title: Deafferentation of Olfactory Bulb in Subjects Dying with COVID-19

abstract: There have been clinical descriptions of diverse neurological effects in COVID-19 disease, involving up to 36% of patients. It appears likely that most of these are not caused by viral brain invasion but by systemic accompaniments of critical illness such as coagulopathy, deleteriously upregulated immune response, autoimmune mechanisms, hypoxia or multiorgan failure. Anosmia or hyposmia is present in a majority of COVID-19 patients, and there is early and severe involvement of the nasopharyngeal mucosa and olfactory epithelium. Preliminary studies by our group have found massive gene expression changes in olfactory bulb, but the magnitude of these changes are not different between subjects with detectable versus non-detectable olfactory bulb SARS-CoV-2 RNA. As spontaneous discharge of olfactory epithelial afferents dictates intra-olfactory bulb neurophysiological activity and connectivity, we hypothesized that olfactory bulb deafferentation during COVID-19 is responsible for a large fraction of our observed olfactory bulb transcriptional changes. As the olfactory marker protein (OMP-1) is a specific marker of olfactory epithelial afferents to the olfactory bulb and is severely depleted in animal model lesions of olfactory epithelium, we quantified OMP-1-immunoreactivity in the olfactory bulb of subjects dying with or without COVID-19. Additionally, we quantified olfactory bulb tyrosine hydroxylase (TH), which is often also reduced after olfactory epithelium lesions, and SNAP-25, a pan-synaptic marker. COVID-19 cases (n = 18) were generally elderly and were not significantly different in age or gender distribution from the non-COVID-19 cases (n = 28). Both COVID-19 and non-COVID-19 cases had a wide range of neuropathological diagnoses. The area occupied by OMP-1 immunoreactivity in COVID-19 cases was significantly less, about 60% of that in control cases but amongst subjects with COVID-19, there was no significant difference between OBT-SARS-CoV-2-PCR-positive and negative cases. There were no significant group differences for TH or SNAP-25, supporting a selective effect for OMP-1. We suggest that olfactory dysfunction, and some of the COVID-19-associated transcriptional changes that we have reported for the olfactory bulb and amygdala, may be due to olfactory bulb deafferentation and subsequent transsynaptic effects. Additionally, animal models of olfactory bulb deafferentation or bulbectomy indicate a possibility for widespread changes in interconnected brain regions, providing a possible substrate for diverse post-acute COVID-19 neurological sequelae.

category: neurology


title: Rapid increase in Omicron infections in England during December 2021: REACT-1 study

abstract:
BackgroundThe highest-ever recorded numbers of daily severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in England has been observed during December 2021 and have coincided with a rapid rise in the highly transmissible Omicron variant despite high levels of vaccination in the population. Although additional COVID-19 measures have been introduced in England and internationally to contain the epidemic, there remains uncertainty about the spread and severity of Omicron infections among the general population.

MethodsThe REal-time Assessment of Community Transmission-1 (REACT-1) study has been monitoring the prevalence of SARS-CoV-2 infection in England since May 2020. REACT-1 obtains self-administered throat and nose swabs from a random sample of the population of England at ages 5 years and over. Swabs are tested for SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) and samples testing positive are sent for viral genome sequencing. To date 16 rounds have been completed, each including [~]100,000 or more participants with data collected over a period of 2 to 3 weeks per month. Socio-demographic, lifestyle and clinical information (including previous history of COVID-19 and symptoms prior to swabbing) is collected by online or telephone questionnaire. Here we report results from round 14 (9-27 September 2021), round 15 (19 October - 05 November 2021) and round 16 (23 November - 14 December 2021) for a total of 297,728 participants with a valid RT-PCR test result, of whom 259,225 (87.1%) consented for linkage to their NHS records including detailed information on vaccination (vaccination status, date). We used these data to estimate community prevalence and trends by age and region, to evaluate vaccine effectiveness against infection in children ages 12 to 17 years, and effect of a third (booster) dose in adults, and to monitor the emergence of the Omicron variant in England.

ResultsWe observed a high overall prevalence of 1.41% (1.33%, 1.51%) in the community during round 16. We found strong evidence of an increase in prevalence during round 16 with an estimated reproduction number R of 1.13 (1.06, 1.09) for the whole of round 16 and 1.27 (1.14, 1.40) when restricting to observations from 1 December onwards. The reproduction number in those aged 18-54 years was estimated at 1.23 (1.14, 1.33) for the whole of round 16 and 1.41 (1.23, 1.61) from 1 December. Our data also provide strong evidence of a steep increase in prevalence in London with an estimated R of 1.62 (1.34, 1.93) from 1 December onwards and a daily prevalence reaching 6.07% (4.06%, 9.00%) on 14 December 2021. As of 1 to 11 December 2021, of the 275 lineages determined, 11 (4.0%) corresponded to the Omicron variant. The first Omicron infection was detected in London on 3 December, and subsequent infections mostly appeared in the South of England. The 11 Omicron cases were all aged 18 to 54 years, double-vaccinated (reflecting the large numbers of people who have received two doses of vaccine in this age group) but not boosted, 9 were men, 5 lived in London and 7 were symptomatic (5 with classic COVID-19 symptoms: loss or change of sense of smell or taste, fever, persistent cough), 2 were asymptomatic, and symptoms were unknown for 2 cases. The proportion of Omicron (vs Delta or Delta sub-lineages) was found to increase rapidly with a daily increase of 66.0% (32.7%, 127.3%) in the odds of Omicron (vs. Delta) infection, conditional on swab positivity. Highest prevalence of swab positivity by age was observed in (unvaccinated) children aged 5 to 11 years (4.74% [4.15%, 5.40%]) similar to the prevalence observed at these ages in round 15. In contrast, prevalence in children aged 12 to 17 years more than halved from 5.35% (4.78%, 5.99%) in round 15 to 2.31% (1.91%, 2.80%) in round 16. As of 14 December 2021, 76.6% children at ages 12 to 17 years had received at least one vaccine dose; we estimated that vaccine effectiveness against infection was 57.9% (44.1%, 68.3%) in this age group. In addition, the prevalence of swab positivity in adults aged 65 years and over fell by over 40% from 0.84% (0.72%, 0.99%) in round 15 to 0.48% (0.39%,0.59%) in round 16 and for those aged 75 years and over it fell by two-thirds from 0.63% (0.48%,0.82%) to 0.21% (0.13%,0.32%). At these ages a high proportion of participants (>90%) had received a third vaccine dose; we estimated that adults having received a third vaccine dose had a three- to four-fold lower risk of testing positive compared to those who had received two doses.

ConclusionA large fall in swab positivity from round 15 to round 16 among 12 to 17 year olds, most of whom have been vaccinated, contrasts with the continuing high prevalence among 5 to 11 year olds who have largely not been vaccinated. Likewise there were large falls in swab positivity among people aged 65 years and over, the vast majority of whom have had a third (booster) vaccine dose; these results reinforce the importance of the vaccine and booster campaign. However, the rapidly increasing prevalence of SARS-CoV-2 infections in England during December 2021, coincident with the rapid rise of Omicron infections, may lead to renewed pressure on health services. Additional measures beyond vaccination may be needed to control the current wave of infections and prevent health services (in England and other countries) from being overwhelmed.

SummaryThe unprecedented rise in SARS-CoV-2 infections is concurrent with rapid spread of the Omicron variant in England and globally. We analysed prevalence of SARS-CoV-2 and its dynamics in England from end of November to mid-December 2021 among almost 100,000 participants from the REACT-1 study. Prevalence was high during December 2021 with rapid growth nationally and in London, and of the proportion of infections due to Omicron. We observed a large fall in swab positivity among mostly vaccinated older children (12-17 years) compared with unvaccinated younger children (5-11 years), and in adults who received a third vs. two doses of vaccine. Our results reiterate the importance of vaccination and booster campaigns; however, additional measures may be needed to control the rapid growth of the Omicron variant.

category: epidemiology


title: Exploration of attitudes regarding uptake of COVID-19 vaccines among vaccine hesitant adults in the UK: A qualitative analysis.

abstract:
BackgroundThe aim of this work was to explore barriers and facilitators to uptake of COVID-19 vaccines and to explore views and reactions to efforts to improve vaccine uptake among those who were vaccine hesitant.

MethodsSemi-structured interviews were conducted with people between the age of 18-29 years who had not had a COVID-19 vaccine, and those between 30-49 years who had not received a second dose of a COVID-19 vaccine (more than 12 weeks after receiving a first).

ResultsA total of 70 participants took part in the study, 35 participants had received one dose of the vaccine, and 35 had not received any vaccine.

Participants described a possible willingness to be vaccinated to keep themselves and those around them safe, and to avoid restrictions and return to normal. Barriers to uptake included: 1) perceived lack of need for COVID-19 vaccinations, 2) concerns about the efficacy of vaccinations, 3) concerns about safety, and 4) access issues. Uptake appeared to be influenced by the age and health status of the individual, trust in government and knowledge and understanding of science. Introduction of vaccine passes may provide a motive for having a vaccine but may also be viewed as coercive.

ConclusionParticipants were hesitant, rather than opposed, and had questions about their need for, and the safety and efficacy of the vaccine. Young people did not consider themselves to be at risk of becoming ill from COVID-19, did not think the vaccination was effective in preventing infection and transmission, and did not think sufficient research had been conducted with regard to the possible long-term side-effects. These concerns were exacerbated by a lack of trust in the government, and misunderstanding of science. In order to promote uptake, public health campaigns should focus on the provision of information from trusted sources that carefully explains the benefits of vaccination and addresses safety concerns more effectively. To overcome inertia in people with low levels of motivation to be vaccinated, appointments must be easily accessible.

category: public and global health


title: Transcriptome deregulation of peripheral monocytes in GBA-related Parkinson's disease

abstract:
BackgroundGenetic mutations in the beta-glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinsons disease (PD). The function of the GBA gene is at the crossroads between the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated.

Methodswe characterized the transcriptomic profiles of circulating monocytes and whole blood in a population of patients with PD and healthy controls (CTRL) with (PD/GBA and CTRL/GBA) and without GBA variants (iPD and CTRL) (monocytes: n = 56 iPD, 66 CTRL, 23 PD/GBA, 13 CTRL/GBA; whole blood: n = 616 iPD, 362 CTRLs, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathways enrichment analysis, and outliers detections were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy.

ResultsWe observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, GBA-PD showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing (i.e. SNCA, LMNA). Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels.

ConclusionsOverall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

category: genetic and genomic medicine


title: Neutralising antibody activity against SARS-CoV-2 variants, including Omicron, in an elderly cohort vaccinated with BNT162b2

abstract: SARS-CoV-2 variants threaten the effectiveness of tools we have developed to mitigate against serious COVID-19. This is especially true in clinically vulnerable sections of society including the elderly. Using sera from BNT162b2 (Pfizer-BioNTech) vaccinated individuals aged between 70 and 89 (vaccinated with two doses 3-weeks apart) we examined the neutralising antibody (nAb) response to wildtype SARS-CoV-2. Between 3 and 20-weeks post 2nd dose, nAb titres dropped 4.9-fold to a median titre of 21.3 (ND80) with 21.6% of individuals having no detectable nAbs at the later time point. Experiments examining the neutralisation of twenty-one different SARS-CoV-2 variant spike proteins confirmed a significant potential for antigenic escape, especially for the Omicron (BA.1), Beta (B.1.351), Delta (B.1.617.2), Theta (P.3), C.1.2 and B.1.638 variants. Interestingly, however, the recently-emerged sub-lineage AY.4.2 was more efficiently neutralised than parental Delta pseudotypes. Combining pseudotype neutralisation with specific receptor binding domain (RBD) ELISAs we confirmed that changes to position 484 in the spike RBD were predominantly responsible for SARS-CoV-2 nAb escape, although the effect of spike mutations is both combinatorial and additive. Lastly, using sera from the same individuals boosted with a 3rd dose of BNT162b2 we showed that high overall levels of neutralising antibody titre can provide significant levels of cross-protection against Omicron. These data provide evidence that SARS-CoV-2 neutralising antibodies wane over time and that antigenically variable SARS-CoV-2 variants are circulating, highlighting the importance of ongoing surveillance and booster programmes. Furthermore, they provide important data to inform risk assessment of new SARS-CoV-2 variants, such as Omicron, as they emerge.

category: infectious diseases


title: Decreased hydraulic forces are incrementally associated with survival beyond conventional measures of diastolic dysfunction

abstract:
AIMSDecreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this study was to determine the association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival.

METHODS AND RESULTSPatients (n=11,734, median [interquartile range] 3.9 [2.4-5.0] years follow-up, 1,213 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) [≥]50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e, left atrial volume index, and LVEF (multivariable global R2=0.15, p<0.001), and not associated with e and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic [95% confidence interval] 0.645 [0.629-0.662] vs 0.607 [0.592-0.623], p<0.001) and E/e (0.639 [0.623-0.655] vs 0.621 [0.604-0.637], p<0.001), respectively.

CONCLUSIONDecreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.

category: cardiovascular medicine


title: Decreased Diastolic Hydraulic Forces Incrementally Associate With Survival Beyond Conventional Measures of Diastolic Dysfunction


title: Single nucleus RNA-sequencing reveals altered intercellular communication and dendritic cell activation in nonobstructive hypertrophic cardiomyopathy

abstract:
End stage, nonobstructive hypertrophic cardiomyopathy (HCM) is an intractable condition with no disease-specific therapies. To gain insights into the pathogenesis of nonobstructive HCM, we performed single nucleus RNA-sequencing (snRNA-seq) on human HCM hearts explanted at the time of cardiac transplantation and organ donor hearts serving as controls. Differential gene expression analysis revealed 64 differentially expressed genes linked to specific cell types and molecular functions. Analysis of ligand-receptor pair gene expression to delineate potential intercellular communication revealed significant reductions in expressed ligand-receptor pairs affecting the extracellular matrix, growth factor binding, peptidase regulator activity, platelet-derived growth factor binding and protease binding in the HCM tissue. Changes in Integrin-{beta}1 receptor expression were responsible for many changes related to extracellular matrix interactions, by increasing in dendritic, smooth muscle and pericyte cells while decreasing in endothelial and fibroblast cells, suggesting potential mechanisms for fibrosis and microvascular disease in HCM and a potential role for dendritic cells. In contrast, there was an increase in ligand-receptor pair expression associated with adenylate cyclase binding, calcium channel molecular functions, channel inhibitor activity, ion channel inhibitor activity, phosphatase activator activity, protein kinase activator activity and titin binding, suggesting important shifts in various signaling cascades in nonobstructive, end stage HCM.

Brief summaryEnd stage, nonobstructive human HCM is associated with altered intercellular communication and dendritic cell activation, providing novel insights into potential disease mechanisms.


title: Tracking community infection dynamics of COVID-19 by monitoring SARS-CoV-2 RNA in wastewater, counting positive reactions by qPCR

abstract:
Wastewater-based epidemiology has proved useful for monitoring the COVID-19 infection dynamics in communities. However, in some countries, low concentrations of SARS-CoV-2 RNA in wastewater make this difficult. Getting meaningful information from wastewater-based epidemiology in regions of low prevalence remains a key challenge. Here we used real-time reverse-transcription PCR (RT-qPCR) to monitor SARS-CoV-2 RNA in wastewater from October 2020 to February 2021 during the third wave of the COVID-19 outbreak in Japan. Viral RNA was below the limit of quantification in all samples. However, by counting the positive reactions in repeated qPCR of each sample, we found that the ratio of positive reactions to all tests in wastewater was significantly correlated with the number of clinically confirmed cases by the date of symptom onset during periods of both increasing and decreasing infection. Time-step analysis indicated that COVID-19 patients excreted large amounts of virus in their feces 2 days either side of symptom onset, which wastewater surveillance could detect. The positive count method is thus useful for tracing COVID-19 dynamics in regions of low prevalence.

HighlightsO_LIPositive ratio by repeated qPCR of low target-molecule numbers correlated with number expected from Poisson distribution.
C_LIO_LIPositive ratio by repeated RT-qPCR of SARS-CoV-2 RNA in wastewater tracked the infection dynamics of COVID-19 in a region of low prevalence.
C_LIO_LIPositive ratios correlated with number of new cases by date of symptom onset.
C_LIO_LICOVID-19 patients might excrete more virus in their feces in the period from 2 days before to 2 days after symptom onset.
C_LI


title: Diversity in antibody titer at an average of 87 days after the second dose of BNT162b2 mRNA coronavirus disease 2019 vaccine: data from a predominantly elderly population in a practice in Tokyo

abstract: It is very important for the elderly, who tend to have serious COVID-19 infection and high mortality rates, to maintain sufficient immunity. We reviewed the medical charts of predominantly elderly population to obtain the data on serum anti-SARS-CoV-2S antibody titer after complete vaccination with the BNT162b2 mRNA vaccine (two doses) and evaluated the background factors associated with the titer. We enrolled 230 participants (101 men and 129 women). Their average age was 71.9 (SD 12.5) years, and median was 72 years. The anti-SARS-CoV-2S antibody titer varied from 0.55 U/mL to 4920 U/mL. We found that the value of the titer varied widely. The value of the titer was negatively associated with age, alcohol consumption, time elapsed from second vaccine dose, and use of immunosuppressive medication. The result that the titer was negatively associated with aging suggests that the timing of additional shot should be carefully determined especially among elderly population.


title: Mitigating isolation: The use of rapid antigen testing to reduce the impact of self-isolation periods

abstract: Isolating, either enforced or self-guided, is a well-recognised and used technique in the limitation and reduction of disease spread. This usually balances the societal harm of disease transmission against the individual harm of being isolated and is typically limited to a very small number of individuals. With the widespread transmission of SARS-CoV-2 and requirements to self-isolate when symptomatic or having tested positive, the number of people affected has grown very large causing noticeable individual cost, and disruption to the provision of essential services. With widespread access to reliable rapid antigen tests (also known as LFD or LFTs), in this paper we examine strategies to utilise this testing technology to limit the individual harm whist maintaining the protective effect of isolation. We extend this work to examine how isolation may be improved and mitigate the release of infective individuals into the population caused by fixed time-periods.


title: Overlooked Trustworthiness of Explainability in Medical AI

abstract: While various methods have been proposed to explain AI models, the trustworthiness of the generated explanation received little examination. This paper reveals that such explanations could be vulnerable to subtle perturbations on the input and generate misleading results. On the public CheXpert dataset, we demonstrate that specially designed adversarial perturbations can easily tamper saliency maps towards the desired explanations while preserving the original model predictions. AI researchers, practitioners, and authoritative agencies in the medical domain should use caution when explaining AI models because such an explanation could be irrelevant, misleading, and even adversarially manipulated without changing the model output. AI researchers, practitioners, and authoritative agencies in the medical domain should use caution when explaining AI models because such an explanation could be irrelevant, misleading, and even adversarially manipulated without changing the model output.

category: radiology and imaging


title: Deep learning based quantification of the accelerated brain aging rate in glioma patients after radiotherapy

abstract:
Background and purposeChanges of healthy appearing brain tissue after radiotherapy have been previously observed, however, they remain difficult to quantify. Due to these changes, patients undergoing radiotherapy may have a higher risk of cognitive decline, leading to a reduced quality of life. The experienced tissue atrophy is similar to the effects of normal aging in healthy individuals. We propose a new way to quantify tissue changes after cranial RT as accelerated brain aging using the BrainAGE framework.

Materials and methodsBrainAGE was applied to longitudinal MRI scans of 32 glioma patients, who have undergone radiotherapy. Utilizing a pre-trained deep learning model, brain age is estimated for all patients pre-radiotherapy planning and follow-up MRI scans to get a quantification of the changes occurring in the brain over time. Saliency maps were extracted from the model to spatially identify which areas of the brain the deep learning model weighs highest for predicting age. The predicted ages from the deep learning model were used in a linear mixed effects model to quantity aging and aging rates for patients after radiotherapy.

ResultsThe linear mixed effects model resulted in an accelerated aging rate of 2.78 years per year, a significant increase over a normal aging rate of 1 (p < 0.05, confidence interval (CI) = 2.54-3.02). Furthermore, the saliency maps showed numerous anatomically well-defined areas, e.g.: Heschls gyrus among others, determined by the model as important for brain age prediction.

ConclusionWe found that patients undergoing radiotherapy are affected by significant radiation-induced accelerated aging, with several anatomically well-defined areas contributing to this aging. The estimated brain age could provide a method for quantifying quality of life post-radiotherapy.

HighlightsUp to 3 times accelerated aging after radiotherapy. // Anatomically well-defined areas for brain age prediction. // Quantifying quality of life after radiotherapy.


title: Multi-scalar data integration links glomerular angiopoietin-tie signaling pathway activation with progression of diabetic kidney disease

abstract: Diabetes is the leading cause of chronic kidney disease. Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of diabetic kidney disease (DKD). In the Clinical Phenotyping and Resource Biobank study, an unbiased, machine learning approach identified a three-marker panel from plasma proteomics which, when added to standard clinical parameters, improved the prediction of outcome of end-stage kidney disease (ESKD) or 40% decline in baseline glomerular filtration rate (GFR) in a discovery DKD group (N=58) and was validated in an independent group (N=68) who also had kidney transcriptomic profiles available. Of the three markers, plasma angiopoietin 2 (ANGPT2) remained significantly associated with composite outcome in 210 Chinese Cohort Study of Chronic Kidney Disease participants with DKD. The glomerular transcriptional Angiopoietin/Tie (ANG-TIE) activation scores, derived from the expression of 154 literature-curated ANG-TIE signaling mediators, positively correlated with plasma ANGPT2 levels and outcome, explained by substantially higher TEK receptor expression in glomeruli and higher ANG-TIE activation scores in endothelial cells in DKD by single cell RNA sequencing. Our work suggests that activation of glomerular ANG-TIE signaling in the kidneys underlies the association of plasma ANGPT2 with disease progression, thereby providing potential targets to prevent DKD progression.

category: nephrology


title: Personalized Feeding Infusion Rate of Nutrition to Improve Glycemic Variability Control in Critical Care Patients

abstract: Control-based algorithms in the intensive care unit (ICU) patients have been developed to deliver a sufficient amount of insulin, but optimizing the rate of feeding of nutrition in ICU patients to improve glycemic variability control has not been done yet. Continuous feeding is commonly used for nutrition in critically ill patients who cannot be fed orally to maintain a normal blood sugar concentration, but optimizing its rate, for these individuals, is needed to avoid the adverse outcomes caused by medications such as insulin. This paper develops a control-based algorithm combines a predictive control algorithm with a revised nonlinear compartmental model used in the ICU to design personalized feeding function rates to improve patient glycemic variability. Our control algorithm is robust and acts very quickly to avoid medical intervention effects.

category: health systems and quality improvement


title: Healthcare workers' COVID-19 Omicron variant uncertainty-related stress, resilience, and coping strategies during the first week of World Health Organization alert

abstract:
BackgroundAs the COVID-19 Omicron variant emerged and spread globally at an alarming speed, healthcare workers (HCWs) uncertainties, worries, resilience, and coping strategies warrant assessment. The COVID-19 pandemic had a severe psychological impact on HCWs, including the development of Post-Traumatic Stress symptoms. Specific subgroups of HCWs, such as front-line and female workers, were more prone to poor mental health outcomes and difficulties facing stress.

MethodsThe responses to an online questionnaire among HCWs in Saudi Arabia (KSA) were collected December 1-5, 2021, aiming to assess their Omicron variants uncertainties, worries, resilience, and coping strategies. Three validated instruments were used to achieve the studys goals: the Brief Resilient Coping Scale, the Standard Stress Scale (SSS), and the Intolerance of Uncertainty Scale (IUS) - Short Form.

ResultsThe online survey was completed by 1285 HCWs. Females made up the majority (64%). The BRCS score of resilient coping was negatively and substantially linked with the SSS score of stress (r=-0.313, p = 0.010). Furthermore, the IUS had a positive and significant relationship with stress (r=0.326, p= 0.010). Increased stress levels were linked to a considerable drop in resilient coping scores. Furthermore, being a Saudi HCW or a nurse was linked to a significant reduction in resilient coping ratings. Coping by following healthcare authorities preventative instructions and using the WHO website as a source of information was linked to a considerable rise in resilient coping.

ConclusionsFollowing the emergence of the Omicron variant of SARS-CoV-2 in late 2021, a rapid investigation into the correlates of stress and resilient coping among the HCWs in KSA was conducted. The negative association between resilient coping and stress was clearly shown, as well as how underlying intolerance of uncertainty is linked to higher stress among HCWs quickly following the development of a new infectious threat. The study provides early insights to develop and promote coping strategies for emerging SARS-CoV-2 variants.


title: Serum anti-Spike antibody titers before and after heterologous booster with mRNA-1273 SARS-CoV-2 vaccine following two doses of inactivated whole-virus CoronaVac vaccine

abstract:
BackgroundThe inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide. However, data on its immunogenicity and reactogenicity to heterologous boosting with mRNA vaccines are lacking.

MethodsIn a cohort of hospital staff in Jakarta, Indonesia, who received two-dose CoronaVac six months prior (median 190 days, IQR165-232), we measured anti-Spike IgG titers on paired serum samples taken before and 28 days after a 100g mRNA-1273 (Moderna) booster. We performed correlations and multivariable ordinal regressions.

FindingsAmong 304 participants, the median age was 31 years (range 21-59), 235 (77.3%) were women, 197 (64.8%) had one or more previous SARS-CoV-2 infections (including 155 [51.0%] who had a post-CoronaVac breakthrough infection. Pre-boost IgG titers correlated negatively with the time since the latest documented "virus exposure" (either by the second CoronaVac or SARS-CoV-2-infection whichever most recent). Previous SARS-CoV-2 infection and a longer time interval between second vaccine and mRNA-1273 boost were associated with a higher pre-boost IgG titer. Post-booster, the median IgG titer increased 9.3-fold, from 250 (IQR32-1389) to 2313 (IQR1226-4324) binding antibody units (BAU/mL) (p<0.001). All participants, including seven whose pre-boost IgG was below assay detection limits, became seropositive and all reached a substantial post-boost titer ([≥]364 BAU/mL). Post-boost IgG was not associated with pre-boost titer or previous SARS-CoV-2 infection. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living (ADL).

InterpretationA heterologous, high-dose mRNA-1273 booster after two-dose CoronaVac was highly immunogenic and safe, including in those most in need of improved immunity.

FundingWellcome Trust, UK

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide, at around 2 billion doses in 54 countries. Concerns that CoronaVac has lower immunogenicity than virus vector or mRNA vaccines, with pronounced decreases of neutralising antibody titres within a few months, and reduced effectiveness in the older population, highlight the urgent need for immunogenic, safe and well-tolerated booster schedules, especially with Omicron rapidly emerging.

We used the terms "SARS-CoV-2", "COVID-19", "vaccine", "booster" to search PubMed and medRxiv up to Dec 22th, 2021, with no language or date restrictions, to identify clinical trials and real-world studies reporting on the immune responses and reactogenicity to a "third booster" of currently approved COVID-19 vaccines. Previous research reported that neutralising antibody responses elicited by all currently approved vaccines (mRNA, adenovirus-vectored, inactivated, and protein subunit) declined to varying degrees after 6-8 months after full-schedule vaccination. Several clinical trials have evaluated heterologous ("mix and match") vaccination schedules, demonstrating robust immune responses in adults. After two-dose CoronaVac, BNT162b2 (Pfizer-BioNTech) boost was significantly more immunogenic than a homologous booster against wild-type and Variants of Concern (VOCs) Beta, Gamma and Delta, and AZD1222 boost increased spike RBD-specific IgG 9-10-fold, with high neutralizing activity against the wild type and VOCs. Compared to previous SARS-CoV-2 variants, current vaccine boosters appeared to neutralise Delta to a slightly lesser degree, and Omicron to a substantially lesser degree, although preliminary data from Moderna found that the authorised dose (50g) of the mRNA-1273 boost increased antibodies 37-fold and the high-dose (100g) boost 83-fold.

Added value of this studyTo our knowledge, this study is the first to provide critical real-world evidence that heterologous boosting with high-dose mRNA-1273 vaccine after CoronaVac is highly immunogenic, safe and well-tolerated in adults. After a primary course of two-dose CoronaVac, we found that a high-dose (100g) mRNA-1273 booster was immunogenic for all participants in a highly exposed cohort of hospital staff in Jakarta, Indonesia, in the context of Delta predominance, particularly for those with the lowest pre-boost antibody levels. All participants became seropositive and all reached a substantial post-boost titer ([≥]364 BAU/mL), up to a median 9.3-fold increase. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living

Implications of all the available evidenceThe study findings contribute to informing policy makers on flexible options in deploying COVID-19 vaccines in mix-and-match schedules, with particular relevance for countries that are largely dependent on inactivated vaccines. Further trials are warranted that assess clinical endpoints of optimized doses of mRNA-1273 booster, and variant-specific or multivalent vaccines in response to decreased protection against emerging SARS-CoV-2 VOCs.


title: Saliva swabs are the preferred sample for Omicron detection

abstract: The Omicron variant is characterised by more than 50 distinct mutations, the majority of which are located in the spike protein. The implications of these mutations for disease transmission, tissue tropism and diagnostic testing are still to be determined. We evaluated the relative performance of saliva and mid-turbinate swabs as RT-PCR samples for the Delta and Omicron variants. The positive percent agreement (PPA) of saliva swabs and mid-turbinate swabs to a composite standard was 71% (95% CI: 53-84%) and 100% (95% CI: 89-100%), respectively, for the Delta variant. However, for the Omicron variant saliva and mid-turbinate swabs had a 100% (95% CI: 90-100%) and 86% (95% CI: 71-94%) PPA, respectively. This finding supports ex-vivo data of altered tissue tropism from other labs for the Omicron variant. Reassessment of the diagnostic testing standard-of-care may be required as the Omicron variant become the dominant variant worldwide.


title: Infrared spectroscopy enables rapid, robust, portable COVID-19 saliva screening based on pathophysiological response to SARS-CoV-2

abstract: Fourier-transform infrared (FTIR) spectroscopy provides a (bio)chemical snapshot of the sample, and was recently proposed for COVID-19 saliva screening in proof-of-concept cohort studies. As a step towards translation of this technology, we conducted controlled validation experiments in multiple biological systems. SARS-CoV-2 or UV-inactivated SARS-CoV-2 were used to infect Vero E6 cells in vitro, and K18-hACE2 mice in vivo. Potentially infectious culture supernatant or mouse oral lavage samples were treated with ethanol or Trizol to 75% (v/v) for attenuated total reflectance (ATR)-FTIR spectroscopy, or RT-PCR, respectively. The control condition, UV-inactivated SARS-CoV-2 elicited strong biochemical changes in culture supernatant/oral lavage despite lack of replication determined by RT-PCR or cell culture infectious dose 50%. Crucially, we show that active SARS-CoV-2 infection induced additional FTIR signals over the UV-inactivated SARS-CoV-2 infection, which correspond to innate immune response, aggregated proteins, and RNA. For human patient cohort prediction, we achieved high sensitivity of 93.48% on leave-on-out cross validation (n=104 participants) for predicting COVID-19 positivity using a partial least squares discriminant analysis model, in agreement with recent studies. However, COVID-19 patients negative on follow-up (RT-PCR on day of saliva sampling) were poorly predicted in this model. Importantly, COVID-19 vaccination did not lead to mis-classification of COVID-19 negatives. Meta-analysis revealed SARS-CoV-2 induced increase in Amide II band in all arms of this study and recent studies, indicative of altered {beta}-sheet structures in secreted proteins. In conclusion, ATR-FTIR is a robust, simple, portable method for COVID-19 saliva screening based on detection of pathophysiological responses to SARS-CoV-2.


title: Echinacea as a Potential Force against Coronavirus Infections? A Mini-Review of Randomized Controlled Trials in Adults and Children

abstract: Echinacea purpurea was shown to broadly inhibit coronaviruses and SARS-CoV-2 in vitro. This review discusses the available clinical evidence from randomized, blinded and controlled human studies. Two RCTs with results on enveloped viruses, respectively coronavirus infections during prevention treatment were detected. Incidence and/or viral loads were measured by RT-PCR and symptom severity was recorded. Jawad et al. (2012) collected nasopharyngeal swabs from adults (N=755) over 4 months of continuous prevention. Overall, 24 and 47 enveloped virus infections occurred, including 21 and 33 coronavirus detections [229E; HKU1; OC43] with Echinaforce(R) extract [2400mg daily] and placebo, respectively (p=0.0114). Ogal et al. (2021) administered the same extract [1200mg] or control for 4 months to children (4 - 12 years) (N=203). Echinacea reduced the incidence of enveloped virus infections from 47 to 29 (p=0.0038) whereas 11 and 13 coronavirus detections [229E, OC43, NL63] were counted (p>0.05). Respiratory symptoms during coronavirus infections were significantly lower with area-under-curve AUC=75.8 (+/-50.24) versus 27.1 (+/-21.27) score points (p=0.0036). Importantly, viral loads in nasal secretions were significantly reduced by 98.5%, with Ct-values 31.1 [95% CI 26.3; 35.9] versus 25.0 [95% CI 20.5; 29.5] (p = 0.0479). Results from clinical studies confirm the antiviral activity found for Echinacea in vitro, embracing enveloped respiratory pathogens and therefore coronaviruses as well. Substantiating results from a new completed study seems to extrapolate these effects to the prevention of SARS-CoV-2 infection. As hypothesized, the testified broad antiviral activity of Echinacea extract appears to be inclusive for SARS-CoV-2.


title: Technology And Its Role In Supporting Tuberculosis Treatment Adherence

abstract: Compliance with TB treatment has now become a problem that must be handled seriously because the high non-adherence rate will give a bad contribution to the success of TB treatment, including MDR-TB and also morbidity and mortality. Many innovations have been made to improve TB treatment adherence, one of which is using mobile-based technology. This article aims to explore the effectiveness of the technology used to improve treatment adherence in TB patients: types, ways of working, advantages, and limitations of each application. This is a systematic review through searching 3 databases, namely Scopus, WoS, and Science Direct. Some of the advantages in applying technology to improve TB treatment adherence are easy to use if you understand how to operate tools/applications are cost-effective because they reduce transportation costs in reaching remote areas or in conditions of transportation difficulties such as after a disaster, the use of this technology provides patient satisfaction in treatment and facilitates the involvement of the family/support system in the treatment of patients. Several things must be considered (limitations) of the technology to be used, including experts, patient knowledge and skills, economic condition, electricity availability, and whether the technology used will not increase the burden on patients related to the stigma of TB disease. We can conclude that the use of technology is indeed very good in supporting the improvement of TB treatment adherence, but the selection of this application must pay attention to the characteristics of the population as well as the advantages and limitations of each application.


title: Three doses of the BNT162b2 vaccine confer neutralising antibody capacity against the SARS-CoV-2 B.1.1.529 (Omicron) variant of concern

abstract: We report the levels of neutralising antibodies against Wuhan, Delta and Omicron variants in healthy individuals pre-infected or not with SARS-CoV-2 and immunized with three doses of the BNT162b2 vaccine. Our observations support the rapid administration of a booster vaccine dose to prevent infection and disease caused by Omicron.


title: Neutralizing antibodies to SARS-CoV-2 Omicron variant after 3rd mRNA vaccination in health care workers and elderly subjects and response to a single dose in previously infected adults

abstract:
The emergence of SARS-CoV-2 Omicron variant (B.1.1.529) with major spike protein mutations has raised concern over potential neutralization escape and breakthrough infections among vaccinated and previously SARS-CoV-2 infected subjects. We measured cross-protective antibodies against variants in health care workers (HCW, n=20) and nursing home residents (n=9) from samples collected 1-2 months following the booster (3rd) dose. We also assessed the antibody responses in prior to Omicron era infected subjects (n=38) with subsequent administration of a single mRNA vaccine dose. Following booster vaccination HCWs had high IgG antibody concentrations to the spike protein and neutralizing antibodies (NAb) were detectable against all variants. IgG concentrations among the elderly remained lower, and some lacked NAbs against the Beta and Omicron variants. NAb titers were significantly reduced against Delta, Beta and Omicron compared to wild-type virus regardless of age. Vaccination induced high IgG concentrations and variable titers of cross-reactive NAbs in previously infected subjects, whereas NAb titers against Omicron were barely detectable 1-month post-infection. High IgG concentrations with cross-protective neutralizing activity were detected after three COVID-19 vaccine doses in HCWs. However, lower NAb titers seen in the frail elderly suggest inadequate protection against Omicron breakthrough infections, yet protection against severe COVID-19 is expected.

O_TBL View this table:
org.highwire.dtl.DTLVardef@84f4c4org.highwire.dtl.DTLVardef@e1a056org.highwire.dtl.DTLVardef@e5a4ecorg.highwire.dtl.DTLVardef@ae8370org.highwire.dtl.DTLVardef@137480e_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOTable 1.C_FLOATNO O_TABLECAPTIONGeometric mean IgG concentrations, GMC [95% CI] expressed as BAU/ml for spike proteins (SFL and RBD) and geometric mean titers, GMT [95% CI] of neutralizing antibodies (NAb) against wild-type (WT) virus and three variants of concern Delta (B.1.617.2), Beta (B.1.351) and Omicron (B.1.1.529) in elderly (n=7-9) and health care workers (HCW) 21-42 (n=7) or 43-77 (n=8) days post booster mRNA vaccination (3rd dose of Comirnaty).

C_TABLECAPTION C_TBL Clinical trial registrationEudraCT 2021-004788-29


title: Sharp Increases in Drug Overdose Deaths Among High-School-Age Adolescents During the US COVID-19 Epidemic and Illicit Fentanyl Crisis

abstract: Although overdose deaths in the US have increased exponentially for the past four decades, these shifts have historically affected adults, while pediatric overdose rates remained stable. However, this may be changing, given that the illicit drug supply has become increasingly hazardous in recent years, as illicitly-manufactured-fentanyls (IMFs) and other synthetic opioid and benzodiazepine analogues are increasingly sold as heroin and counterfeit prescription pills. We calculated drug overdose deaths per 100,000 population by 5-year age groups for the 2010-2021 period. For high-school-aged adolescents (age 14-18), we stratified rates by race/ethnicity, census region, associated substance, and ICD-10 cause-of-death intent categories. Adolescent overdose mortality saw a sharp increase between 2019 and 2020, from 2.35 per 100,000 to 4.58 per 100,000, representing a 94.3% increase, the largest percent increase of any 5-year age group. American Indian or Alaska Native (AIAN) adolescents, Latinx adolescents, and adolescents in the West census region were disproportionately affected, overdose death rates 2.15, 1.31, and 1.68 times the national average in 2021, respectively. Trends were driven by fatalities involving IMFs, which nearly tripled from 2019 to 2020, and represented 76.6% of adolescent overdose deaths in 2021. Sharp increases in adolescent drug overdose deaths, despite flat or declining drug use rates, and no increase in deaths from alcohol or most drugs, reinforce that rising fatalities are likely driven by an increasingly toxic, IMF-contaminated drug supply. Rising racial disparities in overdose require a prevention approach that ameliorates deep-seated social and economic inequalities as well as poor access to mental and physical healthcare and social services for AIAN and Latinx adolescents. Our results should also be understood in the context of rising rates of adolescent mental illness during the COVID-19 pandemic. These findings highlight the urgent need for accurate, harm-reduction-oriented education for early adolescents about the risks of an evolving drug supply, as well as greater access to naloxone and services that check drugs for the presence of IMFs.


title: Population immunity to SARS-CoV-2 in US states and counties due to infection and vaccination, January 2020-November 2021

abstract:
Prior infection and vaccination both contribute to population-level SARS-CoV-2 immunity. We used a Bayesian model to synthesize evidence and estimate population immunity to prevalent SARS-CoV-2 variants in the United States over the course of the epidemic until December 1, 2021, and how this changed with the introduction of the Omicron variant. We used daily SARS-CoV-2 infection estimates and vaccination coverage data for each US state and county. We estimated relative rates of vaccination conditional on previous infection status using the Census Bureaus Household Pulse Survey. We used published evidence on natural and vaccine-induced immunity, including waning and immune escape. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%), compared to 24.9% (95%CrI: 18.5%-34.1%) on January 1, 2021. State-level estimates for December 1, 2021, ranged between 76.9% (95%CrI: 67.6%-87.6%, West Virginia) and 94.4% (95%CrI: 91.2%-97.3%, New Mexico). Accounting for waning and immune escape, the effective protection against the Omicron variant on December 1, 2021, was 21.8% (95%CrI: 20.7%-23.4%) nationally and ranged between 14.4% (95%CrI: 13.2%-15.8%, West Virginia), to 26.4% (95%CrI: 25.3%-27.8%, Colorado). Effective protection against severe disease from Omicron was 61.2% (95%CrI: 59.1%-64.0%) nationally and ranged between 53.0% (95%CrI: 47.3%-60.0%, Vermont) and 65.8% (95%CrI: 64.9%-66.7%, Colorado). While over three-quarters of the US population had prior immunological exposure to SARS-CoV-2 via vaccination or infection on December 1, 2021, only a fifth of the population was estimated to have effective protection to infection with the immune-evading Omicron variant.

SignificanceBoth SARS-CoV-2 infection and COVID-19 vaccination contribute to population-level immunity against SARS-CoV-2. This study estimates the immunity and effective protection against future SARS-CoV-2 infection in each US state and county over 2020-2021. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%). Accounting for waning and immune escape, protection against the Omicron variant was 21.8% (95%CrI: 20.7%-23.4%). Protection against infection with the Omicron variant ranged between 14.4% (95%CrI: 13.2%-15.8%%, West Virginia) and 26.4% (95%CrI: 25.3%-27.8%, Colorado) across US states. The introduction of the immune-evading Omicron variant resulted in an effective absolute increase of approximately 30 percentage points in the fraction of the population susceptible to infection.


title: Population immunity to pre-Omicron and Omicron SARS-CoV-2 variants in US states and counties through December 1, 2021


title: Change in COVID-19 risk over time following vaccination with CoronaVac: A test-negative case-control study

abstract:
ObjectiveTo estimate the change in odds of covid-19 over time following primary series completion of the inactivated whole virus vaccine, CoronaVac (Sinovac Biotech) in Sao Paulo state, Brazil.

DesignTest negative case-control study.

SettingCommunity testing for covid-19 in Sao Paulo state, Brazil.

ParticipantsAdults aged 18-120 years who were residents of Sao Paulo state, without a previous laboratory-confirmed covid-19 infection, who received only two doses of CoronaVac, and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 30 September 2021.

Main outcome measuresRT-PCR-confirmed symptomatic covid-19 and associated hospital admissions and deaths. Cases were pair-matched to test-negative controls by age (in 5-year bands), municipality of residence, healthcare worker (HCW) status, and date of RT-PCR test ({+/-}3 days). Conditional logistic regression was adjusted for sex, number of covid-19-associated comorbidities, race, and previous acute respiratory infection.

ResultsFrom 137,820 eligible individuals, 37,929 cases with symptomatic covid-19 and 25,756 test-negative controls with covid-19 symptoms were formed into 37,929 matched pairs. Adjusted odds ratios of symptomatic covid-19 increased with time since series completion, and this increase was greater in younger individuals, and among HCWs compared to non-HCWs. Adjusted odds ratios of covid-19 hospitalisation or death were significantly increased from 98 days since series completion, compared to individuals vaccinated 14-41 days previously: 1.40 (95% confidence interval 1.09 to 1.79) from 98-125 days, 1.55 (1.16 to 2.07) from 126-153 days, 1.56 (1.12 to 2.18) from 154-181 days, and 2.12 (1.39-3.22) from 182 days.

ConclusionsIn the general population of Sao Paulo state, Brazil, an increase in odds of moderate and severe covid-19 outcomes was observed over time following primary series completion with CoronaVac.

What is already known on this topic- The effectiveness of the inactivated whole virus vaccine, CoronaVac (Sinovac Biotech) against moderate and severe covid-19 has been demonstrated in clinical trials and observational studies.
- Observational studies have suggested that effectiveness of other covid-19 vaccines appears to decrease over time, prompting many countries to deploy additional doses for individuals who have completed their primary series.
- There is currently no evidence for change in the rate of breakthrough infection in individuals who have received a primary series of CoronaVac.

What this study adds- In individuals receiving two doses of CoronaVac, the odds of symptomatic covid-19 increased over time since series completion.
- Larger increases in covid-19 odds were observed in individuals aged 18-40, and in healthcare workers compared to non-healthcare workers.
- Odds of covid-19 hospitalisation or death increased over time since series completion, but to a lesser extent.


title: Endoscopic findings in patients with persistent dyspepsia in a tertiary care hospital of South Punjab

abstract:
BackgroundOne of the most common clinical problem encountered by physicians in clinical practice is dyspepsia. This symptom has great impact on quality of life of patients. There are numerous causes of dyspepsia, organic as well as functional. Endoscopy is the diagnostic test of choice in these patients.

AimThe aim of our study was to see the endoscopic findings in patients with persistent dyspepsia.

MethodsRetrospective analysis of data of patients who underwent Esophagogastroduodenoscopy (EGD) for persistent dyspepsia was collected and evaluated.

ResultsThere were 495 patients in our study, 244 females and 251 males, with a mean age of 41 years. Almost half of the patients belonged to 21-40 years age group. The most common endoscopic finding in patients with persistent dyspepsia was gastritis (n=219, 44.2%), followed by normal endoscopy (n= 94, 19%), incompetent lower esophageal sphincter (n=67, 13.5%), gastric malignancy (n=48, 9.7%). Ulcer disease was found in just 15 patients (3%).

ConclusionMost common endoscopic finding in patients with persistent dyspepsia was gastritis followed by normal endoscopy.

category: gastroenterology


title: Early Treatment with fluvoxamine among patients with COVID-19: a cost-consequence model

abstract:
BackgroundThree randomized trials have been conducted indicating a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. We assessed the cost-consequences associated with the use of this early treatment in outpatient populations.

MethodsUsing results from the three completed trials of fluvoxamine vs. placebo for the treatment of COVID-19, we performed a meta-analysis. We conducted a cost-consequence analysis using a decision-model to assess the health system benefits of the avoidance of progression to severe COVID-19. Outcomes of relevance to resource planning decisions in the US and elsewhere, including costs and days of hospitalization avoided, were reported. We constructed a decision-analytic model in the form of a decision tree to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19, from the perspective of a third-party payer:(1) treatment with a 10-day course of fluvoxamine (100mg twice daily); (2) current standard-of-care; (3) molnupiravir 5-day course. We used a time horizon of 28 days.

ResultsAdministration of fluvoxamine to symptomatic outpatients with COVID-19 at high-risk of developing progression to severe COVID-19 complications is substantially cost-saving in the US, in the amount of $232 per eligible patient, and saves an average of 0.15 hospital days per patient treated is likely to be similarly beneficial in other settings. Fluvoxamine is cost saving in locations where total hospital costs are >$738. Molnupiravir had an additional cost to the healthcare system of $404 per patient treated.

ConclusionsFluvoxamine is cost-saving for COVID-19 outpatient therapy.

FundingFastGrants and Rainwater Charitable Foundation

category: pharmacology and therapeutics


title: Research themes of family and community physicians in Brazil

abstract: Family and community medicine is a specialty dedicated to primary care, the cornerstone of effective health systems. Research capacity in primary care varies worldwide, and bibliographic databases such as MEDLINE, Scopus and Web of Science do not index most primary care research coming from Latin America. Our objective was to investigate the research themes of family and community physicians in Brazil, and to correlate the articles research themes with their authors trajectories in postgraduate education. For that, we compiled a national list of family and community physicians, retrieved their curricula from the Lattes Platform, compiled a list of journal articles, and obtained their keywords from LILACS and MEDLINE. Treating journal articles and their keywords as the two node types in a bipartite network, we derived research themes using the dual-projection algorithm, combining the Leiden algorithm with hierarchical clustering. We found two research themes to be the largest, most developed, and most central ones: human health and primary care. Authors with a masters or PhD in collective health (public health, epidemiology, and social sciences and humanities in health) were as likely as those with no postgraduate degree to publish articles on primary care. On the other hand, authors with a postgraduate degree in medicine were more likely to publish articles on human health. After discussing the findings in light of previous research and methodological aspects, we conclude theres a relative divide between primary care and clinical research, and the highlight policy implications.

category: primary care research


title: Extending upon: What effect might border screening have on preventing importation of COVID-19 compared with other infections? - Considering the additional effect of post-arrival isolation

abstract: We recently described a simple model through which we assessed what effect subjecting travellers to a single on-arrival test might have on reducing risk of importing disease cases during simulated outbreaks of COVID-19, Influenza, SARS, and Ebola. We build upon this work to allow for the additional requirement that inbound travellers also undergo a period of self-isolation upon arrival, where upon completion the traveller is again tested for signs of infection prior to admission across the border. Prior results indicated that a single on-arrival test has the potential to detect 9% of travellers infected with COVID-19, compared to 35%, 10% and 3% for travellers infected with influenza, SARS, and Ebola respectively. Our extended model shows that testing administered after a 2-day isolation period may be able to detect up to 41%, 97%, 44% and 15% of COVID-19, Influenza, SARS, and Ebola infected travellers respectively. Longer self-isolation periods increase detection rates further, with an 8-day self-isolation period suggesting detection rates of up to 94%, 100%, 98% and 62% for travellers infected with COVID-19, Influenza, SARS, and Ebola respectively. These results therefore suggest that testing arrivals after an enforced period of self-isolation may present a reasonable method of protecting against case importation during international outbreaks.


title: Essential Workers COVID-19 Vaccine Hesitancy, Misinformation and Informational Needs in the Republic of North Macedonia.

abstract:
IntroductionThe COVID-19 pandemic is a global health crisis that as of December 2021 has resulted in the death of over 5.2 million people. Despite the unprecedented development and distribution of vaccines, hesitancy to take the vaccine remains a wide-spread public health challenge, especially in Eastern European countries. In this study we focus on a sample of essential workers living in the Republic of North Macedonia to: 1) Describe rates of vaccine acceptance, risk perception and sources of COVID-19 information, 2) Explore predictors of vaccine hesitancy, and 3) Describe informational needs of hesitant and non-hesitant workers.

MethodsDescriptive statistics were used to present frequencies of vaccine acceptance. Logistic regression was used to explore predictors of vaccine hesitancy based on sociodemographic characteristics, hesitancy to take other vaccines in the past, previous diagnosis of COVID-19, and individual risk perception of getting COVID-19. Chi square analysis was used to compare differences in informational needs between hesitant and non-hesitant individuals across socio-demographic groups.

ResultsFrom a sample of 1003 individuals, 439 (44%) reported that they were very likely to get the vaccine, and the rest (66%) reported some level of hesitancy. Older age, Albanian ethnicity, post-secondary school education, previous diagnosis of COVID-19, previous vaccine acceptance of other vaccines, and increased risk perception of COVID-19 infection were all found to be negatively associated with vaccine hesitancy. In particular hesitant individuals, compared to the non-hesitant, wanted to have more information and reassurance that all main international agencies (i.e. FDA, WHO, EMA) were all in accordance in recommending the vaccine and that they would be free to choose if getting the vaccine or not without consequences (p<0.01).


title: Physiological and Psychological Effects of Parental Traditional Thai Massage on Children with Autism: A Protocol for a Randomized Controlled Trial

abstract:
IntroductionAlthough many autistic children receive massage as a complementary therapy, it is not included in evidence-based practices for autism since evidence of its efficacy is lacking. Further, prior studies have failed to identify objective indicators of core symptoms or elucidate their mechanisms. We developed a parent-delivered traditional Thai massage (TTM) on children intervention with autism, aim is to access the physiological (gait and heart rate variability) and psychological effects of intervention.

Methods and analysisA two-armed, parallel randomized controlled trial study will recruit forty-eight children with autism from the XX Special Education School at the beginning of Febuary2022. They will be randomly assigned to either a parental TTM or control group with a ratio of 1:1. Individuals in the parental TTM group will receive 16 parent-delivered TTM sessions over 8 weeks. The outcome will be assessed on admission, after 8 weeks, and as well as at 2-month follow-up, including the Autism Treatment Evaluation Checklist score, heart rate variability, gait, and parenting stress index.

Ethics and disseminationEthical approved by the Khon Kaen University Ethics Committee for Human Research (XXXX). Result will be published in a peer-reviewed journal and give presentations in domestic and international academic conferences to further promote communication.

Trial registration numberXXXXXX

Strengths and limitations of this studyO_LIThis will be the first RCT to explore parental TTM in terms of its physiological and psychological effects on children with autism.
C_LIO_LICompared with previous studies, we access the objective index to discuss the possible mechanisms of observed effects.
C_LIO_LIOur study may highlight the value of complementary and alternative therapies for adjunctive treatment of autism to enhance family-based interventions
C_LIO_LIBoth parents and blind teachers will evaluate for effects to decreases the subjectivity of bias. And the variability massage manipulation by parents is minimized by training with experts, examinations, and supervision.
C_LI

category: rehabilitation medicine and physical therapy


title: Virtual Exam for Parkinson's Disease Enables Frequent and Reliable Measurements of Motor Function

abstract:
Sensor-based remote monitoring could help us better track Parkinsons disease (PD) progression, and measure patients response to putative disease-modifying therapeutic interventions. To be useful, the remotely-collected measurements should be valid, reliable and sensitive to change, and people with PD must engage with the technology.

We developed a smartwatch-based active assessment that enables unsupervised measurement of motor signs of PD. 388 study participants with early-stage PD (Personalized Parkinson Project, 64% men, average age 63 years) wore a smartwatch for a median of 390 days, allowing for continuous passive monitoring. Participants performed unsupervised motor tasks both in the clinic (once) and remotely (twice weekly for one year). Dropout rate was 2% at the end of follow-up. Median wear-time was 21.1 hours/day, and 59% of per-protocol remote assessments were completed.

In-clinic performance of the virtual exam verified that most participants correctly followed watch-based instructions. Analytical validation was established for in-clinic measurements, which showed moderate-to-strong correlations with consensus MDS-UPDRS Part III ratings for rest tremor ({rho}=0.70), bradykinesia ({rho}=-0.62), and gait ({rho}=-0.46). Test-retest reliability of remote measurements, aggregated monthly, was good-to-excellent (ICC: 0.75 - 0.96). Remote measurements were sensitive to the known effects of dopaminergic medication (on vs off Cohens d: 0.19 - 0.54). Of note, in-clinic assessments often did not reflect the patients typical status at home.

This demonstrates the feasibility of using smartwatch-based unsupervised active tests, and establishes the analytical validity of associated digital measurements. Weekly measurements can create a more complete picture of patient functioning by providing a real-life distribution of disease severity, as it fluctuates over time. Sensitivity to medication-induced change, together with the improvement in test-retest reliability from temporal aggregation implies that these methods could help reduce sample sizes needed to demonstrate a response to therapeutic intervention or disease progression.


title: An Aging Focused Unobtrusive and Privacy-Preserving Digital Behaviorome

abstract: AO_SCPLOWBSTRACTC_SCPLOWDigital measures are increasingly used as objective health measures in remote-monitoring settings. In addition to their use in purely clinical research, such as in clinical trials, one promising application area for sensor-derived digital measures is in technology-assisted ageing and ageing-related research. In this context, digital measures may be used to measure the risk of certain adverse events such as falls, and also to provide novel research insights into ageing and ageing-related conditions, like cognitive impairment. While major emphasis has been placed on deriving one or more digital measures from wearable devices, a more holistic approach inspired by systems biology that leverages large, non-exhaustive sets of digital measures may prove highly beneficial. Such an approach would be useful if combined with modern big data approaches like machine learning. As such, extensive sets of digital measures, which may be referred to as digital behavioromes, could help characterise new phenotypes in deep phenotyping efforts. These measures could also assist in the discovery of novel digital biomarkers or in the creation of digital clinical outcome assessments. While clinical research into digital measures focuses primarily on measures derived from wearable devices, proven technology used for long-term remote monitoring of older adults is generally contactless, unobtrusive, and privacy-preserving. In this context, we introduce and describe a digital behaviorome: a large, non-exhaustive set of digital measures based entirely on contactless, unobtrusive, and privacy-preserving sensor technologies. We also demonstrate how such a behaviorome can be used to build digital clinical outcome assessments that are relevant to ageing and derived from machine learning. These outcomes included fall risk, frailty, mild cognitive impairment, and late-life depression. With the exception of late-life depression, all digital outcome assessments demonstrated a promising ability (ROC AUC[≥] 0.7) to discriminate between positive and negative health outcomes, often in the range of comparable work with wearable devices. Finally, we highlight the possibility of using these digital behaviorome-based outcome assessments to discover novel potential digital biomarkers for each outcome. Here, we found reasonable contributors but also some potentially interesting new candidates regarding fall risk and mild cognitive impairment.

category: health informatics


title: Transcriptomic Fingerprint of Bacterial Infection in Lower Extremity Ulcers

abstract:
Clinicians and researchers utilize subjective classification systems based on clinical parameters to stratify lower extremity ulcer infections for treatment and research. This study compared clinical infection classifications (mild to severe) of lower extremity ulcers (n = 44) with transcriptomic profiles and direct measurement of bacterial RNA signatures by RNA-sequencing. Samples demonstrating similar transcriptomes were clustered and characterized by transcriptomic fingerprint. Clinical infection severity did not explain the major sources of variability among the samples and samples with the same clinical classification demonstrated high inter-sample variability. High proportions of bacterial RNA, however, resulted in a strong effect on transcription and increased expression of genes associated with immune response and inflammation. K-means clustering identified two clusters of samples, one of which contained all of the samples with high levels of bacterial RNA. A support vector classifier identified a fingerprint of 20 genes, including immune-associated genes such as CXCL8, GADD45B, and HILPDA, which accurately identified samples with signs of infection via cross-validation. This suggests that stratification of infection states based on a transcriptomic fingerprint may be a useful tool for studying host-bacterial interactions in these ulcers, as well as an objective classification method to identify the severity of infection.

Significance StatementClinicians and researchers utilize classification schemes based on clinically measurable parameters to describe infection severity in lower extremity ulcers. However, here we show that the local host gene expression is often discordant to clinical classification scores. We observed this inconsistency is explained by the increased presence of bacteria, which promotes increased immune and inflammatory responses. Two groups of host gene expression, predominantly differentiated by the levels of bacterial RNA, could be classified with less than 20 genes. These results provide significant insights into host response to bacterial infection where bacteria are directly observed, rather than implied from clinical observation, and illustrated the limitations of clinical observations to stratify lower extremity ulcers.


title: Effectiveness of BNT162b2 and mRNA-1273 Second Doses and Boosters for SARS-CoV-2 infection and SARS-CoV-2 Related Hospitalizations: A Statewide Report from the Minnesota Electronic Health Record Consortium

abstract: Using vaccine data combined with electronic health records, we report that mRNA boosters provide greater protection than a two-dose regimen against SARS-CoV-2 infection and related hospitalizations. The benefit of a booster was more evident in the elderly and those with comorbidities. These results support the case for COVID-19 boosters.


title: Immunogenicity and Safety Following a Homologous Booster Dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): A Phase 2 Randomized Placebo-Controlled Trial

abstract:
BackgroundEmerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present significant obstacles toward controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines may address these concerns by both amplifying and broadening the immune responses seen with initial vaccination regimens.

MethodsIn a phase 2 study, a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) was administered to healthy adult participants 18 to 84 years of age approximately 6 months following their primary two-dose vaccination series. Safety and immunogenicity parameters were assessed, including assays for IgG, MN50, and hACE2 receptor binding inhibition against the ancestral SARS-CoV-2 strain and select variants (B.1.351 [Beta], B.1.1.7 [Alpha], B.1.617.2 [Delta], and B.1.1.529 [Omicron]). This trial is registered with ClinicalTrials.gov, NCT04368988.

FindingsAn incremental increase in the incidence of solicited local and systemic reactogenicity events was observed with subsequent vaccinations. Following the booster, incidence rates of local and systemic reactions were 82.5% (13.4% [≥] Grade 3) and 76.5% (15.3% [≥] Grade 3), respectively, compared to 70.0% (5.2% [≥] Grade 3) and 52.8% (5.6% [≥] Grade 3), respectively, following the primary vaccination series. Events were primarily mild or moderate in severity and transient in nature, with a median duration of 1.0 to 2.5 days. Immune responses seen 14 days following the primary vaccination series were compared with those observed 28 days following the booster (Day 35 and Day 217, respectively). For the ancestral SARS-CoV-2 strain, serum IgG geometric mean titers (GMTs) increased [~]4.7-fold from 43,905 ELISA units (EU) at day 35 to 204,367 EU at Day 217. Neutralization (MN50) assay GMTs showed a similar increase of [~]4.1-fold from 1,470 at day 35 to 6,023 at Day 217. A functional hACE2 receptor binding inhibition assay analyzing activity against ancestral and variant strains of SARS-CoV-2 at Day 189 vs Day 217 found 54.4-fold (Ancestral), 21.9-fold (Alpha), 24.5-fold (Beta), 24.4-fold (Delta), and 20.1-fold (Omicron) increases in titers. An anti-rS IgG activity assay comparing the same time points across the same SARS-CoV-2 strains found titers improved 61.2-fold, 85.9-fold, 65.0-fold, 92.5-fold, and 73.5-fold, respectively.

InterpretationAdministration of a booster dose of NVX-CoV2373 approximately 6 months following the primary vaccination series resulted in an incremental increase in reactogenicity along with enhanced immune responses. For both the prototype strain and all variants evaluated, immune responses following the booster were notably higher than those associated with high levels of efficacy in phase 3 studies of the vaccine.

FundingNovavax(R) and the Coalition for Epidemic Preparedness Innovations (CEPI(R)).


title: CMV seropositivity is a potential novel risk factor for severe COVID-19 in non-geriatric patients

abstract:
BackgroundCOVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19.

MethodsNational German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV serostatus of patients who experienced mild (n=101), moderate (n=130) or severe to critical (n=80) disease by CMV IgG serology. We then investigated the relationship between disease severity and CMV serostatus via statistical models.

ResultsNon-geriatric patients (< 70 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19.

ConclusionsWe identified  CMV-seropositivity as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.


title: SARS-CoV-2 vaccine Alpha and Delta variant breakthrough infections are rare and mild, but happen relative early after vaccination

abstract:
IntroductionCOVID-19 vaccines significantly reduce SARS-CoV-2 (SCoV2)-related hospitalization and mortality in randomized controlled clinical trials, as well as in real-world effectiveness against different circulating SCoV2-lineages. However, some vaccine recipients show breakthrough infection and it remains unknown, which host and viral factors contribute to this risk and how many resulted in severe outcomes. Our aim was to identify demographic and clinical risk factors for SCoV2 breakthrough infections and severe disease in fully vaccinated individuals and to compare patient characteristics in breakthrough infections caused by SCoV2 Alpha or Delta variant.

MethodsWe conducted an exploratory retrospective case-control study from 28th of December to 25th of October 2021 dominated by the Delta SCoV2 variant. All cases of infection had to be reported by law to the local health authorities. Vaccine recipients data was anonymously available from the national Vaccination Monitoring Data Lake and the main local vaccine center. We compared anonymized patients characteristics of breakthrough infection (n=492) to two overlapping control groups including all vaccine recipients from the Canton of Basel-City (group 1 n=126586 and group 2 n=109382). We also compared patients with breakthrough infection caused by the Alpha to Delta variant. We used different multivariate generalized linear models (GLM).

ResultsWe found only 492/126586 (0.39%) vaccine recipients with a breakthrough infection after vaccination during the 10 months observational period. Most cases were asymptomatic or mild (478/492 97.2%) and only very few required hospitalization (14/492, 2.8%). The time to a positive SCoV2 test shows that most breakthrough infections occurred between a few days to about 170 days after full vaccination, with a median of 78 days (interquartile range, IQR 47-124 days). Factors associated with a lower odds for breakthrough infection were: age (OR 0.987, 95%CI 0.983-0.992), previous COVID-19 infection prior to vaccination (OR 0.296, 95%CI 0.117-0.606), and (self-declared) serious side-effects from previous vaccines (OR 0.289, 95%CI 0.033-1.035). Factors associated with a higher odds for breakthrough infection were: vaccination with the Pfizer/BioNTech vaccine (OR 1.459, 95%CI 1.238-1.612), chronic disease as vaccine indication (OR 2.109, 95%CI 1.692-2.620), and healthcare workers (OR 1.404, 95%CI 1.042-1.860). We did not observe a significantly increased risk for immunosuppressed patients (OR 1.248, 95% CI 0.806-1.849).

ConclusionsOur study shows that breakthrough infections are rare and show mild illness, but that it occurs early after vaccination with more than 50% of cases within 70 to 80 days post-full vaccination. This clearly implies that boost vaccination should be much earlier initiated compared to the currently communicated 180-day threshold. This has important implications especially for risk groups associated with more frequent breakthrough infections such as healthcare workers, and people in high-risk care facilities. Due to changes in the epidemiological dynamic with new variants emerging, continuous monitoring of breakthrough infections is helpful to provide evidence on booster vaccines and patient groups at risk for potential complications.


title: Remote Covid Assessment in Primary Care (RECAP) risk prediction tool: derivation and real-world validation studies.

abstract:
BackgroundAccurate assessment of COVID-19 severity in the community is essential for best patient care and efficient use of services and requires a risk prediction score that is COVID-19 specific and adequately validated in a community setting. Following a qualitative phase to identify signs, symptoms and risk factors, we sought to develop and validate two COVID-19-specific risk prediction scores RECAP-GP (without peripheral oxygen saturation (SpO2)) and RECAP-O2 (with SpO2).

MethodsProspective cohort study using multivariable logistic regression for model development. Data on signs and symptoms (model predictors) were collected on community-based patients with suspected COVID-19 via primary care electronic health records systems and linked with secondary data on hospital admission (primary outcome) within 28 days of symptom onset. Data sources: RECAP-GP: Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC) primary care practices (development), Northwest London (NWL) primary care practices, NHS COVID-19 Clinical Assessment Service (CCAS) (validation). RECAP-O2: Doctaly Assist platform (development, and validation in subsequent sample). Estimated sample size was 2,880 per model.

FindingsData were available from 8,311 individuals. Observations, such SpO2, were mostly missing in NWL, RSC, and CCAS data; however, SpO2 was available for around 70% of Doctaly patients. In the final predictive models, RECAP-GP included sex, age, degree of breathlessness, temperature symptoms, and presence of hypertension (Area Under the Curve (AUC): 0.802, Validation Negative Predictive Value (NPV) of  low risk 98.8%. RECAP-O2 included age, degree of breathlessness, fatigue, and SpO2 at rest (AUC: 0.843), Validation NPV of  low risk 99.4%.

InterpretationBoth RECAP models are a valid tool in the assessment of COVID-19 patients in the community. RECAP-GP can be used initially, without need for observations, to identify patients who require monitoring. If the patient is monitored at home and SpO2 is available, RECAP-O2 is useful to assess the need for further treatment escalation.

Research in context panelO_ST_ABSEvidence before the studyC_ST_ABSThis study was conceived during the first COVID-19 wave in the UK (March - April 2020), as members of the research team contributed to the development of national clinical guidelines for COVID-19 management in the community and to the Oxford COVID-19 rapid review to track signs and symptoms of COVID-19 internationally. The review was carried out according to Cochrane Collaboration standards for rapid reviews and identified systematic reviews and large-scale observational studies describing the signs and symptoms of COVID-19. Evidence gathered showed worsening of COVID-19 symptoms around the 7th day of disease and challenges in identifying patients with higher likelihood of severity to increase their monitoring. To this end, tools such NEWS2 have been used in the UK to assess COVID-19 patients in primary care, but they do not capture the characteristics of COVID-19 infection and/or are not suitable for community remote assessment. Several COVID-19 risk scores have been developed. QCOVID provides a risk of mortality considering patients existing risk factors but does not include acute signs and symptoms. ISARIC 4C Deterioration model has been specifically developed for hospital settings. In England, the NHS has implemented the Oximetry @home strategy to monitor patients with acute COVID-19 deemed at risk (older than 64 years old or with comorbidities) by providing pulse oximeters; however, the criteria for monitoring or for escalation of care have not been validated. There is, therefore, the need to develop a risk prediction score to establish COVID-19 patients risk of deterioration to be used in the community for both face to face or remote consultation.

Added value of this studyWe developed and validated two COVID-19 specific risk prediction scores. One to be used in the initial remote assessment of patients with acute COVID-19 to assess need for monitoring (RECAP-GP). The second one to assess the need for further treatment escalation and includes peripheral saturation of oxygen among the model predictors (RECAP-O2). To our knowledge, this is the first COVID-19 specific risk prediction score to assess and monitor COVID-19 patients risk of deterioration remotely. This will be a valuable resource to complement the use of oximetry in the community clinical decision-making when assessing a patient with acute COVID-19.

Implications of all available evidenceTo manage pandemic waves and their demand on healthcare, acute COVID-19 patients require close monitoring in the community and prompt escalation of their treatment. Guidance available so far relies on unvalidated tools and clinician judgement to assess deterioration. COVID-19 specific community-based risk prediction scores such as RECAP may contribute to reducing the uncertainty in the assessment and monitoring of COVID-19 patients, increase safety in clinical practice and improve outcomes by facilitating appropriate treatment escalation.


title: A Pattern Recognition Diagnostic Model to Restore and Emulate Knee Mobility

abstract: Electromyography (EMG) is an electrical voltage potential linked to muscle contraction, resulting in human joint motion, such as knee flexion. Knee injuries, such as knee osteoarthritis (KOA), disrupt functional mobility of the knee joint and subsequently atrophy the muscles controlling knee movement during activities of daily living (ADL). Consequently, weakened muscles exhibiting deteriorated EMG signal fidelity are hypothesized to have discernible signal patterns from a healthy individuals EMG signals. Pattern recognition algorithms are useful for mapping a set of complex inputs (EMG signals and knee angles) to classify knee health status (injured vs. healthy). A secondary outcome is to predict future knee angles from previous input signals to inform a robotic knee exoskeleton to apply real-time torque assistance to a patient during ADL. A Decision Tree Classifier, Random Forest, Naive Bayes, and a Feed Forward Neural Network (Fully Connected) were used for binary classification (healthy vs. injured). Partial Least Squares Regression, Decision Tree Regressor, and XGBoost were used to predict future joint angles for the regression task (knee angle prediction). Overall, the Random Forest Classifier had the best overall classification performance. XGBoost and Decision Tree Regression performed the best among regression algorithms for predicting real-time angles during walking while Partial Least Squares Regression performed the best during the standing tasks. In summary, our Machine Learning methods are useful for assisting clinicians and patients during physical rehabilitation by providing quantitative insight into the patients neuromuscular control of the knee.


title: COVID-19 vaccination effectiveness rates by week and sources of bias

abstract:
ImportanceRandomized clinical trials and observational studies have demonstrated high overall effectiveness for the three US-authorized COVID-19 vaccines against symptomatic COVID-19 infection. Nevertheless, the challenges associated with the use of observational data can undermine the results of the studies.

ObjectiveTo assess the feasibility of using observational data for vaccine effectiveness studies by examining granular weekly effectiveness.

Design, Settings and ParticipantsIn this retrospective cohort study, we used Columbia University Medical Center data linked to State and City Immunization Registries to assess the weekly effectiveness of mRNA COVID-19 vaccines. We conducted manual chart review of cases in week one in both groups along with a set of sensitivity analyses for Pfizer-BioNTech, Moderna and Janssen vaccines.

Main Outcomes and MeasuresWe used propensity score matching with up to 54,987 covariates and fitted Cox proportional hazards models to estimate hazard ratios and constructed Kaplan-Meier plots for two main outcomes (COVID-19 infection and COVID-19-associated hospitalization).

ResultsThe study included 179,666 patients. We observed increasing effectiveness after the first dose of mRNA vaccines with week 6 effectiveness approximating 84% (95% CI 72-91%) for COVID-19 infection and 86% (95% CI 69-95) for COVID-19-associated hospitalization. When analyzing unexpectedly high effectiveness in week one, chart review revealed that vaccinated patients are less likely to seek care after vaccination and are more likely to be diagnosed with COVID-19 during the encounters for other conditions. Sensitivity analyses showed potential outcome misclassification for COVID-19 ICD10-CM diagnosis and the influence of excluding patients with prior COVID-19 infection and anchoring in the unexposed group. Overall vaccine effectiveness analysis in fully vaccinated patients matched the results of the randomized trials.

Conclusions and RelevanceObservational data can be used to ascertain vaccine effectiveness if potential biases are accounted for. The data need to be scrutinized to ensure that compared groups exhibit similar health seeking behavior and are equally likely to be captured in the data. Given the difference in temporal trends of vaccine exposure and baseline characteristics, indirect comparison of vaccines may produce biased results.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhen accounted for all potential biases, what is the weekly effectiveness of COVID-19 vaccines?

FindingsIn this cohort study we replicated the results of randomized clinical trials, discovered plausible increase in effectiveness after week one following the first dose of mRNA COVID-19 vaccines and found differences in temporal trends of vaccine exposure and baseline characteristics in vaccinated groups.

MeaningObservational data can be used to reliably estimate vaccine effectiveness if the biases are accounted for. Vaccines need to be directly compared.


title: COMPARATIVE ANALYSIS OF ANTIBODY RESPONSES FROM COVID-19 CONVALESCENTS RECEIVING VARIOUS VACCINES REVEALS CONSISTENT HIGH NEUTRALIZING ACTIVITY FOR SARS-CoV-2 VARIANT OF CONCERN OMICRON.

abstract: The novel SARS-CoV-2 Omicron variant of concern (VOCs), with its escape from unboosted vaccines and monoclonal antibodies, demonstrates the continued relevance of COVID19 convalescent plasma therapies. Lessons learnt from previous usage of CCP suggests focusing on outpatients and using high nAb-titer units in early disease stages. In this systematic analysis, we show that CCP from unvaccinated donors is not effective against Omicron, while CCP from vaccinees convalescents from previous VOCs or third-dose uninfected vaccinees is likely to remain effective against Omicron. CCP remains the only antibody-based therapy that keeps up with the variants and provides an effective tool to combat the emergence of variants that defeat monoclonal antibodies. Consequently, there is a need for continue study of the variables that determine CCP efficacy.


title: Unsuspected clonal spread of Methicillin-resistant Staphylococcus aureus causing bloodstream infections in hospitalized adults detected using whole genome sequencing

abstract:
BackgroundThough detection of transmission clusters of methicillin-resistant Staphylococcus aureus (MRSA) infections is a priority for infection control personnel in hospitals, the transmission dynamics of MRSA among hospitalized patients with bloodstream infections (BSIs) has not been thoroughly studied. Whole genome sequencing (WGS) of MRSA isolates for surveillance is valuable for detecting outbreaks in hospitals, but the bioinformatic approaches used are diverse and difficult to compare.

MethodsWe combined short-read WGS with genotypic, phenotypic, and epidemiological characteristics of 106 MRSA BSI isolates collected for routine microbiological diagnosis from inpatients in two hospitals over 12 months. Clinical data and hospitalization history were abstracted from electronic medical records. We compared three genome sequence alignment strategies to assess similarity in cluster ascertainment. We conducted logistic regression to measure the probability of predicting prior hospital overlap between clustered patient isolates by the genetic distance of their isolates.

ResultsWhile the three alignment approaches detected similar results, they showed some variation. A pangenome-based alignment method was most consistent across MRSA clonal complexes. We identified nine unique clusters of closely-related BSI isolates. Most BSI were healthcare-associated and community-onset. Our logistic model showed that with 13 single nucleotide polymorphisms the likelihood that any two patients in a cluster overlapped in a hospital was 50 percent.

ConclusionsMultiple clusters of closely related MRSA isolates can be identified using WGS among strains cultured from BSI in two hospitals. Genomic clustering of these infections suggest that transmission resulted from a mix of community spread and healthcare exposures long before BSI diagnosis.

SummaryMultiple clusters of closely related MRSA bloodstream infections were identified using WGS in two hospitals using three bioinformatic workflows. Genomic epidemiology suggests that transmission resulted from a mix of community spread and healthcare exposures long before symptom onset.


title: The HUNT Study: a population-based cohort for genetic research

abstract: The Trondelag Health Study (HUNT) is a population-based cohort of [~]229,000 individuals recruited in four waves beginning in 1984 in Trondelag County, Norway. [~]88,000 of these individuals have available genetic data from array genotyping. HUNT participants were recruited during 4 community-based recruitment waves and provided information on health-related behaviors, self-reported diagnoses, family history of disease, and underwent physical examinations. Linkage via the Norwegian personal identification number integrates digitized health care information from doctor visits and national health registries including death, cancer and prescription registries. Genome-wide association studies of HUNT participants have provided insights into the mechanism of cardiovascular, metabolic, osteoporotic and liver-related diseases, among others. Unique features of this cohort that facilitate research include nearly 40 years of longitudinal follow-up in a motivated and well-educated population, family data, comprehensive phenotyping, and broad availability of DNA, RNA, urine, fecal, plasma, and serum samples.


title: Genomic surveillance reveals the emergence of SARS-CoV-2 Lineage A from Islamabad Pakistan

abstract: The lineage A of SARS-CoV-2 has been around the world since the start of the pandemic. In Pakistan the last case of lineage A was reported in April, 2021 since then no case has been reported. In November, 2021 during routine genomic surveillance at National Institute of Health we have found 07 cases of lineage A from Islamabad, Pakistan. The study reports two novel deletions in the spike glycoprotein. One 09 amino acid deletion (68-76 a.a) is found in the S1 subunit while another 10 amino acid deletion (679-688 a.a) observed at the junction of S1/S2 referred as furin cleavage site. The removal of furin cleavage site may result in impaired virus replication thus decreasing its pathogenesis. The actual impact of these two deletions on the virus replication and disease dynamics needs to be studied in detail. Moreover, the enhanced genomic surveillance will be required to track the spread of this lineage in other parts of the country.


title: Are COVID-19 data reliable? The case of the European Union

abstract: Previous studies have used Benfords distribution to assess whether there is misreporting of COVID-19 cases and deaths. Data inaccuracies provide false information to the media, undermine global response, and hinder the preventive measures taken by countries worldwide. In this study, daily new cases and deaths from all the countries of the European Union were analyzed and the conformance to Benfords distribution was estimated. For each country, two statistical tests and two measures of deviation were calculated to determine whether the reported statistics comply with the expected distribution. Four country-level developmental indexes were also included, the GDP per capita, health expenditures, the Universal Health Coverage index, and the full vaccination rate. Regression analysis was implemented to show whether the deviation from Benfords distribution is affected by the aforementioned indexes. The findings indicate that four countries were in line with the expected distribution, Bulgaria, Croatia, Lithuania, and Romania. For the daily cases, Denmark, Greece, and Ireland, showed the greatest deviation from Benfords distribution and for deaths, Malta, Cyprus, Greece, Italy, and Luxemburg exhibited the highest deviation from Benfords law. Furthermore, it was found that the vaccination rate is positively associated with deviation from Benfords distribution. These results suggest that overall, official data provided by authorities are not confirming Benfords law, yet this approach is not conclusive; it acts as a preliminary tool for data verification. More extensive studies should be made with a more thorough investigation of countries that showed the greatest deviation.


title: Applying Benford's law to COVID-19 data: The case of the European Union