title: Effectiveness of a text message intervention promoting seat belt use among targeted young adults: A randomized trial

abstract:
BackgroundSeat belt use is an effective way to reduce the morbidity and mortality of motor vehicle crashes. However, 1 in 10 adults do not always wear a seat belt, with the lowest use rates of seat belt use among young adults. Digital behavioral interventions could be useful to increase seat belt use, but remain under-developed. This randomized clinical trial tested the efficacy of a 6-week behavioral text message program promoting seat belt use among young adults.

MethodsA parallel, 2-group, single-blind, individually randomized clinical trial. Eligible individuals recruited from 4 Emergency Departments were aged 18 to 25 years who reported driving or being a passenger without always using a seat belt in the past 2-weeks. Two hundred eighteen participants completed the 2-week trial run-in phase were randomly assigned 1:1 to intervention: self-monitoring control. The intervention arm (n = 110) received SaVE, a 6-week automated interactive text message program including weekly seat belt use queries with feedback and goal support to promote consistent use of a seat belt. The control arm (n = 108) received identical weekly seat belt use queries but no additional feedback. The primary and secondary outcomes were the proportion of young adults reporting always wearing a seat belt at 6- and 12-weeks, collected via web-based self-assessments and analyzed under intent-to-treat models.

ResultsThe mean (SD) age was 21.5 (2.2) years, 137 (63%) were female, 110 (50%) were White, and 33 (15%) were Hispanic. The 6-week follow-up rate was 86.2% (n = 187), with no differential attrition. At 6-weeks, 39.1% (95% CI, 30.0%-48.9%) of intervention participants always wore a seat belt vs. 23.1% (95% CI, 15.6%-32.2%) of control participants (odds ratio, 2.13; 95% CI, 1.18-3.84; P = .01). The 12-week follow-up rate was 64.2% (n = 140), with no differential attrition. At 12 weeks, 42.7% (95% CI, 15.6%-32.2%) of intervention participants always wore a seatbelt vs. 32.3% (95% CI, 20.6%-44.0%) of control participants (odds ratio, 1.25; 95% CI, 0.67-2.31; P=.48).

ConclusionsResults of this randomized clinical trial demonstrated that an interactive text message intervention using goal support was more effective at promoting seat belt use among targeted young adults than self-monitoring at 6-weeks. These findings, if replicated, suggest a scalable approach to help improve seat belt use and reduce crash-related morbidity and mortality.

Trial registrationClinicalTrials.gov Identifier: NCT03833713


title: PSMA-Hornet: fully-automated, multi-target segmentation of healthy organs in PSMA PET/CT images

abstract:
Prostate-specific membrane antigen (PSMA) PET imaging represents a valuable source of information reflecting disease stage, response rate, and treatment optimization options, particularly with PSMA radioligand therapy. Quantification of radiopharmaceutical uptake in healthy organs from PSMA images has the potential to minimize toxicity by extrapolation of the radiation dose delivery towards personalization of therapy. Furthermore, factors affecting biodistribution of PSMA radiotracers that remain mostly unknown can be investigated by analyzing PSMA PET images with segmented organs. However, segmentation and quantification of uptake in organs requires labor-intensive organ delineations that are often not feasible in the clinic nor scalable for large clinical trials. In this work we have developed and tested the PSMA Healthy organ segmentation network (PSMA-Hornet), a fully-automated deep neural net for effective and robust segmentation and labelling of 14 healthy organs representing the normal biodistribution of [18F]DCFPyL on PET/CT images.

MethodsThe study used manually-segmented [18F]DCFPyL PET/CT images from 100 subjects, and 526 similar images without segmentations. The unsegmented images were used for self-supervised model pretraining. For supervised training, 3-fold cross-validation was used to evaluate the network performance, with 85 subjects reserved for model training, 5 for validation, and 10 for testing. Image segmentation and quantification metrics were evaluated on the test set with respect to manual segmentations by a nuclear medicine physician.

ResultsWith our best model, the lowest mean Dice coefficient on the test set was 0.826 for the sublingual gland, and the highest was 0.964 for liver. The highest mean error in tracer uptake quantification was 13.9% in the sublingual gland. Self-supervised pretraining improved training convergence, train-to-test generalization, and segmentation quality. In addition, we found that a multi-target network produced significantly higher segmentation accuracy than single-organ networks.

ConclusionThe developed network can be used to automatically obtain high-quality organ segmentations for PSMA image analysis tasks. It can be used to reproducibly extract imaging data, and holds promise for clinical applications such as personalized radiation dosimetry and improved radioligand therapy.

category: radiology and imaging


title: Estimation and interpretation of vaccine efficacy in COVID-19 randomized clinical trials

abstract: An exceptional effort by the scientific community has led to the development of multiple vaccines against COVID-19. Efficacy estimates for these vaccines have been widely communicated to the general public, but are nonetheless challenging to compare because they are based on phase 3 trials that differ in study design, definition of vaccine efficacy and in the handling of cases arising shortly after vaccination. In this work, we investigate the impact of these choices on vaccine efficacy estimates, both theoretically and by re-analyzing the Janssen and Pfizer COVID-19 trial data under a uniform protocol. We moreover study the causal interpretation that can be assigned to per-protocol analyses typically performed in vaccine trials. Finally, we propose alternative estimands to measure the intrinsic vaccine efficacy in settings with delayed immune response.

category: infectious diseases


title: Identities of women who have an autoimmune rheumatic disease (ARD) during pregnancy planning, pregnancy and early parenting: A qualitative study

abstract:
ObjectiveWomen of reproductive age who have autoimmune rheumatic diseases (ARDs) have expressed a need to be better supported with making decisions about pregnancy. Women with ARDs want their motherhood identities and associated preferences to be taken into account in decisions about their healthcare. The aim of this study was to explore the interplay between illness and motherhood identities of women with ARDs during preconception decision making.

MethodsTimeline-facilitated qualitative interviews with women diagnosed with an ARD (18-49 years old). Participants were purposively sampled based on the following three criteria: thinking about getting pregnant, currently pregnant, or had young children. Interviews were thematically analysed.

ResultsTwenty-two women were interviewed face-to-face (N=6) or over the telephone (N=16). Interview length ranged from 20 minutes to 70 minutes, with a mean length of 48 minutes. Three main themes were identified: prioritisation, discrepancy, and trade-off. Difficulties in balancing multiple identities in healthcare encounters were reported. Women used  self-guides as a reference for priority setting in a dynamic process that shifted as their level of disease activity altered and as their motherhood identity became more or less of a focus at a given point in time. Womens illness and motherhood identities did not present in isolation but were intertwined.

ConclusionsFindings highlight the need for holistic person-centred care that supports women with the complex and emotive decisions relating to preconception decision-making. In practice, health professionals need to consider womens multiple and sometimes conflicting identities, and include both their condition and family associated goals and values within healthcare communication.

category: rheumatology


title: Anterior connectivity critical for recovery of connected speech after stroke

abstract: Connected speech recovers to different degrees across people after left hemisphere stroke, but white matter predictors of differential recovery from the acute stage of stroke are unknown. We assessed changes in lexical-syntactic aspects of connected speech in a longitudinal analysis of 41 individuals (19 females) from the acute stage of LH stroke (within an average 4 days post-stroke) to subacute (within 2 months) and chronic stages (early: 6 months, late: 1 year) while measuring the extent of acute lesions on white-matter tracts to identify tracts predictive of recovery. We found that acute damage to the frontal aslant tract led to decreased recovery of the fluency and structural complexity of connected speech during the year following left hemisphere stroke. In addition, acute damage of the frontal aslant tract and the posterior and long segments of the arcuate fasciculus negatively impacted the recovery of syntactic accuracy, although the associations did not survive correction for multiple comparisons. Results were independent of baseline performance, overall lesion volume, and the proportion damage to tract-adjacent gray matter. This longitudinal analysis from acute to chronic stroke provides the first evidence that recovery of fluent and structurally complex spontaneous connected speech requires intact left frontal connectivity via the frontal aslant tract. That the frontal aslant tract was critical for recovery at early as well as later stages of stroke demonstrates that anterior connectivity plays a lasting and important role for the reorganization of function related to the successful production of connected speech.

category: neurology


title: The Simple One-step stool processing method for detection of Pulmonary tuberculosis: a study protocol to assess the robustness, stool storage conditions and sampling strategy for global implementation and scale-up

abstract:
BackgroundXpert MTB/RIF Ultra (Xpert-Ultra) provides timely results with good sensitivity and acceptable specificity with stool samples in children for bacteriological confirmation of tuberculosis (TB). This study aims to optimize the Simple One-Step (SOS) stool processing method for testing stool samples using the Xpert-Ultra in children and adults in selected health facilities in Addis Ababa, Ethiopia. The study is designed to assess the robustness of the SOS stool method, to help fine-tune the practical aspects of performing the test and to provide insights in stool storage conditions and sampling strategies before the method can be implemented and scaled in routine settings in Ethiopia as well as globally.

Methods and designThe project "painless optimized diagnosis of TB in Ethiopian children" (PODTEC) will be a cross sectional study where three key experiments will be carried out focusing on 1) sampling strategy to investigate if the Xpert-Ultra M.tuberculosis (MTB) -positivity rate depends on stool consistency, and if sensitivity can be increased by taking more than one stool sample from the same participant, or doing multiple tests from the same stool sample, 2) storage conditions to determine how long and at what temperature stool can be stored without losing sensitivity, and 3) optimization of sensitivity and robustness of the SOS stool processing method by varying sample processing steps, stool volume, and sampling from the stool-sample reagent mixture.

Stool samples will be collected from participants (children and adults) who are either sputum or naso-gastric aspiration (NGA) and/or stool Xpert-Ultra MTB positive depending on the experiment. Stool samples from these participants, recruited from 22 sites for an ongoing related study, will be utilized for the PODTEC experiments. The sample size is estimated will be 50 participants.

We will use EpiData for data entry and Stata for data analysis purposes. The main analyses will include computing the loss or gain in the Xpert-Ultra MTB positivity rate, and rates of unsuccessful test results. The differences in the positivity rate regarding testing more than one sample per child, different storage, and processing conditions, will be compared to the baseline (on-site) Xpert-Ultra result.

Ethics and disseminationThe protocol was reviewed and approved by the Ethical Review Board of the Ethiopian Public Health Institute (EPHI-IRB) (Protocol no EPHI-IRB-234-2020). The study results will be shared with the national TB program and stakeholders to the benefit of further roll out of the test in a routine Ethiopian setting. The results will also be disseminated in peer-reviewed scientific journals.

category: public and global health


title: Causal relationship between Environmental Enteric Dysfunction (EED), WaSH practices and growth failure in children from Rukwa-Tanzania

abstract: This was a hospital based prospective cohort study aimed at assessing causal relationship between environmental enteric dysfunction (EED), WaSH practices and growth failure in children aged between 1-2 years from Rukwa, Tanzania, using univariate and multivariate logistic regression models. We found very significant causal relationship between growth failure and combined water availability (p=0.0055), toilet sharing by parents/caregivers (OR= 2.632, CI: 1.156 - 6.233, p=0.023 from univariate analysis, and OR=4.067, CI: 1.484 - 12.206, p=0.008 from multivariate analysis), and handwashing by parents/caregivers before food (OR=3.363, CI: 0.928 -11.454, p=0.05 from univariate analysis and OR=15.038, CI:2.422 - 115.8, p=0.005 from multivariate analysis). This significant causal relationship may be linked to increased diarrheal incidence and intestinal worm infections among the studied children, which may then lead to inadequate absorption of nutrients and subsequent growth failure. The findings herein should therefore improve policy and programs designed to deliver targeted intervention strategies in Tanzania, to also identify and include other entry points for managing child growth failure and improving WaSH practices.

category: nutrition


title: Results From the REsCue Trial: A Randomized Controlled Trial with Extended-Release Calcifediol in Symptomatic Outpatients with COVID-19.

abstract:
ImportanceThe benefit of vitamin D treatment for coronavirus disease 2019 (COVID-19) remains unclear.

ObjectiveTo investigate the effect of raising serum total 25-hydroxyvitamin D (25D) to 50-100 ng/mL with oral extended-release calcifediol (ERC) on time to symptom resolution in mild to moderate COVID-19.

Design, Setting, and ParticipantsA multicenter, randomized, double-blind, placebo-controlled study evaluated treatment of 160 outpatients with COVID-19 diagnosed between November 2020 and October 2021.

InterventionsPatients were treated for 4 weeks with ERC (30 mcg/capsule; 300 mcg on Days 1-3 and 60 mcg on Days 4-27) or placebo.

Outcome MeasuresPrimary endpoints were raising serum 25D to [≥]50 ng/mL at Day 14 and resolution time for five aggregated symptoms. Secondary endpoints included resolution time for aggregated and individual symptoms as a function of serum 25D and changes in clinical biomarkers.

Results171 subjects randomized, 160 treated and 134 (65 ERC and 69 placebo) retained. Average age was 43 (range: 18-71); 59% female, 92% White, 80% Hispanic, 7% African-American, 1% Other, 76% overweight, 40% obese, 26% comorbidities, mean baseline 25D of 37{+/-}1 (SE) ng/mL. ERC increased mean 25D to 82{+/-}4 ng/mL (p<0.001) by Day 7; 88% of subjects attained a level [≥]50 ng/mL; the placebo group trended lower. Resolution time for five aggregated symptoms was unchanged by ERC given that two composite non-respiratory symptoms responded poorly. Prespecified analyses showed that respiratory symptoms tended to resolve earlier when serum 25D levels reached [≤]50 ng/mL, but statistical significance was limited by small sample size and non-compliance: 25D increased in seven placebo subjects (unauthorized supplementation) and none occurred in five ERC subjects (failure to dose). A post-hoc composite of three respiratory symptoms (trouble breathing, chest congestion and dry or hacking cough) resolved 3.0 days faster when 25D was elevated at Days 7 and 14 (p<0.05); chest congestion resolved 4.0 days faster with 25D increases of [≥]25 ng/mL (p<0.05). Safety concerns including hypercalcemia were absent with ERC treatment.

Conclusions and RelevanceERC was effective in increasing serum 25D in outpatients with COVID-19, which may have accelerated resolution of respiratory symptoms suggesting mitigation of COVID-19 pneumonia risk, findings which warrant further study.


title: Safety and Immunogenicity of An Egg-Based Inactivated Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomized, Placebo-Controlled, Phase 1/2 Trial in Vietnam

abstract: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18-59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 g +/-CpG1018 (a toll-like receptor 9 agonist), 3 g alone, 10 g alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 g formulation group was highest, followed by 1 g +CpG1018, 3 g, and 1 g formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 g, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 g, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a [≥] 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N=29, 72.93 95% CI 33.00-161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4 - 4.6) for 1 g +/-CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 g dose was advanced to phase 2 along with a 6 g dose. The 10 g dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.


title: Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number

abstract: The time-varying reproduction number (Rt) can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of Rt from case data. However, these are not easily adapted to point prevalence data nor can they infer Rt across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020 - December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of Rt over the period of two subsequent rounds (6-8 weeks) and single rounds (2-3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in Rt over shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in Rt over the summer of 2020 as restrictions were eased, and a reduction in Rt during England s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics.


title: Profiling of humoral immune responses to norovirus in children across Europe

abstract:
Human noroviruses are a major cause of gastroenteritis outbreaks worldwide. The majority of outbreaks and sporadic cases are caused by norovirus genotype GII.4 but 48 capsid genotypes and 60 polymerase genotypes (P-types) have been described, some of which are frequently reported while others are rarely detected. Little is known about the circulation and reservoirs of the less common genotypes. In this study, we have investigated whether children could pose a possible reservoir for undetected circulation of norovirus diversity. We, therefore, tested IgG and IgA responses of sera obtained from 287 children aged <1-month to 5.5-years on a protein microarray against P particles representing 30 norovirus GI and GII genotypes. We further profiled immune responses against the P-type by assessing antigenicity and seroprevalence of the non-structural proteins. The overall seroprevalence was 95.3% in children up to six months old (maternal antibodies), followed by a decrease to 59.6% up to 12 months, and an increase to 84.7% by the age of 5.5 years. We detected antibody responses against all tested genotypes, with the most specific IgG and IgA responses directed against the GII.2, GII.3, GII.4, and GII.6 capsid genotypes, which are the most frequently reported noroviruses in outbreaks. We also detected antibodies against the non-structural proteins p48 and p22 in sera of older children, predominantly against GII genotypes.

While we found no evidence to suggest that rarely detected genotypes widely circulate in children, this is the first study to investigate seroprevalence against such a wide variety of human norovirus capsid and polymerase genotypes.

ImportanceNorovirus is a leading cause of epidemic acute gastroenteritis, causing severe disease in children, the elderly, and immunocompromised individuals. Although norovirus is a diverse genus of viruses, the majority of reported cases are caused by viruses of the GII.4 genotype. Many of the genotypes are rarely detected and it is unknown where they circulate between outbreaks. Here we investigated the possibility of children posing a reservoir for undetected circulation. While previous serological studies have tested antibodies against a limited set of capsid genotypes, we profiled the antibody repertoire of children against the capsid and the non-structural proteins, representing the known diversity of human noroviruses. While we detected high seroprevalence in children older than one year, we found no evidence to suggest a wide circulation of rare genotypes in children in Europe.


title: Sibling Experiences of Adverse Childhood Experiences: A Scoping Review.

abstract: Adverse childhood experiences (ACEs) are traumatic events during childhood known to affect health and wellbeing across the life-span. The purpose of this scoping review was to understand what we currently know about the experiences of siblings living with ACEs. Sibling relationships are unique, and for some the most enduring we experience. These relationships can be categorised by love and warmth, however, can also be a point of escalating conflict and problems. This scoping review was conducted following Arksey and OMalleys (2005) methodological framework, complemented by the PAGER framework (Bradbury-Jones et al, 2021), offering a structured approach to the reviews analysis and reporting through presenting the Patterns, Advances, Gaps, and Evidence for practice and Research. In June 2020 we searched 12 databases, with 11,469 results. Articles were screened for eligibility by the review team leaving a total of 148 articles meeting the inclusion criteria. Findings highlighted five main patterns: (1) the influence of birth order (older siblings shielding younger); (2) the influence of sibling relationships (lack of research exploring sibling types outside of biological siblings); (3) identifying siblings experiencing ACEs (when one sibling experiences adversity, it is likely that their other siblings also do, or experience vicariously); (4) siblings who cause harm (siblings harming other siblings is often normalised and minimised, especially by parents); (5) focus on individual ACEs (the majority of studies explore ACEs in isolation). Our findings suggest future research would benefit from an increase in theoretical understanding and exploration of different types of sibling relationships (full, step, half).


title: Wastewater Surveillance of U.S. Coast Guard Installations and Seagoing Military Vessels to Mitigate the Risk of COVID-19 Outbreaks

abstract: Military training centers may be high risk environments for the spread of disease such as COVID-19. Individuals arrive after traveling from many parts of the country, live in communal settings, and undergo high-interaction training. A pilot study of wastewater testing was initiated in February, 2021 to determine its feasibility as a sentinel surveillance tool in the U.S. Coast Guard for SARS-CoV-2. Wastewater was analyzed for the presence of two viral genes, N and E, and quantified relative to levels of a fecal indicator virus, Pepper Mild Mottle Virus (PMMoV). A stability control, Bovine Syncytial Respiratory Virus vaccine, was added to samples to assess sample stability and degradation. Wastewater data was validated by comparison with concomitant screening and surveillance programs that identified asymptomatic individuals infected with SARS-CoV-2 by diagnostic testing at on site medical clinics using PCR. Elevated levels of SARS-CoV-2 in wastewater were frequently associated with diagnosed cases, and in several instances, led to screenings of asymptomatic individuals that identified infected personnel, mitigating the risk of spread of disease. Wastewater screening also successfully indicated the presence of breakthrough cases in vaccinated individuals. A method for assessing blackwater from Coast Guard vessels was also developed, allowing detection of SARS-CoV-2 virus in shipboard populations. In one instance, virus was detected in the blackwater four weeks following the diagnosis of a single person on a Coast Guard cutter. These data show that wastewater testing is an effective tool for measuring the presence and prevalence of SARS-CoV-2 in military populations so that mitigation can occur and suggest other diseases may be assessed similarly. As a result, the Coast Guard has established three laboratories with wastewater testing capability at strategic locations and is actively continuing its wastewater testing program.


title: The Effect of Cryo-auriculotherapy on Post-Operative Pain Management following Rotator Cuff Surgery: A Randomized, Placebo-Controlled Study

abstract:
BackgroundIn the context of the current opioid crisis, there is a growing interest in evaluating non-pharmacological solutions to manage post-operative pain. Evidence supports the concept that auriculotherapy may provide significant analgesia

ObjectiveInvestigating the efficacy of cryo-auriculotherapy to reduce postoperative opioid consumption following a rotator cuff surgery.

SettingsAcademic medical center, USA

MethodsThis trial was registered to Clinicaltrials.gov (NCT03860259). A total of 39 subjects undergoing rotator cuff surgery and randomized to receive either an active cryo-auriculotherapy treatment (Auriculotherapy; n=20) or a placebo treatment (placebo; n=19) were included in the analysis. For each cryo-auriculotherapy subject, the treatment was performed in the recovery room. The primary endpoint was overall opioid consumption (oral morphine equivalent = OME). Secondary endpoints included pain and overall non-narcotic analgesic consumption on postoperative day 5, patient satisfaction and function recovery using the 12-Item Short Form Health Survey (SF-12), time to discharge from the recovery room and the hospital and patient satisfaction, as well as the number of subjects from each group readmitted because of pain-related issues.

ResultsThe use of cryo-auriculotherapy was associated with a 35% decrease in total opioid requirement over the first five-day recovery period and a 15% decrease in pain with movement. Pain with movement in the auriculotherapy group remained lower compared to the placebo group for at least 14 days (4.47 {+/-} 2.12 vs 5.84 {+/-} 2.39, respectively; p=0.0394).

ConclusionsOur data suggests that cryo-auriculotherapy represents an alternative to opioids in patients undergoing rotator-cuff surgery.

category: pain medicine


title: Unpicking the Gordian knot: Mendelian randomization to elucidate the risk factors for infectious diseases, using EBV as a model pathogen

abstract:
BackgroundWhy particular individuals are more at risk of a given infectious disease than others has been a topic of interest for scientists, clinicians, and polymaths for millennia. Complex webs of factors-sociodemographic, clinical, genetic, environmental-intersect, rendering causality difficult to decipher. We aimed to demonstrate the ability of Mendelian Randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of infectious diseases, using Epstein Barr Virus (EBV) as a model pathogen.

MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8,422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.

ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed educational attainment, number of sexual partners, and smoking as causal risk factors for EBV serostatus.

ConclusionsOur study demonstrates the power of MR to decipher complex webs of putative risk factors and determine which are causal for the acquisition of an infectious disease. The factors identified for EBV will be important for vaccine deployment.

Key messagesO_LIThe risk of infectious disease acquisition is dependent on many interacting sociodemographic, lifestyle, clinical, genetic, environmental, and national and international health governance factors.
C_LIO_LITraditional epidemiological studies of these risk factors are often hindered by issues of confounding and therefore whether a given putative risk factor is causally associated with infection acquisition is difficult to decipher.
C_LIO_LIUsing Epstein Barr Virus (EBV) as a model pathogen, we demonstrate the power of Mendelian randomization to understand if putative risk factors are causal, while controlling for confounding.
C_LIO_LIBetter understanding of infectious disease risk factors using Mendelian randomization can inform vaccine strategies and deployment e.g. by identifying priority populations for vaccination.
C_LI

category: epidemiology


title: From Volume to Value: Comparative value, quality, and cost between three treatment modalities for early childhood caries

abstract:
ContextIn recent decades there has been a shift from a reimbursement system based upon treatment "volume" to "value."

AimsTo compare value, quality, and cost of three treatment modalities for early childhood caries: surgical care with and without general anesthesia, and non-surgical care with disease management.

Settings and DesignThrough an analytical, observational, cross-sectional design, data was collected from 487 pediatric subjects treated at health centers in seven states. Nearly 95% of the subjects were beneficiaries of the United States government Medicaid health insurance program, which supports families with low socioeconomic status.

Methods and MaterialQuality was measured with a Parental-Reported Symptom and Service Quality questionnaire, adapted from the validated Early Child Oral Health Impact Scale, Child-Oral Impacts on Daily Performance, and Dental Consumer Assessments of Healthcare Providers and Systems surveys. Cost was measured by the labor cost for clinicians and adjusted by total relative value units for all treatment procedures. Value was calculated as the quotient of the weighted quality score and the adjusted cost, multiplied by a coefficient.

Statistical AnalysisValue comparisons were analyzed using chi-square, ANOVA, and likelihood ratio tests.

ResultsChildren treated with non-surgical, disease management had significantly higher parental-perceived quality, lower cost, and higher value when compared to the two surgical treatment modalities.

ConclusionsDentists should consider that non-surgical treatment yields higher "value" than surgical treatments for the management of early childhood caries. Payers and consumers would benefit by comparing treatment "value" when choosing institutions and providers for the management of early childhood caries.

category: dentistry and oral medicine


title: Comparative effectiveness of different primary vaccination courses on mRNA based booster vaccines against SARs-COV-2 infections: A time-varying cohort analysis using trial emulation in the Virus Watch community cohort

abstract:
ImportanceThe Omicron (B.1.1.529) variant has increased SARs-CoV-2 infections in double vaccinated individuals globally, particularly in ChAdOx1 recipients. To tackle rising infections, the UK accelerated booster vaccination programmes used mRNA vaccines irrespective of an individuals primary course vaccine type with booster doses rolled out according to clinical priority. There is limited understanding of the effectiveness of different primary vaccination courses on mRNA based booster vaccines against SARs-COV-2 infections and how time-varying confounders can impact the evaluations comparing different vaccines as primary courses for mRNA boosters.

ObjectiveTo evaluate the comparative effectiveness of ChAdOx1 versus BNT162b2 as primary doses against SARs-CoV-2 in booster vaccine recipients whilst accounting for time-varying confounders.

DesignTrial emulation was used to reduce time-varying confounding-by-indication driven by prioritising booster vaccines based upon age, vulnerability and exposure status e.g. healthcare worker. Trial emulation was conducted by meta-analysing eight cohort results whose booster vaccinations were staggered between 16/09/2021 to 05/01/2022 and followed until 23/01/2022. Time from booster vaccination until SARS-CoV-2 infection, loss of follow-up or end-of-study was modelled using Cox proportional hazards models for each cohort and adjusted for age, sex, minority ethnic status, clinically vulnerability, and deprivation.

SettingProspective observational study using the Virus Watch community cohort in England and Wales.

ParticipantsPeople over the age of 18 years who had their booster vaccination between 16/09/2021 to 05/01/2022 without prior natural immunity.

ExposuresChAdOx1 versus BNT162b2 as a primary dose, and an mRNA booster vaccine.

ResultsAcross eight cohorts, 19,692 mRNA vaccine boosted participants were analysed with 12,036 ChAdOx1 and 7,656 BNT162b2 primary courses with a median follow-up time of 73 days (IQR:54-90). Median age, clinical vulnerability status and infection rates fluctuate through time. 7.2% (n=864) of boosted adults with ChAdOx1 primary course experienced a SARS-CoV-2 infection compared to 7.6% (n=582) of those with BNT162b2 primary course during follow-up. The pooled adjusted hazard ratio was 0.99 [95%CI:0.88-1.11], demonstrating no difference between the incidence of SARs-CoV-2 infections based upon the primary vaccine course.

Conclusion and RelevanceIn mRNA boosted individuals, we found no difference in protection comparing those with a primary course of BNT162b2 to those with aChAdOx1 primary course. This contrasts with pre-booster findings where previous research shows greater effectiveness of BNT162b2 than ChAdOx1 in preventing infection.


title: Estimating the incidence and key risk factors of cardiovascular disease in patients at high risk of imminent fracture using routinely collected real-world data from the UK

abstract: The objective of this work was to estimate the incidence rate of cardiovascular disease (CVD) events (myocardial infarction, stroke or CVD-death) at 1 year among 3 cohorts of patients at high risk of fracture (osteoporosis; previous fracture; and anti-osteoporosis medication), and to identify the key risk factors of CVD events in these three cohorts. To do so, this prospective cohort study used data from the Clinical Practice Research Datalink, a primary care database from United Kingdom. MACE events (a composite outcome for the occurrence of either myocardial infarction (MI), stroke or CVD death) were identified in patients aged fifty or over at high or imminent fracture risk identified in three different cohorts (not mutually exclusive): recently diagnosed with osteoporosis (OST, n=65,295), incident fragility fracture (IFX, n=80,587), and starting oral bisphosphonates (OBP, n=145,959). MACE incidence rates (cases/1000 person-years) were: 19.63 (18.54;20.73) in OST, 51.09 (49.39;52.80) in IFX, and 26.26 (25.41;27.12) in OBP cohorts. Candidate risk factors from QRISK tool, and candidates from literature selected by lasso regression, were fitted into prediction models to estimate 1-year risk of MACE for each cohort. OST and OBP models had a discrimination of [≥] 70% and IFX cohort [≥] 60%. Calibration plots showed good internal validity of the models. Generally, models from lasso regression were better than QRISK. Main risk factors common in all MACE models were sex, alcohol, atrial fibrillation, anti-hypertensive medication, age, prior MI/stroke, established CVD, glomerular filtration rate, systolic blood pressure, and number of GP visits and concomitant medicines. Incidence of MACE in the studied populations was 4.35% or lower, with IFX as the cohort with the higher risk. Identified key risk factors highlight the differences of patients at high risk of fracture versus general population. Proposed models could improve prediction of CVD events in patients with osteoporosis in primary care settings.


title: The GLasses Against transmission of SARS-CoV-2 in the communitY (GLASSY) trial: A pragmatic randomized trial (study protocol)

abstract:
BackgroundA systematic review of observational studies indicated that eye protection may be an effective measure to prevent SARS-CoV-2 infections. Randomized trials are needed to assess whether the observed associations are caused by protection of the eye or confounding factors such as other systematic differences between users and non-users of eye protection, co-interventions, or changes in COVID-19 incidence when comparisons were done over time.

MethodsPragmatic, virtual, parallel group, 1:1 randomized, superiority trial. We will recruit and randomize participants via an online portal. The trial will be fully remote and virtual without any personal interaction between investigators and participants. All members of the public are eligible who confirm that they are at least 18 years of age, do not regularly wear glasses, have not contracted COVID-19 since December 15th 2021, and are willing to be randomized to wear, or not wear glasses in public when close to other people, for a 2-week period. Persons who are dependent on visual aids but typically use contact lenses are eligible. The participants will be randomized (1:1) to wear glasses (sunglasses or other types of glasses) in public spaces when close to others (public transport, shopping centers etc.), or to the control group. The control group will be asked not to wear glasses in public spaces when close to others. The primary outcome is positive test for COVID-19. We aim to include about 25,000 participants to have a statistical power of 80% to detect a relative risk reduction of 25% for the primary outcome.

DiscussionMany have easy access to sunglasses or other glasses. Wearing glasses may provide eye protection and repurposing sunglasses for infection control could be a simple, readily available, environmentally friendly, safe, and sustainable infection prevention measure.

Trial registrationNCT05217797 (Clinicaltrials.gov)


title: The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking.

abstract:
Intravesical Bacillus Calmette-Guerin vaccine (BCG) is an established immunotherapeutic in bladder cancer (BlCa), provoking inflammation leading to tumour-specific immunity. Immune checkpoint blockers such as anti-PD-L1 have potential for enhancing tumour-specific lymphocyte-mediated cytotoxicity in BCG-refractive or advanced disease. In both cases, Interferon-gamma (IFN{gamma}) plays a central role. We investigated the transcriptomic response of normal human urothelium to IFN{gamma} to disentangle mechanisms of BCG and anti-PD-L1 therapy failure.

Exposure of differentiated human urothelium to IFN{gamma} resulted in upregulated MHC class I and class II and de novo expression of CXCL9-11 chemokine genes. Normal urothelium expressed only immuno-inhibitory B7 family members: PD-L1 expression was induced by IFN{gamma}, whereas VISTA was expressed constitutively.

A urothelial IFN{gamma} response gene set was derived and used for unsupervised clustering of tumours, which predicted longer recurrence-free survival in non-muscle invasive bladder cancer (NMIBC). In muscle invasive bladder cancer (MIBC), the IFN{gamma}-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak/absent.

Normal urothelium has few resident lymphocytes. Tumour cell killing requires recruitment and activation of IFN{gamma}-secreting pro-inflammatory/cytotoxic lymphocytes while surmounting both innate (VISTA) and upregulated (PD-L1) inhibitory mechanisms. This study offers supportive evidence for strategies to enhance immunotherapy via the IFN{gamma} and VISTA/PD-L1 nexus.

Patient SummaryImmunotherapy brings promise of harnessing a patients own immune system to seek and destroy malignant cells, but it has yet to deliver widespread clinical benefit. We exposed human urothelium to interferon gamma, a key messenger of the immune system and identified a novel signature of 33 genes that predicted cancers with better outcomes. Our study revealed alternative strategies for targeting checkpoint proteins to improve immunotherapy in the future.

category: urology


title: Establishing a marine monitoring programme to assess antibiotic resistance: a case study from the Gulf Cooperation Council (GCC) region

abstract: The World Health Organization considers antimicrobial resistance as one of the most pressing global issues which poses a fundamental threat to human health, development, and security. Due to demographic and environmental factors, the marine environment of the Gulf Cooperation Council (GCC) region may be particularly susceptible to the threat of antimicrobial resistance. However, there is currently little information on the presence of AMR in the GCC marine environment to inform the design of appropriate targeted surveillance activities. The objective of this study was to develop, implement and conduct a rapid regional baseline monitoring survey of the presence of AMR in the GCC marine environment, through the analysis of seawater collected from high-risk areas across four GCC states: (Bahrain, Oman, Kuwait, and the United Arab Emirates). 560 Escherichia coli strains were analysed as part of this monitoring programme between December 2018 and May 2019. Multi-drug resistance (resistance to three or more structural classes of antimicrobials) was observed in 32.5% of tested isolates. High levels of reduced susceptibility to ampicillin (29.6%), nalidixic acid (27.9%), tetracycline (27.5%), sulfamethoxazole (22.5%) and trimethoprim (22.5%) were observed. Reduced susceptibility to the high priority critically important antimicrobials: azithromycin (9.3%), ceftazidime (12.7%), cefotaxime (12.7%), ciprofloxacin (44.6%), gentamicin (2.7%) and tigecycline (0.5%), was also noted. A subset of 173 isolates was whole genome sequenced, and high carriage rates of qnrS1 (60/173) and blaCTX-M-15 (45/173) were observed, correlating with reduced susceptibility to the fluoroquinolones and third generation cephalosporins, respectively. This study is important because of the resistance patterns observed, the demonstrated utility in applying genomic-based approaches to routine microbiological monitoring, and the overall establishment of a transnational AMR surveillance framework focussed on coastal and marine environments.


title: Minimizing school disruption under high incidence conditions due to the Omicron variant in early 2022

abstract: As record cases due to the Omicron variant are currently registered in Europe, schools remain a vulnerable setting suffering large disruption. Extending previous modeling of SARS-CoV-2 transmission in schools in France, we estimate that at high incidence rates reactive screening protocols (as currently applied in France) require comparable test resources as weekly screening (as currently applied in some Swiss cantons), for considerably lower control. Our findings can be used to define incidence levels triggering school protocols and optimizing their cost-effectiveness.


title: Effects of socio-economic factors on elementary school student COVID-19 infections in Ontario, Canada

abstract:
BackgroundThe prevalence of SARS-CoV-2 infections in Ontario is disproportionately concentrated in areas with lower-income and racialized groups. We examined whether school-level and area-level socio-economic factors were associated with elementary school student infections in Ontario.

MethodsWe performed multi-level modeling analyses using data from the Ministry of Education on school-based infections in Ontario in the 2020-21 school year and on school-level demographics, the Ontario Marginalization Index, and census data to estimate the variability of the cumulative incidence of SARS-CoV-2 infections amongst elementary school students attributable to individual schools (school level, Level 1) and forward sortation areas (FSAs) of schools (area level, Level 2). We explored whether socio-economic factors within individual schools and/or factors common to schools within FSAs predicted the incidence of elementary school student infections.

ResultsAt the school level, the proportion of students from low-income households within a school was positively related with the cumulative incidence of SARS-CoV-2 elementary school student infections ({beta} = .083, p < 0.001). At the area level, the dimensions of FSA marginalization were significantly related with cumulative incidence. Ethnic concentration ({beta} = .454, p < 0.001), residential instability ({beta} = .356, p < 0.001), and material deprivation ({beta} = .212, p < 0.001) were positively related. Area-related variables were more likely to explain variance in cumulative incidence than school-related variables (58% versus 1%, respectively).

InterpretationSocio-economic characteristics of the geographic location of schools were more important in determining the cumulative incidence of SARS-CoV-2 elementary school student infections than individual school characteristics. Given inequitable effects of protracted education disruption, schools in marginalized areas should be prioritized for infection prevention measures and education continuity and recovery plans.


title: Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children

abstract: Systematic SARS-CoV-2 testing is a valuable tool for infection control and surveillance1. However, broad application of high sensitive RT-qPCR testing in children is often hampered due to unpleasant sample collection, limited RT-qPCR capacities, and high costs2-4. Here, we developed a high-throughput approach ( Lolli-Method) for sensitive SARS-CoV-2 detection in children, combining non-invasive sample collection with an RT-qPCR-pool testing strategy. SARS-CoV-2 infections were diagnosed with sensitivities of 100% and 93.9% when viral loads were >106 copies/ml and >103 copies/ml in corresponding Naso-/Oropharyngeal-swabs, respectively. For effective application of the Lolli-Method in schools and daycare facilities, SIR-modeling indicated a preferred frequency of two tests per week. The developed test strategy was implemented in 3,700 schools and 698 daycare facilities in Germany, screening over 800,000 individuals twice per week. In a period of 3 months, 6,364 pool-RT-qPCRs tested positive (0.64%) ranging from 0.05% to 2.61% per week. Notably, infections correlated with local SARS-CoV-2 incidences as well as with a school social deprivation index. Moreover, in comparison with the alpha variant, statistical modeling revealed a 31% increase for multiple ([≥]2 children) infections per class following infections with the delta variant5. We conclude that the Lolli-Method is a powerful tool for SARS-CoV-2 surveillance and infection control in schools and daycare facilities.


title: Post-peak dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022

abstract:
BackgroundRapid transmission of the SARS-CoV-2 Omicron variant has led to the highest ever recorded case incidence levels in many countries around the world.

MethodsThe REal-time Assessment of Community Transmission-1 (REACT-1) study has been characterising the transmission of the SARS-CoV-2 virus using RT-PCR test results from self-administered throat and nose swabs from randomly-selected participants in England at ages 5 years and over, approximately monthly since May 2020. Round 17 data were collected between 5 and 20 January 2022 and provide data on the temporal, socio-demographic and geographical spread of the virus, viral loads and viral genome sequence data for positive swabs.

ResultsFrom 102,174 valid tests in round 17, weighted prevalence of swab positivity was 4.41% (95% credible interval [CrI], 4.25% to 4.56%), which is over three-fold higher than in December 2021 in England. Of 3,028 sequenced positive swabs, 2,393 lineages were determined and 2,374 (99.2%) were Omicron including 19 (0.80% of all Omicron lineages) cases of BA.2 sub-lineage and one BA.3 (0.04% of all Omicron) detected on 17 January 2022, and only 19 (0.79%) were Delta. The growth of the BA.2 Omicron sub-lineage against BA.1 and its sub-lineage BA.1.1 indicated a daily growth rate advantage of 0.14 (95% CrI, 0.03, 0.28) for BA.2, which corresponds to an additive R advantage of 0.46 (95% CrI, 0.10, 0.92).

Within round 17, prevalence was decreasing overall (R=0.95, 95% CrI, 0.93, 0.97) but increasing in children aged 5 to 17 years (R=1.13, 95% CrI, 1.09, 1.18). Those 75 years and older had a swab-positivity prevalence of 2.46% (95% CI, 2.16%, 2.80%) reflecting a high level of infection among a highly vulnerable group. Among the 3,613 swab-positive individuals reporting whether or not they had had previous infection, 2,334 (64.6%) reported previous confirmed COVID-19. Of these, 64.4% reported a positive test from 1 to 30 days before their swab date. Risks of infection were increased among essential/key workers (other than healthcare or care home workers) with mutually adjusted Odds Ratio (OR) of 1.15 (95% CI, 1.05, 1.26), people living in large compared to single-person households (6+ household size OR 1.73; 95% CI, 1.44, 2.08), those living in urban vs rural areas (OR 1.24, 95% CI, 1.13, 1.35) and those living in the most vs least deprived areas (OR 1.34, 95% CI, 1.20, 1.49).

ConclusionsWe observed unprecedented levels of infection with SARS-CoV-2 in England in January 2022, an almost complete replacement of Delta by Omicron, and evidence for a growth advantage for BA.2 compared to BA.1. The increase in the prevalence of infection with Omicron among children (aged 5 to 17 years) during January 2022 could pose a risk to adults, despite the current trend for prevalence in adults to decline. (Funded by the Department of Health and Social Care in England.)


title: An assessment of the vaccination of school-aged children in England

abstract:
BackgroundChildren and young persons are known to have a high number of close interactions, often within the school environment, which can facilitate rapid spread of infection; yet for SARS-CoV-2 it is the elderly and vulnerable that suffer the greatest health burden. Vaccination, initially targeting the elderly and vulnerable but later expanded to the entire adult population, has been transformative in the control of SARS-CoV-2 in England. However, early concerns over adverse events and the lower risk associated with infection in younger individuals means that the expansion of the vaccine programme to those under 18 year of age needs to be rigorously and quantitatively assessed.

MethodsHere, using a bespoke mathematical model matched to case and hospital data for England, we consider the potential impact of vaccinating 12-17 and 5-11 year olds. This analysis is reported from an early model (generated in June 2021) that formed part of the evidence base for the decisions in England, and a later model (from November 2021) that benefits from a richer understanding of vaccine efficacy, greater knowledge of the Delta variant wave and uses data on the rate of vaccine administration. For both models we consider the population wide impact of childhood vaccination as well as the specific impact on the age-group targeted for vaccination.

ResultsProjections from June suggested that an expansion of the vaccine programme to those 12-17 years old could generate substantial reductions in infection, hospital admission and deaths in the entire population, depending on population behaviour following the relaxation of control measures. The benefits within the 12-17 year old cohort were less marked, saving between 656 and 1077 (95% prediction interval 281-2260) hospital admissions and between 22 and 38 (95% PI 9-91) deaths depending on assumed population behaviour. For the more recent model, the benefits within this age group are reduced, saving on average 631 (95% PI 304-1286) hospital admissions and 11 (95% PI 5-28) deaths for 80% vaccine uptake, while the benefits to the wider population represent a reduction of 8-10% in hospital admissions and deaths. The vaccination of 5-11 year olds is projected to have a far smaller impact, in part due to the later roll-out of vaccines to this age-group.

ConclusionsVaccination of 12-17 year olds and 5-11 year olds is projected to generate a reduction in infection, hospital admission and deaths for both the age-groups involved and the population in general. For any decision involving childhood vaccination, these benefits needs to be balanced against potential adverse events from the vaccine, the operational constraints on delivery and the potential for diverting resources from other public health campaigns.


title: Correlates of functional physical capacity in physically active older adults: a conceptual-framework-based cross-sectional analysis of social determinants of health and clinical parameters

abstract: This study aimed to explore social determinants of health and health/clinical determinants on two outcomes of functional physical capacity. Therefore, a population-based sample of 327 older adults (69{+/-}7 years; 83.5% women) underwent demographical and clinical questionnaires, risk factors assessments, six-minute walk testing (walking capacity), and handgrip strength testing. Based on multivariable linear regression models, age (-4.05m; - 5.3 to -2.8), being men (71.40m; 50.5 to 92.3), body mass index (-3.88m; -5.6 to -2.1), and quality of life (18.48m; 6.3 to 30.6) remained as predictive variables for walking capacity (R2=30.8%). In the final model for handgrip strength, age (-0.6% kgf; 0.89 to 0.2) and male sex (65.2% kgf; 55.3 to 75.8) remained as predictive variables. Despite exploratory analyses including contextual factors as potential predictors of walking capacity and handgrip strength, only outcomes at the individual levels were associated, either positively or negatively, with the variations presented by this studied sample of older adults.


title: Attitudes Towards Coronavirus (COVID-19) Vaccine and Sources of Information Across Diverse Ethnic Groups in the UK: a Qualitative Study

abstract:
ObjectivesTo explore attitudes and intentions towards COVID-19 vaccination, and influences and sources of information about COVID-19 across diverse ethnic groups (EGs) in the UK.

DesignRemote qualitative interviews and focus groups (FGs) conducted June-October 2020 before UK COVID-19 vaccine approval. Data were transcribed and analysed through inductive thematic analysis.

SettingGeneral public in the community across England and Wales.

Participants100 participants from 19 self-identified EGs with spoken English or Punjabi.

ResultsMistrust and doubt were common themes across all EGs including white British and minority EGs, but more pronounced amongst Bangladeshi, Pakistani, Black ethnicities and Travellers. Many participants shared concerns about perceived lack of information about COVID-19 vaccine safety, efficacy and potential unknown adverse effects. Across EGs participants stated occupations with public contact, older adults and vulnerable groups should be prioritised for vaccination. Perceived risk, social influences, occupation, age, co-morbidities and engagement with healthcare influenced participants intentions to accept vaccination once available; all Jewish FG participants intended to accept, while all Traveller FG participants indicated they probably would not.

Facilitators to COVID-19 vaccine uptake across all EGs included: desire to return to normality and protect health and wellbeing; perceived higher risk of infection; evidence of vaccine safety and efficacy; vaccine availability and accessibility.

COVID-19 information sources were influenced by social factors, culture and religion and included: friends, family; media and news outlets; and research literature. Participants across most different EGs were concerned about misinformation or had negative attitudes towards the media.

ConclusionsDuring vaccination programme roll-out, including boosters, commissioners and vaccine providers should provide accurate information, authentic community outreach, and use appropriate channels to disseminate information and counter misinformation. Adopting a context-specific approach to vaccine resources, interventions and policies and empowering communities has potential to increase trust in the programme.

Article summary: strengths and limitationsO_LIThis is amongst the largest qualitative studies on attitudes to the COVID-19 pandemic in the UK general public across ethnic groups (EGs), ages and religions, adding insights from a broader range of participants.
C_LIO_LIQualitative methodology enabled discussion of participants responses around COVID-19 vaccination, probing to collect rich data to inform recommendations across EGs.
C_LIO_LIMost data collection was undertaken in English, possibly excluding sectors of the population who may access COVID-19 information through different sources due to language.
C_LIO_LIData collection was June-October 2020 before COVID-19 vaccines were licensed. Attitudes are highly responsive to current information around a COVID-19 vaccine, as well as the state of the pandemic and perceived risk. Data were collected prior to much of the intervention work, putting the attitudes and intentions expressed in this study in a context of minimal community engagement and support. This provides a baseline snapshot of attitudes, providing the option to explore and assess the impact of such interventions.
C_LIO_LISocioeconomic data and index of multiple deprivation were not collected, limiting the ability to determine a possible accumulative effect of factors such as socioeconomic status, ethnicity and age.
C_LI


title: Measuring patient centeredness with German language Patient-Reported Experience Measures (PREM) - a systematic review and qualitative analysis according to COSMIN

abstract:
BackgroundPatient centeredness is an integral part of the quality of care. Patient-reported experience measures (PREMs) are assumed to be an appropriate tool to assess patient-centredness. An evaluation of German-speaking PREMs is lacking.

ObjectiveTo perform a systematic review and qualitative analysis of psychometric measurement qualities of German-speaking PREMs.

MethodsA systematic literature search was performed in Medline, PsycInfo, CINHAL, Embase, Cochrane database (last search 9th November 2021) for studies describing generic, surgery-or cancer-specific PREMs. Subsequently, questionnaires that were not in German or for which no German translation exists were excluded. Furthermore, questionnaires, that are for healthcare professionals rather than patients as well as disease-specific questionnaires were excluded. Baseline data for all studies was extracted by two independent reviewers. Psychometric measurement qualities of the questionnaires were assessed according to the COSMIN guidelines.

ResultsIn total, 3457 abstracts were screened, of which 3345 were excluded. The remaining 112 articles contained 51 PREMs, of which 12 were either developed in or translated into German: 8 generic (NORPEQ, PPE-15, PEACS, HCAHPS, QPPS, DUQUE, PEQ-G, Schoenfelder et al.), 4 cancer-specific (EORTC IN-PATSAT32, PSCC-G, Danish National Cancer Questionnaire, SCCC) and no surgery-specific PREM. None of the PREMs covered all 16 domains patient-centeredness. Overall rating of structural validity was adequate only for PEACS and HCAHPS. High ratings for internal consistency were given for NORPEQ, Schoenfelder et al., PSCC-G and the SCCC. Cross-cultural validity for translated questionnaires was adequate only for the PSCC-G, while reliability was adequately assessed only for the EORTC IN-PATSAT32. Due to a lack of measurement gold standard and minimal important change, criterion validity and measurement invariance could not be assessed Most PREMs showed the expected outcomes for hypotheses testing for construct validity.

ConclusionNone of the PREMs has been fully evaluated in German. Based on current evidence, the EORTC IN-PATSAT32 and PSCC-G can be recommended for cancer patients, while HCAHPS, NORPEQ, PPE-15 and PEACS might be used as generic PREMs. Compared to other languages PREM development in German is rudimentary and no comprehensive PREM system is currently available.

RegistrationPROSPERO CRD42021276827

FundingNone

category: health systems and quality improvement


title: Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data

abstract:
BackgroundCo-circulating respiratory pathogens can interfere with or promote each other, leading to important effects on disease epidemiology. Estimating the magnitude of pathogen-pathogen interactions from clinical specimens is challenging because sampling from symptomatic individuals can create biased estimates.

MethodsWe conducted an observational, cross-sectional study using samples collected by the Seattle Flu Study between 11 November 2018 and 20 August 2021. Samples that tested positive via RT-qPCR for at least one of 17 potential respiratory pathogens were included in this study. Semi-quantitative cycle threshold (Ct) values were used to measure pathogen load. Differences in pathogen load between monoinfected and coinfected samples were assessed using linear regression adjusting for age, season, and recruitment channel.

Results21,686 samples were positive for at least one potential pathogen. Most prevalent were rhinovirus (33{middle dot}5%), Streptococcus pneumoniae (SPn, 29{middle dot}0%), SARS-CoV-2 (13.8%) and influenza A/H1N1 (9{middle dot}6%). 140 potential pathogen pairs were included for analysis, and 56 (40%) pairs yielded significant Ct differences (p < 0.01) between monoinfected and co-infected samples. We observed no virus-virus pairs showing evidence of significant facilitating interactions, and found significant viral load decrease among 37 of 108 (34%) assessed pairs. Samples positive with SPn and a virus were consistently associated with increased SPn load.

ConclusionsViral load data can be used to overcome sampling bias in studies of pathogen-pathogen interactions. When applied to respiratory pathogens, we found evidence of viral-SPn facilitation and several examples of viral-viral interference. Multipathogen surveillance is a cost-efficient data collection approach, with added clinical and epidemiological informational value over single-pathogen testing, but requires careful analysis to mitigate selection bias.


title: USA Winter 2021 CoVID-19 Resurgence Post-Christmas Update

abstract:
We have successfully modeled every USA CoVID-19 wave using: O_FD O_INLINEFIG[Formula 1]C_INLINEFIGM_FD(1)C_FD where N (t) is the total number of new CoVID-19 cases above a prior baseline, and tR sets the doubling time tdbl = tR (ln 2). The new parameters {S ;{delta} o} measure mitigation efforts among the uninfected population, with {S > 0} being associated with Social Distancing and vaccinations ; while {{delta}o > 0 }is associated with mask-wearing, which gives a faster [Formula] post-peak drop-off. The predicted pandemic wave end is when N (t) no longer increases.

Using data from 11/15/21-12/30/21, our prior medrxiv.org preprint* showed this initial Omicron CoVID-19 wave had values that matched the initial stage of the prior USA Winter 2020 resurgence {tR {approx}8 05 days ; S {approx} 0 011 / day}, when practically no one was vaccinated. In addition, this initial Winter 2021 wave showed virtually no mask-wearing {{delta}o{approx} x 0 001 10-3 / day}, making it capable of infecting virtually everyone. These parameter values indicated that the Omicron variant was likely evading the vaccines in people who thought they were protected.

As a result, stopping the Omicron CoVID-19 spread must once again rely on enhanced Social Distancing and mask-wearing, just like the initial pandemic wave in March 2020. Analyzing the USA follow-on data from 12/25/21-1/31/22 shows that people did exactly that after the Christmas Holiday season, resulting in the following model parameters and values: O_FD O_INLINEFIG[Formula 2]C_INLINEFIGM_FD(2)C_FD for this wave by itself, with all prior waves subtracted out as a baseline. Combining all the USA CoVID-19 waves gives these updated totals: O_FD O_INLINEFIG[Formula 3]C_INLINEFIGM_FD(3)C_FD assuming no future CoVID-19 Resurgence (with 4 Figures).

*(10.1101_2021.10.15.21265078)


title: The usefulness of D-dimer as a predictive marker for mortality in patients with COVID-19 hospitalized during the first wave in Italy.

abstract:
BackgroundThe coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources.

AimsThe primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality.

MethodsThis was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrells C-index and model calibration was assessed using a calibration plot.

ResultsOut of 1049 patients, 501 patients had evaluable data. Of these 501 patients, 96 died. The cumulative incidence of in-hospital mortality within 30 days was 20% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot.

ConclusionThe predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.


title: Epigenetic clock acceleration is linked to age-at-onset of idiopathic and LRRK2 Parkinson's disease

abstract: Parkinsons disease is a clinically and genetically heterogeneous movement disorder with highly variable age-at-onset. DNA methylation (DNAm) age is an epigenetic clock that could reflect biological aging. Studies of DNAm-age acceleration (difference between DNAm-age and chronological age) are pertinent to neurodegenerative diseases (e.g., Parkinsons disease), for which aging is the strongest risk-factor. We assessed DNAm-age in idiopathic Parkinsons disease (n=96) and a longitudinal LRRK2 cohort at four time-points over a 3-year period (n=220), including manifesting (n=91) and non-manifesting (n=129) G2019S-carriers. A highly variable age-at-onset was observed in both the idiopathic cohort (26-77 years) and manifesting G2019S-carriers (39-79 years). Increased DNAm-age acceleration was significantly associated with younger onset in idiopathic and LRRK2-related Parkinsons disease, suggesting that every 5-year increase in DNAm-age acceleration is linked to about 6-year earlier onset. At an individual level, DNAm-age acceleration remained steady over a 3-year period for most G2019S-carriers, indicating that it might serve as a stable biomarker of biological aging. Future studies should evaluate the stability of DNAm-age acceleration over longer time-periods, especially for phenoconverters from non-manifesting to manifesting subjects. In conclusion, DNAm-age acceleration is linked to disease onset, and could be used in disease-modifying clinical trials of prodromal Parkinsons disease.


title: Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults

abstract: As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.


title: Optical Genome Mapping And Single Nucleotide Polymorphism Microarray: An Integrated Approach For Investigating Challenging Cases Of Products Of Conception.

abstract: Conventional cytogenetic analysis of products of conception (POC) is of limited utility because of failed cultures, microbial and maternal cell contamination (MCC). Optical genome mapping (OGM) is an emerging technology that has the potential to replace conventional cytogenetic methods. The use of OGM precludes the requirement for culturing (and related microbial contamination). However, a high percentage of MCC impedes a definitive diagnosis, which can be addressed by an additional pre-analytical quality control step that includes histological assessment of H&E stained slides from FFPE tissue with macro-dissection for Chorionic villi to enrich fetal tissue component for Single nucleotide polymorphism (SNP) microarray analysis. An internal audit of POC cases subjected to karyotype-only analysis showed a low yield on clinically actionable information that contributed to patient care. To improve the diagnostic yield, an integrated workflow was devised that included MCC characterization of POC tissue, followed by OGM for MCC negative cases or SNPM with histological assessment for MCC positive cases. A result was obtained in 93% (29/31) cases with a diagnostic yield of 45.1% (14/31) with proposed workflow compared to 9.6% (3/31) and 6.4% (2/31) with routine workflow, respectively. The integrated workflow with these technologies demonstrates the clinical utility and higher diagnostic yield in evaluating POC specimens.

category: genetic and genomic medicine


title: Best Practices on Big Data Analytics to Address Sex-Specific Biases in our Understanding of the Etiology, Diagnosis and Prognosis of Diseases

abstract: A bias in health research to favor understanding of diseases as they present in men can have a grave impact on the health of women. This paper reports on a conceptual review of the literature that used machine learning or NLP techniques to interrogate big data for identifying sex-specific health disparities. We searched Ovid MEDLINE, Embase, and PsycINFO in October 2021 using synonyms and indexing terms for (1) "women" or "men" or "sex," (2) "big data" or "artificial intelligence" or "NLP", and (3) "disparities" or "differences." From 902 records, 22 studies met the inclusion criteria and were analyzed. Results demonstrate that the inclusion by sex is inconsistent and often unreported, although the inclusion of men in the included studies is disproportionately less than women. Even though AI and NLP techniques are widely applied in health research, few studies use them to take advantage of unstructured text to investigate sex-related differences or disparities. Researchers are increasingly aware of sex-based data bias, but the process towards correction is slow. We reflected on what would be the best practices on using big data analytics to address sex-specific biases in understanding the etiology, diagnosis, and prognosis of diseases.

category: health informatics


title: ARTIFICIAL INTELLIGENCE TOOLS FOR EFFECTIVE MONITORING OF POPULATION AT DISTANCE DURING COVID-19 PANDEMIC. RESULTS FROM AN ITALIAN PILOT FEASIBILITY STUDY (RICOVAI-19 STUDY).

abstract:
In order to reduce the burden on healthcare systems and in particular to support an appropriate way to the Emergency Department (ED) access, home tele-monitoring patients was strongly recommended during the COVID-19 pandemic. Furthermore, paper from numerous groups has shown the potential of using data from wearable devices to characterize each individuals unique baseline, identify deviations from that baseline suggestive of a viral infection, and to aggregate that data to better inform population surveillance trends. However, no evidence about usage of Artificial Intelligence (AI) applicatives on digitally data collected from patients and doctors exists. With a growing global population of connected wearable users, this could potentially help to improve the earlier diagnosis and management of infectious individuals and improving timeliness and precision of tracking infectious disease outbreaks.

During the study RICOVAI-19 (RICOVero ospedaliero con strumenti di Artificial Intelligence nei pazienti con COVid-19) performed in the Marche Region, Italy, we evaluated 129 subjects monitored at home in a six-months period between March 22, 2021 and October 22, 2021. During the monitoring, personal on demand health technologies were used to collect clinical and vital data in order to feed the database and the machine learning engine. The AI output resulted in a clinical stability index (CSI) which enables the system to deliver suggestions to the population and doctors about how intervene.

Results showed the beneficial influence of CSI for predicting clinical classes of subjects and identifying who of them need to be admitted at ED. The same pattern of results was confirming the alert included in the decision support system in order to request further testing or clinical information in some cases.

In conclusion, our study does support a high impact of AI tools on COVID-19 outcomes to fight this pandemic by driving new approaches to public awareness.


title: Comparative study of immunogenicity and safety of Gam-COVID-Vac and Sinopharm BBIBP-CorV vaccines in Belarus

abstract:
IntroductionLack of comparative studies on efficiency of a broad range of COVID19 vaccines leads to lower levels of adoption and subsequent lower total immunity in several regions, including Republic of Belarus. This clinical study captures and transparently demonstrates varying immunogenic responses to Sputnik V and Sinopharm vaccines.

Aim of this study wasto compare the immunogenicity and reactogenicity of Sputnik V (Gam-COVID-Vac), RF and Sinopharm (BBIBP-CorV), PRC vaccines in vaccinated individuals.

Materials and MethodsA total of 60 adults participated the study. The immune response after vaccination was assessed using enzyme immunoassay. IgG levels measured in all participants at three time points: before the vaccination, 42 days after the first vaccine dose, and 6 months after the first vaccine dose. The results of the SARS-CoV-2 antibody test is quantified according to the WHO First International Standard (NIBSC code:20/136) and expressed in international units (BAU/ml).

ResultsThe study participants were divided into two groups, where 30 people (50%) were vaccinated with Sputnik V (Gam-COVID-Vac), and 30 people were vaccinated with Sinopharm (BBIBP-CorV), with no gender differences in the groups. The IgG levels at 42 days after the first vaccine dose were: Sputnik V (Gam-COVID-Vac)(42 days): Me=650.4 (642.2-669.4); Sinopharm (BBIBP-CorV)(42 days): Me=376.5 (290.9-526.4); p<0,001). The IgG levels at 6 months after the first vaccine dose were: Sputnik V (Gam-COVID-Vac)(6 months) Me=608.7 (574.6-647.1); Sinopharm (BBIBP-CorV)(6 months): Me=106.3 (78.21-332.4); p<0,001). Reactions after vaccination appeared in 27 vaccinated individuals (45%).

ConclusionThe study showed that Sputnik V (Gam-COVID-Vac) vaccine was more immunogenic than Sinopharm (BBIBP-CorV) vaccine. IgG levels in vaccinated individuals who previously recovered from SARS-CoV-2 infection ("hybrid immunity") were higher than in SARS-CoV-2 naive individuals. Reactions after vaccines administration were mild to moderate.


title: Emulation of a target trial from observational data to compare effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for early treatment of non-hospitalized patients with COVID-19

abstract:
ObjectivesComparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta.

MethodsAllocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7.

Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period.

ResultsCOVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% -1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharingeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7.

ConclusionsIn a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.


title: Impacts of the COVID-19 pandemic on future seasonal influenza epidemic

abstract: Seasonal influenza viruses typically cause annual epidemics worldwide infecting 5-15% of the human population1. However, during the first two years of the COVID-19 pandemic, seasonal influenza virus circulation was unprecedentedly low with very few reported infections2. The lack of immune stimulation to influenza viruses during this time, combined with waning antibody titres to previous influenza virus infections, could lead to increased susceptibility to influenza in the coming seasons and to larger and more severe epidemics when infection prevention measures against COVID-19 are relaxed3,4. Here, based on serum samples from 165 adults collected longitudinally before and during the pandemic, we show that the waning of antibody titres against seasonal influenza viruses during the first two years of the pandemic is likely to be negligible. Using historical influenza virus epidemiological data from 2003-2019, we also show that low country-level prevalence of each influenza subtype over one or more years has only small impacts on subsequent epidemic size. These results suggest that the risks posed by seasonal influenza viruses remained largely unchanged during the first two years of the COVID-19 pandemic and that the sizes of future seasonal influenza virus epidemics will likely be similar to those observed before the pandemic.


title: Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine

abstract: The skin at the site of HSV-2 reactivation is enriched for HSV-2 specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells we studied skin biopsies and HSV-2-reactive CD4+ T cells from peripheral blood mononuclear cells (PBMCs) by T-cell receptor (TCR) sequencing before and after vaccination with a replication-incompetent whole virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ T cell sequences from PBMCs increased from a median of 0.03% (range 0-0.09%) to 0.6% (range 0-1.3%) of the total skin TCR repertoire after the first vaccine dose. We found sustained expansion after vaccination in unique, skin-based T-cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. While detection of skin clonotypes in the blood was related to abundance in the skin it was not related to expansion after vaccination. In one participant a switch in immunodominance was observed after vaccination with the emergence of a newly dominant TCRa/b pair in skin that was not detected in blood. We confirmed that the newly dominant clonotype was derived from an HSV-specific CD4+ T cell by creation of a synthetic TCR in a Jurkat-based cell line with a NR4A1-mNeonGreen reporter system. Our data indicate that the skin in areas of HSV-2 reactivation possesses an oligoclonal TCR repertoire that is distinct from the circulation with prominent clonotypes infrequently detected in the circulation by standard methods. Defining the influence of therapeutic vaccination on the HSV-2-specific TCR repertoire requires tissue-based evaluation.


title: SARS-CoV-2 Omicron symptomatic infections in previously infected or vaccinated South African healthcare workers

abstract:
We investigated Omicron infections among healthcare workers (HCW) presenting with symptoms of SARS-CoV-2 infection and evaluated the protective effect of vaccination or prior infection.

Between 24th November and 31st December 2021, HCW in Johannesburg, South Africa, were tested for SARS-CoV-2 infection by Nucleic Acid Amplification Test (NAAT). Blood samples collected either at the symptomatic visit or within 3-months prior, were tested for spike protein immunoglobulin G (IgG).

Overall, 433 symptomatic HCW were included in the analysis, with 190 (43.9%) having an Omicron infection; 69 (16.7%) were unvaccinated and 270 (62.4%) received a single dose of Ad26.COV.2 vaccine. There was no difference in the odds of identifying Omicron between unvaccinated and Ad26.COV.2 vaccinated HCW (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI]: 0.46, 1.43). One-hundred and fifty-four (35.3%) HCW had at least one SARS-CoV-2 NAAT-confirmed prior infection; these had lower odds of Omicron infection compared with those without past infection (aOR 0.55, 95%CI: 0.36, 0.84). Anti-spike IgG concentration of 1549 binding antibody unit/mL was suggestive of significant reduction in the risk of symptomatic Omicron infection.

We found high reinfection and vaccine breakthrough infection rates with the Omicron variant among HCW. Prior infection and high anti-spike IgG concentration were protective against Omicron infection.


title: Effects of cannabidiol on activated immune-inflammatory pathways in major depressive patients and healthy controls.

abstract:
BackgroundMajor depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). Cannabidiol (CBD) is a phytocannabinoid isolated from the cannabis plant which was reported to have antidepressant-like and anti- inflammatory effects. The aim of the present study is to examine the effects of CBD on IRS, CIRS, M1, T helper (Th)-1, Th-2, Th-17, T regulatory (Treg) profiles, and growth factors in depression and healthy controls.

MethodsCulture supernatant of stimulated (5 g/mL of PHA and 25 g/mL of LPS) whole blood of 30 depressed patients and 20 controls was assayed for cytokines using the LUMINEX assay. The effects of three CBD concentrations (0.1 {micro}g/ml, 1 {micro}g/mL, and 10 {micro}g/mL) were examined.

ResultsDepression was characterized by significantly increased Th-1, Th-2, Th-17, Treg, IRS, CIRS and neurotoxicity profiles. CBD 0.1 {micro}g/mL did not have any immune effects. CBD 1.0 {micro}g/mL decreased CIRS activities but increased growth factor production, while CBD 10.0 {micro}g/mL suppressed Th-1, Th-17, IRS, CIRS, and a neurotoxicity profile and enhanced T cell growth and growth factor production. CBD 1.0 to 10.0 {micro}g/mL dose-dependently decreased sIL- 1RA, IL-8, IL-9, IL-10, IL-13, CCL11, G-CSF, IFN-{gamma}, CCL2, CCL4, and CCL5, and increased IL-1{beta}, IL-4, IL-15, IL-17, GM-CSF, TNF-, FGF, and VEGF.

ConclusionCBD has very complex immunomodulatory effects which depend on the CBD dose. CBD does not normalize the activated immune profiles observed in depression while higher concentrations can worsen inflammatory processes.

category: allergy and immunology


title: The Relevance of Lactate Levels in Acute Seizure

abstract:
IntroductionSeizures can result in profound elevations of serum lactate. A paucity of investigation into whether lactate levels in these patients is associated with increased mortality. We sought to evaluate the significance in patients presenting with a seizure and elevated lactate.

MethodsThis is a retrospective study involving patients presenting to the Emergency Department (ED) with a diagnosis of seizure from September 1st, 2016 until March 31st, 2018. Those with normal serum lactate (< 2mmol/L) were compared with patients that had an elevated serum lactate ([≥] 2mmol/L).

ResultsPatients with normal serum lactate levels had a significantly longer length of stay in the ED (60 minutes p = 0.04) when compared to those with elevated serum lactate levels. Additionally, a higher percentage of patients with elevated serum lactate received intravenous fluids in the ED (54.69% vs. 35.4%, P=0.01). There was no significant difference in other measured variables.

ConclusionThis study illustrates that serum lactate levels do not directly correlate with indicators of disease severity or outcomes when elevated secondary to seizure. However, patients with normal serum lactate levels had a longer length of stay in the ED.

category: emergency medicine


title: Using multiple sampling strategies to estimate SARS-CoV-2 epidemiological parameters from genomic sequencing data

abstract: SARS-CoV-2 virus genomes are currently being sequenced at an unprecedented pace. The choice of viral sequences used in genetic and epidemiological analysis is important as it can induce biases that detract from the value of these rich datasets. This raises questions about how a set of sequences should be chosen for analysis, and which epidemiological parameters derived from genomic data are sensitive or robust to changes in sampling. We provide initial insights on these largely understudied problems using SARS-CoV-2 genomic sequences from Hong Kong and the Amazonas State, Brazil. We consider sampling schemes that select sequences uniformly, in proportion or reciprocally with case incidence and which simply use all available sequences (unsampled). We apply Birth-Death Skyline and Skygrowth methods to estimate the time-varying reproduction number (Rt) and growth rate (Rt) under these strategies as well as related R0 and date of origin parameters. We compare these to estimates from case data derived from EpiFilter, which we use as a reference for assessing bias. We find that both Rt and Rt are sensitive to changes in sampling whilst R0 and the date of origin are relatively robust. Moreover, we find that the unsampled datasets, which reflect an opportunistic sampling scheme, engender the most biased Rt and Rt estimates for both our Hong Kong and Amazonas case studies. We highlight that sampling strategy choices may be an influential yet neglected component of sequencing analysis pipelines. More targeted attempts at genomic surveillance and epidemic analyses, particularly in resource-poor settings with limited sequencing capabilities, are necessary to maximise the informativeness of virus genomic datasets.


title: Using Digital Humanities for Understanding COVID-19: Lessons from Digital History about earlier Coronavirus Pandemic

abstract:
BackgroundAt the time of the COVID-19 epidemic, it is useful to look at what lessons (digital) history can give us about the past pandemics and dealing with them. We show that the Google Ngram (GNV) can discover hidden patterns in history and, therefore, can be used as a window into history. By using the approach of Digital Humanities, we analysed the epidemiological literature on the development of the Russian flu pandemic for hints on how the COVID-19 might develop in the following years.

ObjectiveOur study is searching for evidence that the COVID-19 is not a unique phenomenon in human history. We are testing the hypothesis that the flu-like illness that caused loss of taste and smell in the late 19th century (Russian flu) was caused by a coronavirus. We are aware that it is difficult to formulate a hypothesis for a microbiological aetiology of a pandemic that occurred 133 years ago. But differentiating an influenza virus infection from a COVID-19 patient purely on the clinical ground is difficult for a physician because the symptoms overlap. The most crucial observation of similarities between the Russian flu pandemic and COVID-19 is the loss of smell and taste (anosmia and ageusia). The objective was to calculate the ratio of increasing to decreasing trends in the changes in frequencies of the selected words representing symptoms of the Russian flu and COVID-19.

MethodsThe primary methodological concept of our approach is to analyse the ratio of increasing to decreasing trends in the changes in frequencies of the selected words representing symptoms of the Russian flu and COVID-19 with the Google NGram analytical tool. Initially, keywords were chosen that are specific and common for the Russian flu and COVID-19. We show the graphic display on the Y-axis what percentage of words in the selected corpus of books (collective memory) over the years (X-axis) make up the word. To standardise the data, we requested the data from 1800 to 2019 in English, German and Russian (to 2012) book corpora and focused on the ten years before, during and after the outbreak of the Russian flu. We compared this frequency index with "non-epidemic periods" to test the models analytical potential and prove the signification of the results.

ResultsThe COVID-19 is not a unique phenomenon because the Russian flu was probably the coronavirus infection. Results show that all the three analysed book corpora (including newspapers and magazines) show the increase in the mention of the symptoms "loss of smell" and "loss of taste" during the Russian flu (1889-1891), which are today undoubtedly proven to be key symptoms of COVID-19.

In the English corpus, the frequency rose from 0.0000040433 % in 1880 to 0.0000047123 % in 1889. The frequency fell sharply after the pandemic stopped in 1900 (0.0000033861%). In the Russian corpus, the frequency rises from 0 % in 1880 to 0.0000004682 % in 1889 and decreased rapidly after the pandemic (1900 = 0.0000011834 %). In the German corpus, the frequency rose from 0.0000014463 % in 1880 to 0.0000018015 % in 1889 and decreased also rapidly after the pandemic (1900 = 0.0000016600 %).

According to our analysis of historical records with the approach of GNV, 1) the  natural length of a pandemic is two to five years; 2) the pandemic stops on their own; 3) the viruses weaken over time; 4) the so-called "herd immunity" is not necessary to stop the pandemic; 5) history has shown that a significant crisis does not need to occur after the COVID-19 pandemic.

ConclusionAccording to our study, the Google Books Ngram Viewer (GNV) gives a clear evidence of the influence that social changes have on word frequency. The results of this study open a discussion on the usefulness of the Google Ngram insights possibilities into past socio-cultural development, i.e. epidemics and pandemics that can serve as lessons for today. We showed hidden patterns of conceptual trends in history and their relationships with current development in the case of the pandemic COVID-19.

The benefit of this method could help complement historical medical records, which are often woefully incomplete. However, this method comes with severe limitations and can be useful only under cautious handling and testing. Despite the numerous indications we have shown, we are aware that this thesis still cannot be confirmed and that it is necessary to require further historical and medical research.