or antibody responses to SARS-CoV-2 as compared to 99% convalescent individuals. However, we observed that among vaccinees, males and individuals 55 years or older developed significantly lower anti-RBD, anti-NP and neutralizing antibody responses as well as antigen-induced IL-2 production by T cells.

InterpretationEven though some studies indicated Coronavac helped reduce mortality among elderly people, considering the current dominance of the gamma variant of concern (VOC) and potential increase of the delta VOC, in Brazil, our data support that Coronavac vaccinees above 55 years old Coronavac vaccinees above 55 years old could benefit from a heterologous third dose/booster vaccine to improve immune response and protection.

FundingBrazilian Ministry for Science, Technology and Innovation, Sao Paulo State Foundation for Scientific research (FAPESP), JBS S.A.


title: Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study.

abstract: Exposure to respiratory syncytial virus (RSV) during childhood is nearly ubiquitous by age two, and infants who develop severe RSV bronchiolitis are more likely to develop asthma later in life. In the Factors Influencing Pediatric Asthma (FIPA) study including 319 children from a Northern Plains American Indian community, we found 73% of children to have high concentrations of RSV-specific IgG (>40 IU/mL). High concentration of RSV-specific IgG was associated with increased exposure to second-hand tobacco smoke (p=7.5x10-4), larger household size (p=4.0x10-3), and lower levels of total serum IgE (p=5.1x10-3). Parents of children with asthma more often reported an RSV diagnosis and/or hospitalization due to RSV, and children with asthma had lower concentrations of RSV IgG as compared to those without asthma among RSV-exposed individuals (mean 117 IU/mL vs. 154, p=7.1x10-4). However, lower RSV IgG was surprisingly exclusive to children with asthma recruited during the winter months when RSV is thought to circulate more broadly. Multivariate regression indicated the strongest predictors of RSV-specific IgG concentration included asthma status (p=0.040), per cent eosinophils (p=0.035), and an asthma x RSV season interaction (p=3.7x10-3). Among candidate genes, we identified a genetic association between an intronic variant in IFNL4 and RSV-specific IgG concentration whereby the minor allele (A) was associated with higher concentration (rs12979860, p=4.3x10-3). Overall our findings suggest there are seasonal differences in immunological response to RSV infection in asthma cases vs. controls, and identify both environmental and genetic contributions that warrant further investigation.


title: Early Platelet dynamics during Staphylococcus aureus bacteremia is associated with dysregulated cytokine response and predictive of microbial persistence and mortality

abstract:
BackgroundPlatelets play key roles in host immune response during sepsis. Microbial persistence and early dysregulated cytokine response predict poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). Our objective was to determine the relationship between early platelet trends and cytokine response, microbial persistence and 30-day mortality in patients with SAB.

MethodsA two-center observational study was conducted in hospitalized patients with monomicrobial SAB. Electronic medical records were reviewed for pertinent demographic, laboratory, and clinical information. Eligible subjects were grouped by platelet count at onset and Day 4 of SAB: normal platelet (NP, [≥] 150 x 109/L) and thrombocytopenia (TC, < 150 x 109/L). The groups were compared for clinical characteristics and outcomes.

Results812 patients met inclusion criteria. The median age was 59 years with MRSA accounting for 34% of SAB. The most common comorbidities were hypertension followed by diabetes then renal disease. Thrombocytopenia (TC) occurred in 29% of patients at SAB onset: 15% (n = 120) were mild and 14% (n = 114) were moderate-to-severe (MS). Compared to patients with normal platelet (NP) at SAB onset (n = 578), higher proportion of patients with TC had alcohol use disorder (p = 0.015), active malignancy (p = 0.002), liver disease (p < 0.001), in addition to requiring intensive care unit (ICU) level of care during hospital stay (p < 0.001). TC patients had a longer duration of bacteremia (3 days vs 2 days; p = 0.008) and higher risk for 30-day mortality (18% vs 6%; p < 0.001) overall compared to those with NP. Changes in platelet count from SAB onset to Day 4 differed significantly between those with persistent (PB) versus resolving bacteremia (RB). Notably, patients who had NP at SAB onset but developed new onset of TC by Day 4 had a higher risk for 30-day mortality compared to those who maintained NP at Day 4 (20% vs 4%; p < 0.001). Those with recovery of their platelet count from TC to NP by Day 4 (n = 20) had their SAB shortened by one day (2 days vs 3 days; p = 0.413) and trended toward lower risk for 30-day mortality (5% vs 22%; p = 0.068) compared to those with sustained TC by Day 4 (n = 88).

ConclusionOur results suggest that platelet dynamics during early course of SAB are associated with dysregulated cytokine response and predictive of 30-day mortality. Future studies should be conducted to assess the impact of utilizing platelet count within the first four days of S. aureus bacteremia to guide clinical interventions and to further investigate S. aureus virulence factors that impair recovery of platelet count in patients with thrombocytopenia.

FundingNone

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPersistent S. aureus bacteremia is associated with high mortality and morbidity despite receipt of anti-staphylococcal agents with apparent in vitro activity. We have previously reported that early dysregulated host cytokine response biased towards an anti-inflammatory state (high IL-10/TNF ratio) during clinical course of S. aureus bacteremia is predictive of persistence and mortality. Additionally, we showed that mortality risk increases by 16% for each continued day with S. aureus bacteremia. In recent experimental models, others have shown that platelets play key roles in host immunity and bacterial clearance. Specifically, S. aureus virulence factor, -toxin, induced aberrant platelet aggregation resulting in thrombocytopenia and compromised bacterial clearance from the blood. We performed literature review using PubMed to identify any clinical studies published between January 1, 1996 and April 30, 2021 with the term "thrombocytopenia" AND ("Staphylococcus aureus" OR "S. aureus bacteremia" OR "persistent bacteremia" OR "duration of S. aureus bacteremia" OR "dysregulated immune response"). We identified three related clinical studies published previously: 1) a retrospective study with a main objective of identifying risk factors associated with thrombocytopenia at sepsis onset during S. aureus bacteremia, 2) another retrospective study aiming to evaluate the prognostic impact of thrombocytopenia at onset, Day 3, and Day 7 of methicillin-susceptible S. aureus bacteremia for predicting mortality, and 3) one prospective study that evaluated the association between ICU admission platelet count and host immune response but did not include infections with S. aureus.

Added value of this studyTo extend the findings from the few earlier clinical studies by performing a more in-depth analysis of the relationship between platelet count, cytokine response, and outcome of bacteremia caused by both methicillin-sensitive and methicillin-resistant S. aureus in a large patient cohort. We examined early platelet dynamics by accounting for changes in daily platelet count over the course of initial 7 days of bacteremia which revealed that platelet count during the first three days of S. aureus bacteremia was significantly associated with a dysregulated cytokine response and predictive of 30-day mortality. Notably, for every 20 x 109/L drop in platelet count by day 4, the risk of death increased by 25%. Importantly, we observed a significant reduction in the risk of mortality in those with platelet count recovery to normal range by day 4 of bacteremia comparable to those whose platelet count remained normal throughout the course of infection, suggesting a critical window for early therapeutic interventions to mitigate platelet consumption and injury.

Implications of all available evidenceOur observations provide strong clinical relevance to the experimental findings implicating the role of S. aureus -toxin in causing platelet injury as well as destruction and sequestration in the microvasculature leading to death in mouse models of bacteremia. The strong link between thrombocytopenia and mortality in S. aureus bacteremia support the need for close monitoring of platelets and a more timely and precise approach to S. aureus bacteremia management that is based on the host-pathogen interface. Considering the distinct patterns of platelet dynamics observed early during the course of S. aureus bacteremia associated with differential mortality risk and the significant improvement in survival among those with platelet recovery by day 4 of bacteremia, follow-up studies should focus on evaluating clinical microbiology procedures that could provide the -toxin phenotype of the infecting strains with prognostic significance to clinicians and investigating therapeutic agents that could mitigate -toxin-mediated insults to platelets to improve treatment outcome.


title: Predicting SARS-CoV-2 infections for children and youth with single symptom screening

abstract:
Symptom-based SARS-CoV-2 screening and testing decisions in children have important implications on daycare and school exclusion policies. Single symptoms account for a substantial volume of testing and disruption to in-person learning and childcare, yet their predictive value is unclear, given the clinical overlap with other circulating respiratory viruses and non-infectious etiologies. We aimed to determine the relative frequency and predictive value of single symptoms for paediatric SARS-CoV-2 infections from an Ottawa COVID-19 assessment centre from October 2020 through April 2021.

Overall, 46.3% (n=10,688) of pediatric encounters were for single symptoms, and 2.7% of these tested positive. The most common presenting single symptoms were rhinorrhea (31.8%), cough (17.4%) and fever (14.0%). Among children with high-risk exposures children in each age group, the following single symptoms had a higher proportion of positive SARS-CoV-2 cases compared to no symptoms; fever and fatigue (0-4 years); fever, cough, headache, and rhinorrhea (5-12 years); fever, loss of taste or smell, headache, rhinorrhea, sore throat, and cough (13-17 years). There was no evidence that the single symptom of either rhinorrhea or cough predicted SARS-CoV-2 infections among 0-4 year olds, despite accounting for a large volume (61.1%) of single symptom presentations in the absence of high-risk exposures.

Symptom-based screening needs to be responsive to changes in evidence and local factors, including the expected resurgence of other respiratory viruses following relaxation of social distancing/masking, to reduce infection-related risks in schools and daycare settings.


title: Immunological Insights Into the Therapeutic Roles of CD24Fc Against Severe COVID-19

abstract:
BACKGROUNDSARS-CoV-2 causes COVID-19 through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns (DAMPs) and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) is able to blunt the broad inflammatory response induced by DAMPs in multiple models. A recent randomized phase III trial evaluating the impact of CD24Fc in patients with severe COVID-19 demonstrated encouraging clinical efficacy.

METHODSWe studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial (NCT04317040) collected before and after treatment with CD24Fc or placebo. We performed high dimensional spectral flow cytometry analysis of peripheral blood mononuclear cells and measured the levels of a broad array of cytokines and chemokines. A systems analytical approach was used to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19.

FINDINGSTwenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found systemic hyper-activation of multiple cellular compartments in the placebo group, including CD8+ T cells, CD4+ T cells, and CD56+ NK cells. By contrast, CD24Fc-treated patients demonstrated blunted systemic inflammation, with a return to homeostasis in both NK and T cells within days without compromising the ability of patients to mount an effective anti-Spike protein antibody response. A single dose of CD24Fc significantly attenuated induction of the systemic cytokine response, including expression of IL-10 and IL-15, and diminished the coexpression and network connectivity among extensive circulating inflammatory cytokines, the parameters associated with COVID-19 disease severity.

INTERPRETATIONOur data demonstrates that CD24Fc treatment rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

FUNDINGNIH


title: Treatment with Soluble CD24 Attenuates COVID-19-Associated Systemic Immunopathology


title: The idea is to help people achieve greater success and liberty: a qualitative study of expanded methadone take-home access in opioid use disorder treatment

abstract:
BackgroundPrior to the COVID-19 pandemic, the United States (US) was already facing an epidemic of opioid overdose deaths. Overdose deaths continued to surge during the pandemic. To limit COVID-19 spread and to avoid disruptions in access to medications for opioid use disorder (MOUD), including buprenorphine and methadone, US federal and state agencies granted unprecedented exemptions to existing MOUD guidelines for Opioid Treatment Programs (OTPs), including loosening criteria for unsupervised take-home doses. We conducted a qualitative study to evaluate the impact of these policy changes on MOUD treatment experiences for providers and patients at an OTP in California.

MethodsWe interviewed 10 providers and 20 patients receiving MOUD. We transcribed, coded, and analyzed all interviews to identify emergent themes.

ResultsProviders discussed clinical decision-making processes and experiences providing take-homes. Implementation of expanded take-home policies was cautious. Providers reported making individualized decisions, using patient factors to decide if benefits outweighed risks of overdose and misuse. Decision-making factors included patient drug use, overdose risk, housing status, and vulnerability to COVID-19. New patient groups started receiving take-homes and providers noted few adverse events. Patients who received take-homes reported increased autonomy and treatment flexibility, which in turn increased likelihood of treatment stabilization and engagement. Patients who remained ineligible for take-homes, usually due to ongoing non-prescribed opioid or benzodiazepine use, desired greater transparency and shared decision-making.

ConclusionFederal exemptions in response to COVID-19 led to the unprecedented expansion of access to MOUD take-homes within OTPs. Providers and patients perceived benefits to expanding access to take-homes and experienced few adverse outcomes, suggesting expanded take-home policies should remain post-COVID-19. Future studies should explore whether these findings are generalizable to other OTPs and assess larger samples to quantify patient-level outcomes resulting from expanded take-home policies.

category: addiction medicine