title: Genetic study of late-onset neonatal sepsis reveals significant differences by sex

abstract: Late-Onset Neonatal Sepsis (LOS) is a rare, but life-threatening condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not 100% preventable, identifying susceptibility factors is critical to defining neonates at greater risk. Prior studies demonstrated that both genetics and infant sex influence susceptibility. We, therefore, performed a genome wide association study (GWAS) with 224 cases and 273 controls from six European countries to identify genetic risk factors. We tested for association with both autosomal and X-chromosome variants in the total sample and in the samples stratified by sex. In total 71 SNPs associated with neonatal sepsis at p<1x10-4 in at least one analysis. Most importantly, the sex stratified analyses revealed associations with multiple SNPs (28 SNPs in males and 16 in females), but none of 44 SNPs from single-sex analyses associated with sepsis in the other sex at p<0.05, and the vast majority showed significant SNP X sex interactions (17 of 28 from the male-only analyses and all 16 from the female-only study). Pathway analyses showed that NOTCH signaling is over-represented among loci identified by the analyses. Our results indicate that susceptibility to LOS is genetically sexually dimorphic, and suggest that NOTCH signaling is likely to play a role in it.


title: Plasmodium falciparum malaria during pregnancy: the impact of parasitaemia and anaemia on birthweight

abstract: Malaria in pregnancy remains a major problem of public health concern in Sub-Saharan Africa due to its endemicity and the diverse consequences on both the mother and the baby. Much attention, therefore, is needed to fully understand the epidemiology of the disease and to mitigate the devastating outcomes. The present study aimed at investigating malaria in pregnancy, its adverse effects on pregnant women and the impact on birthweight of babies. A total of 222 pregnant women gave their consent and were recruited into the study during their routine Antenatal care visits. This study employed a combination of cross-sectional and longitudinal cohort study designs. For 122 women in the cross-sectional arm, blood samples and data were obtained once, whilst 100 women in the longitudinal cohort arm were followed up from recruitment until delivery. Demographic information, obstetric history and risk factors were obtained by administering questionnaires. About 1.0 ml of venous blood was drawn to determine malaria parasitaemia and anaemia status of the participants. The birthweights of the babies were also taken at delivery. The prevalence of malaria and anaemia was 19.8% and 27.0% respectively at registration for all 222 participants. All infections were P. falciparum malaria. One hundred and forty-six (65.8%) of participants had ITN but only 72 (32.4%) used it the previous night. Young age and rural settings were risk factors for malaria. Young age and malaria positive pregnant women had increased risk of anaemia. In the follow-up group which ended with 54 participants, the overall prevalence of malaria and anaemia were 18.7% and 32.4% respectively. Fifty-two (96.3%) of pregnant women attended ANC [≥] 4 times and 55.6% took [≥] 3 doses of SP. There were two cases of miscarriage. Low birthweight occurred in 5.6% of babies. Both malaria and anaemia during pregnancy had no significant impact on birthweight of the babies. Although few of the babies had low birthweight, this number can be further reduced when pregnant women attend ANC and take SP at the recommended number of times.

category: infectious diseases


title: Seroprevalence of anti-SARS-CoV-2 antibodies six months into the vaccination campaign in Geneva, Switzerland

abstract:
BackgroundUp-to-date seroprevalence estimates are critical to describe the SARS-CoV-2 immune landscape in the population and guide public health measures. We aimed to estimate the seroprevalence of anti-SARS-CoV-2 antibodies 15 months into the COVID-19 pandemic and six months into the vaccination campaign.

MethodsWe conducted a population-based cross-sectional serosurvey between June 1 and July 7, 2021, recruiting participants from age- and sex-stratified random samples of the general population. We tested participants for anti-SARS-CoV-2 antibodies targeting the spike (S) or nucleocapsid (N) proteins (Roche Elecsys immunoassays). We estimated the anti-SARS-CoV-2 antibodies seroprevalence following vaccination and/or infection (anti-S antibodies), or infection only (anti-N antibodies).

ResultsWe included 3355 individuals, of which 1814 (54.1%) were women, 697 (20.8%) were aged <18 years and 449 (13.4%) were aged [≥]65 years, 2161 (64.4%) tested positive for anti-S antibodies, and 906 (27.0%) tested positive for anti-N antibodies. The total seroprevalence of anti-SARS-CoV-2 antibodies was 66.1% (95% credible interval, 64.1-68.0). We estimated that 29.9% (28.0-31.9) of the population developed antibodies after infection; the rest having developed antibodies only via vaccination. Seroprevalence estimates were similar across sexes, but differed markedly across age groups, being lowest among children aged 0-5 years (20.8% [15.5-26.7]) and highest among older adults aged [≥]75 years (93.1% [89.6-96.0]). Seroprevalence of antibodies developed via infection and/or vaccination was higher among participants with a higher educational level.

ConclusionsMost adults have developed anti-SARS-CoV-2 antibodies, while most teenagers and children remain vulnerable to infection. As the SARS-CoV-2 Delta variant spreads and vaccination rates stagnate, efforts are needed to address vaccine hesitancy, particularly among younger individuals and socioeconomically disadvantaged groups, and to minimize spread among children.

category: epidemiology


title: COVID-19 vaccine uptake among older people in relation to sociodemographic factors: cohort results from southern Sweden

abstract:
The aim of this cohort study was to investigate sociodemographic determinants of COVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden (n = 216 243 at baseline). Uptake of the first dose was high (91.9%) overall, but markedly lower (75.3%) among persons born outside the Nordic countries. Vaccine uptake was generally satisfactory among native Swedes also in areas with lower socioeconomic status, but dropped substantially among non-Nordic born in those areas. The identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement.

Key pointsO_LICOVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden, was high (91.9%) overall, but markedly lower (75.3%) within the group born outside the Nordic countries
C_LIO_LIInverse associations between indicators of neighbourhood deprivation and vaccine uptake were observed, which lowered the uptake among persons born outside the Nordic countries further
C_LIO_LIThe identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement
C_LI


title: Factors influencing wellbeing in young people during COVID-19.

abstract: COVID-19 infection and the resultant restrictions has impacted all aspects of life across the world. This study explores factors that promote or support wellbeing for young people during the pandemic, how they differ by age, using a self-reported online survey with those aged 8 - 25 in Wales between September 2020 and February 2021. Open-ended responses were analysed via thematic analysis to provide further context. A total of 6,291 responses were obtained from 81 education settings across Wales (including primary and secondary schools as well as sixth form, colleges and universities). Wellbeing was highest in primary school children and boys and lowest in those who were at secondary school children, who were girls and, those who preferred not to give a gender. Among primary school children, higher wellbeing was seen for those who played with others (rather than alone), were of Asian ethnicity (OR 2.3, 95% CI: 1.26 to 4.3), lived in a safe area (OR: 2.0, 95% CI: 1.67 to 2.5) and had more sleep. To support their wellbeing young people reported they would like to be able to play with their friends more. Among secondary school children those who were of mixed ethnicity reported lower wellbeing (OR: 5.10, 95% CI: 1.70 to 15.80). To support their wellbeing they reported they would like more support with mental health (due to anxiety and pressure to achieve when learning online). This study found self-reported wellbeing differed by gender, ethnicity and deprivation and found younger children report the need for play and to see friends to support wellbeing but older children/young people wanted more support with anxiety and educational pressures.

category: public and global health


title: The production of anti-PF4 antibodies in anti-phospholipid antibody-positive patients is not affected by COVID-19 vaccination

abstract:
Antibodies against cationic platelet chemokine, platelet factor 4 (PF4/CXCL4) have been described in heparin-induced thrombocytopenia (HIT) but also in patients positive for anti-phospholipid antibodies (aPL) even in the absence of heparin treatment and HIT-related clinical manifestations. Anti-PF4 antibodies have been recently described also in subjects who developed thrombosis with thrombocytopenia syndrome (TTS) in association with adenoviral vector-based, but not with mRNA-based COVID-19 vaccines.

We investigated whether COVID-19 vaccination affects the production of anti-PF4 immunoglobulins detectable by solid phase assay in aPL-positive patients and their ability to induce in vitro platelet activation. Anti-PF4 were found in 9/126 aPL-positive patients, 4/50 COVID-19, 9/49 other infections and 1/50 aPL-negative systemic lupus erythematosus patients. Clinical manifestations of TTS were not observed in any aPL patient positive for anti-PF4, whose sera failed to cause platelet aggregations. The administration of COVID-19 vaccines did not affect the production of anti-PF4 immunoglobulins or their ability to cause platelet aggregation in 44 aPL-positive patients tested before and after vaccination. In conclusion, heparin treatment-independent anti-PF4 antibodies can be found in aPL-positive patients and asymptomatic carriers, but their presence, titer as well as in vitro effect on platelet activation are not affected by COVID-19 vaccination.

category: rheumatology


title: Cognition-oriented treatments and physical exercise on cognitive function in Huntington's disease: Protocol for systematic review

abstract:
IntroductionCognitive impairments are prevalent in Huntingtons disease (HD), occurring many years prior to clinical diagnosis and are the most impactful on quality of life of patients. Cognitive interventions and exercise have been found to be efficacious in improving cognitive function in several clinical populations (e.g., older adults with mild cognitive impairment and dementia). However, the utility of cognitive interventions has not been systematically reviewed in HD. This systematic review aims to examine the efficacy of cognitive and physical interventions on cognitive function in HD.

MethodsElectronic databases (MEDLINE, EMBASE, PsycINFO, CENTRAL) were searched through till 10 May 2021 for interventional studies investigating the effect of cognition-oriented treatments and physical exercise on cognitive function in individuals with HD, compared to any control or no control. The primary outcome is change on objective measures of cognition. Additional outcomes include change in psychosocial, functional and neuroimaging measures. Variations of effects based on population and study factors will be considered. Risk of bias will be assessed using the Cochrane RoB 2 tool and ROBINS-I tool. Where appropriate, outcomes will be pooled using random-effects meta-analyses, heterogeneity will be examined using tau2 and I2 statistics, and moderators will be examined using meta-regression models.

DiscussionThis review will systematically evaluate the efficacy of cognitive and physical interventions on improving cognitive function in HD. The eligibility criteria and planned analyses will allow for a comprehensive assessment of certainty in the evidence that will inform future trials and clinical practice.

RegistrationThis protocol was registered on PROSPERO (CRD42021259152).

category: neurology


title: Characterising the persistence of RT-PCR positivity and incidence in a community survey of SARS-CoV-2

abstract:
BackgroundCommunity surveys of SARS-CoV-2 RT-PCR swab-positivity provide prevalence estimates largely unaffected by biases from who presents for routine case testing. The REal-time Assessment of Community Transmission-1 (REACT-1) has estimated swab-positivity approximately monthly since May 2020 in England from RT-PCR testing of self-administered throat and nose swabs in random non-overlapping cross-sectional community samples. Estimating infection incidence from swab-positivity requires an understanding of the persistence of RT-PCR swab positivity in the community.

MethodsDuring round 8 of REACT-1 from 6 January to 22 January 2021, of the 2,282 participants who tested RT-PCR positive, we recruited 896 (39%) from whom we collected up to two additional swabs for RT-PCR approximately 6 and 9 days after the initial swab. We estimated sensitivity and duration of positivity using an exponential model of positivity decay, for all participants and for subsets by initial N-gene cycle threshold (Ct) value, symptom status, lineage and age. Estimates of infection incidence were obtained for the entire duration of the REACT-1 study using P-splines.

ResultsWe estimated the overall sensitivity of REACT-1 to detect virus on a single swab as 0.79 (0.77, 0.81) and median duration of positivity following a positive test as 9.7 (8.9, 10.6) days. We found greater median duration of positivity where there was a low N-gene Ct value, in those exhibiting symptoms, or for infection with the Alpha variant. The estimated proportion of positive individuals detected on first swab, P0, was found to be higher for those with an initially low N-gene Ct value and those who were pre-symptomatic. When compared to swab-positivity, estimates of infection incidence over the duration of REACT-1 included sharper features with evident transient increases around the time of key changes in social distancing measures.

DiscussionHome self-swabbing for RT-PCR based on a single swab, as implemented in REACT-1, has high overall sensitivity. However, participants time-since-infection, symptom status and viral lineage affect the probability of detection and the duration of positivity. These results validate previous efforts to estimate incidence of SARS-CoV-2 from swab-positivity data, and provide a reliable means to obtain community infection estimates to inform policy response.


title: Rapid antigen testing as a reactive public health response to surges in SARS-CoV-2 outbreak risk in healthcare settings

abstract: Healthcare facilities are vulnerable to SARS-CoV-2 introductions and subsequent nosocomial outbreaks. Antigen rapid diagnostic testing (Ag-RDT) is widely used for population screening, but its health and economic benefits as a reactive response to local surges in outbreak risk are unclear. We simulate SARS-CoV-2 transmission in a long-term care hospital with varying COVID-19 containment measures in place (social distancing, face masks, vaccination). Across scenarios, nosocomial incidence is reduced by up to 40-47% (range of means) with routine symptomatic RT-PCR testing, 59-63% with the addition of a timely round of Ag-RDT screening, and 69-75% with well-timed two-round screening. For the latter, a delay of 4-5 days between the two screening rounds is optimal for transmission prevention. Screening efficacy varies depending on test sensitivity, test type, subpopulations targeted, and community incidence. Efficiency, however, varies primarily depending on underlying outbreak risk, with health-economic benefits scaling by orders of magnitude depending on the COVID-19 containment measures in place.


title: Rapid antigen testing as a reactive response to surges in nosocomial SARS-CoV-2 outbreak risk


title: How did people cope during the COVID-19 pandemic? A Structural Topic Modelling Analysis of Free-Text Data from 11,000 UK Adults

abstract:
BackgroundThe COVID-19 pandemic has had substantial impacts on lives across the globe. Job losses have been widespread, and individuals have experienced significant restrictions on their usual activities, including extended isolation from family and friends. While studies suggest population mental health worsened from before the pandemic, not all individuals appear to have experienced poorer mental health. This raises the question of how people managed to cope during the pandemic.

MethodsTo understand the coping strategies individuals employed during the COVID-19 pandemic, we used structural topic modelling, a text mining technique, to extract themes from free-text data on coping from over 11,000 UK adults, collected between 14 October and 26 November 2020.

ResultsWe identified 16 topics. The most discussed coping strategy was  thinking positively and involved themes of gratefulness and positivity. Other strategies included engaging in activities and hobbies (such as doing DIY, exercising, walking and spending time in nature), keeping routines, and focusing on one day at a time. Some participants reported more avoidant coping strategies, such as drinking alcohol and binge eating. Coping strategies varied by respondent characteristics including age, personality traits and sociodemographic characteristics and some coping strategies, such as engaging in creative activities, were associated with more positive lockdown experiences.

ConclusionA variety of coping strategies were employed by individuals during the COVID-19 pandemic. The coping strategy an individual adopted was related to their overall lockdown experiences. This may be useful for helping individuals prepare for future lockdowns or other events resulting in self-isolation.

CorrectionDue to an error in the analytical syntax, in an earlier version of this manuscript (posted August 13, 2021), topic labels in Figure 2 were mixed up. This - and the resulting discussion - have now been corrected.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/21262002v2_fig2.gif" ALT="Figure 2">
View larger version (52K):
org.highwire.dtl.DTLVardef@62f742org.highwire.dtl.DTLVardef@15748b9org.highwire.dtl.DTLVardef@1678a2borg.highwire.dtl.DTLVardef@a04c58_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 2:C_FLOATNO Association between document topic proportion and participants age (+ 95% confidence intervals). Derived from OLS regression models including adjustment for gender, ethnicity, age, education level, living arrangement, psychiatric diagnosis, long-term physical health conditions, self-isolation status, Big-5 personality traits and keyworker status.

C_FIG


title: ZCWPW1 loss-of-function variants in Alzheimer's Disease

abstract: Genome-wide association studies (GWAS) have identified more than 75 genetic risk loci for Alzheimers Disease (AD), however for a substantial portion of these loci the genetic variants or genes directly involved in AD risk remain to be found. A GWAS locus defined by the index SNP rs1476679 in ZCWPW1 is one of the largest AD loci as the association signal spans 56 potential risk genes. The three most compelling candidate genes in this locus are ZCWPW1, PILRA and PILRB, based on genetic, transcriptomic, and proteomic evidence. We performed amplicon-based target enrichment and next-generation sequencing of the exons, exon-intron boundaries, and UTRs of ZCWPW1, PILRA and PILRB on an Illumina MiSeq platform in 1048 Flanders-Belgian late-onset AD patients and 1037 matched healthy controls. Along with the single-marker association testing, the combined effect of Sanger-validated rare variants was evaluated in SKAT-O. No common variants (n = 40) were associated with AD. We identified 20 validated deleterious rare variants (MAF < 1%, CADD score [≥] 20), 14 of which in ZCWPW1. This included 4 predicted loss-of-function (LoF) mutations that were exclusively found in patients (P = 0.011). Haplotype sharing analysis revealed distant common ancestors for two LoF mutations. Single-molecule long-read Nanopore sequencing analysis unveiled that all LoF mutations are phased with the risk haplotype in the locus. Our results support the recent report for the role of ultra-rare LoF ZCWPW1 variants in AD and suggest a potential risk mechanism for AD through ZCWPW1 haploinsufficiency.


title: Focal gamma activity in frontal control regions revealed using intraoperative electrocorticography

abstract: Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language, cingulo-opercular and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries.


title: High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks


title: Healthcare presentations with self-harm and the association with COVID-19: an e-cohort whole-population-based study using individual-level linked routine electronic health records in Wales, UK, 2016 - March 2021

abstract:
BackgroundMulti-setting population-based studies on healthcare service presentations with self-harm covering the first 12 months of the COVID-19 pandemic are yet to be published.

AimsAscertain changes across settings in healthcare service presentations with self-harm during Waves 1 and 2 of the COVID-19 pandemic.

MethodE-cohort study using individual-level linked routine healthcare data from Wales, UK, 2016-March 2021. We measured weekly proportion of self-harm contacts and people who self-harmed in contact with general practice (GP), emergency department (ED) and hospital admissions. We modelled weekly trends using linear regression and generalised estimated equations, quantifying time differences using difference-in-difference (DiD).

ResultsWe included 3,552,210 Welsh residents aged [≥]10 years. Counts of self-harm presentations across settings was at a minimum at the start of stay-at-home restrictions during both waves and recovered compared to previous years in 3-5 months. Those who self-harmed in April 2020 were more likely to be seen in GP compared to other settings and previous years - mean rate of OR=1.2, although actual numbers fell. The proportion of self-harm ED contacts admitted to hospital dropped from June 2020 (1.9 [1.5-2.3] pp/month). Self-harm and COVID-19 infection had a bidirectional effect - self-harm history had OR=1.4 [1.2-1.6] and incidence had DiD=1.1 [0.8-1.4].

ConclusionsThose that self-harmed and sought help during the COVID-19 pandemic potentially encountered stringent criteria for hospitalisation, particularly in Wave 2, while in Wave 1 they preferentially presented to GP. Reductions in contacts likely resulted in unmet healthcare needs which may later emerge placing further burden on individuals and healthcare services.

Relevance statementThis study provides novel findings on how the COVID-19 pandemic and the measures taken to curb its spread affected self-harm healthcare service presentations. To our knowledge no other population-based studies in the UK have linked routinely collected general practice (GP), emergency department (ED) and hospital admission data covering Waves 1 and 2 of the pandemic.

Reductions in presentations with self-harm during the pandemic may be the result of those not requiring ED care or hospitalisation avoiding seeking help during the pandemic as often as before. Those that did seek help potentially encountered more stringent criteria for hospitalisation, particularly during Wave 2. This likely resulted in unmet healthcare needs which may later emerge placing further burden on individuals and healthcare services. Measures should be put in place to ensure that those who self-harm receive appropriate assessment and intervention.

category: health informatics


title: Protocol for a qualitative study exploring the experiences and perceptions of dolutegravir/lamivudine dual antiretroviral therapy (the PEDAL Study) in people living with HIV

abstract:
INTRODUCTIONAntiretroviral treatment turned HIV infection into a chronic disease and improved quality of life for people living with HIV. Dual-drug combinations can potentially reduce long-term drug-associated toxicities. We aim to investigate patients perceptions and experiences on the safety, effectiveness, tolerability, and unmet needs of the dual-drug combination dolutegravir/lamivudine focusing on patients receiving care in Brighton, United Kingdom. In addition, we will conduct a comparative analysis between patients on dolutegravir/lamivudine and patients on other dual-drug and three-drug combinations. Lastly, the study aims to provide recommendations to improve doctor-patient communication, knowledge and understanding of the treatment plan, and additional care that ought to be considered in patient-centred, holistic care plans.

METHODS AND ANALYSISOur qualitative methodological framework is based on three main methods: cultural domain analysis, focus group discussions, and in-depth interviews. Cultural domain analysis employs a range of techniques (free listing, pile sorts, and rankings) to elicit terms from informants regarding specific cultural domains (i.e., groups of items that are perceived to be of the same kind). This framework has been co-designed with a patient representative to ensure relevance, suitability, and co-production of knowledge. All methods have been tested to take place online via Zoom(R), Skype(R), or Microsoft Teams(R) should participants prefer to participate digitally rather than in person. Padlet(R), an application to create online boards, will be used during the cultural domain analysis session. Data collected will be analysed following the completion of each method embracing an iterative approach through applied thematic analysis.

ETHICS AND DISSEMINATIONEthical approval was obtained from the Health Research Authority (Reference 21/NW/0070). Findings will be used to produce recommendations to improve doctor and patient communication by identifying patients fears, worries, misconceptions, and general concerns of their drug regimen. Conclusions will be disseminated via journal articles, conference papers, and discussions through public engagement events.

PROJECT REGISTRATION NUMBERIRAS Number: 286277

SPONSOR Number: 076 VIL/ 286277

FUNDER Number: 214249

ClinicalTrials.org Registration Number: NCT04901728

STRENGHTS AND LIMITATIONS OF THE STUDYO_ST_ABSStrengthsC_ST_ABS{blacktriangleright} This study will gather qualitative data through three research methods (cultural domain analysis, focus group discussions, and in-depth interviews) to triangulate the findings emerging from patients experiences and perceptions of the dolutegravir/lamivudine (DTG/3TC) dual-drug combination
{blacktriangleright}This study is the first of its kind to provide patient-centred insight into DTG/3TC treatment combination to improve clinical care through an in-depth qualitative, iterative, and comparative approach (against previous survey studies on patients reported outcomes)
{blacktriangleright}The studys protocol has been co-designed with a representative of people living with HIV in Brighton and Hove to ensure co-production of knowledge
{blacktriangleright}Data gathered will be analysed through applied thematic analysis to produce recommendations to improve doctor and patient communication after identifying patients concerns of their drug regimen
{blacktriangleright}The possibility of taking part in research both in-person and online will allow for increased anonymity and flexibility for patients to participate while simultaneously ensuring that they are safe in the COVID-19 environment by reducing in-person meetings

Limitations{blacktriangleright} The cohort in Brighton might not be representative of the whole country and groups like women living with HIV, ethnic minorities, and transgender individuals might be underrepresented
{blacktriangleright}Potential participants who might not feel comfortable meeting in person and who lack the digital skills required might be unable to take part in the study
{blacktriangleright}Patients with complex ARV regimens will not be included given their limited treatment options

category: hiv aids


title: Altered increase in STAT1 expression and phosphorylation in severe COVID-19

abstract: The interferon pathway represents a key antiviral defense mechanism and is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and blocking interferon signaling through JAK STAT inhibition to limit cytokine storms have been proposed. However, little is known so far about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. In the current study, we investigated downstream targets of interferon signaling, including STAT1, pSTAT1 and 2 and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID-19, 17 with mild and 13 with severe infection. We report an upregulation of STAT1 and IRF9 in mild and severe COVID-19 cases, which correlated with the IFN-signature assessed by Siglec-1 (CD169) expression on peripheral monocytes. Most interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe COVID-19 cases compared to mild cases. Contrary to the baseline whole protein STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID-19 cases, indicating a dysbalanced JAK STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN- and IFN-{gamma} stimulation of PBMCs from patients with severe COVID-19. The data suggest impaired STAT1 transcriptional upregulation among severely infected patients which may represent a potential predictive biomarker and may allow stratification of patients for certain interferon-pathway targeted treatments.


title: Another step toward final call on Remdesivir efficacy as a treatment for hospitalized COVID-19 patients: a multicenter open-label trial

abstract:
IntroductionAfter emerging the global pandemic of SARS-CoV2 some preliminary studies demonstrated the efficacy of antiviral treatments. But shortly thereafter, inconsistencies in the results of further clinical trials raised doubts on the efficacy of these agents. In this study, we aimed to evaluate the effect of Remdesivir on hospitalized COVID-19 patients outcomes.

Material and methodsThis study was an open-label, single-armed, clinical trial on hospitalized patients diagnosed with COVID-19 who had progressive respiratory symptoms despite receiving standard care. All patients received Remdesivir and their characteristics, outcomes, time of treatment initiation, and respiratory support stages during hospitalization were registered and followed up for 14 days.

Results145 patients with the mean age of 52.89 {+/-} 1.12 years enrolled in this study, 38 (26.2%) died at the end of 14 days period. The mean time interval from the onset of the symptoms to antiviral treatment was 10.63{+/-}0.56 days. Thirty deceased patients (78.9%) were men, showing 2.8 times higher mortality chance compared to women (ORadj=2.77; 95%CI=1.08-7.09). The type of respiratory support on the first day of treatment initiation showed a significantly lower mortality chance in patients receiving O2 only than those who needed non-invasive and/or mechanical ventilation (ORadj=3.91; 95%CI=1.64-9.32). The start time (early vs late administration) and duration (less or more than 7 days) of antiviral treatment had no statistically significant association with mortality or ventilation escalation among the patients (p-value > 0.05).

ConclusionIn this study, we showed that Remdesivir probably is not effective on the outcome of hospitalized COVID-19 patients.


title: Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: the VITAL-AF Randomized Controlled Trial

abstract:
BackgroundUndiagnosed atrial fibrillation (AF) may cause preventable strokes. Guidelines differ regarding AF screening recommendations. We tested whether point-of-care screening with a handheld single lead electrocardiogram (ECG) at primary care practice visits increases diagnoses of AF.

MethodsWe randomized 16 primary care clinics 1:1 to AF screening using a handheld single-lead ECG (AliveCor KardiaMobile) during vital sign assessments, or usual care. Patients included were aged [≥] 65 years. Screening results were provided to primary care clinicians at the encounter. All confirmatory diagnostic testing and treatment decisions were made by the primary care clinician. New AF diagnoses over one-year follow-up were ascertained electronically and manually adjudicated. Proportions and incidence rates were calculated. Effect heterogeneity was assessed.

ResultsOf 30,715 patients without prevalent AF (n=15,393 screening [91% screened], n=15,322 control), 1.72% of individuals in the screening group had new AF diagnosed at one year versus 1.59% in the control group (risk difference [RD] 0.13%, 95% confidence interval [CI] -0.16-0.42, P=0.38). New AF diagnoses in the screening and control groups differed by age with the greatest effect observed for those aged [≥] 85 years (5.56% versus 3.76%, respectively, RD 1.80%, 95% CI 0.18-3.30). The difference in newly diagnosed AF between the screening period and the prior year was marginally greater in the screening versus control group (0.32% versus -0.12%, RD 0.43%, 95% CI -0.01-0.84). The proportion of individuals with newly diagnosed AF who were initiated on oral anticoagulants was similar in the screening (n=194, 73.5%) and control (n=172, 70.8%) arms (RD 2.7%, 95% CI -5.5-10.4).

ConclusionsScreening for AF using a single-lead ECG at primary care visits was not associated with a significant increase in new AF diagnoses among individuals aged 65 years or older compared to usual care. However, screening may be associated with an increased likelihood of diagnosing AF among individuals aged 85 years or older and warrants further evaluation.

This study is registered with ClinicalTrials.gov, NCT03515057

FundingBristol Myers Squibb-Pfizer Alliance

category: cardiovascular medicine


title: A Third Dose of SARS-CoV-2 Vaccine Increases Neutralizing Antibodies Against Variants of Concern in Solid Organ Transplant Recipients

abstract: Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralizing activity. A third SARS-CoV-2 vaccine dose increased median anti-spike (1.6-fold) and receptor-binding domain (1.5-fold) IgG, as well as pseudoneutralization against VOCs (2.5-fold versus Delta). However, IgG and neutralization activity were significantly lower than healthy controls (p<0.001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination. Correlation with nAb was seen at anti-spike IgG >4 AU on the clinical assay and >10^4 AU on the research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.


title: Beneficial Effects of novel Aureobasidium Pullulans strains produced Beta-1,3-1,6 Glucans on Interleukin-6 and D-Dimer levels in COVID-19 patients; results of a randomized multiple-arm pilot clinical study

abstract:
ObjectiveCytokine storm and Coagulopathy have been implicated as major causes of morbidity and mortality in COVID-19 patients. A black yeast Aureobasidium pullulans AFO-202 strain produced beta 1,3-1,6 glucan has been reported to offer potential immune enhancement and metabolism balancing, as well as mitigation of coagulopathy risks. The N-163 strain produced beta glucan is an efficient anti-inflammatory immune modulator. In this pilot clinical study, we report the beneficial effects of these two beta glucans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients.

MethodsA total of 24 RT-PCR positive COVID-19 patients were recruited (Age range: 18[~]62; 17 males and 7 females). Patients were randomly divided into three groups (Gr): Gr. 1 control (n=8); Gr. 2: AFO-202 beta glucan (n=8); and Gr. 3, a combination of AFO-202 and N-163 beta glucans (n=8). All three groups received the standard care while groups 2 and 3 received additional supplementation of beta glucans for 30 days. In addition to basic clinical parameters, we periodically evaluated D-Dimer, IL-6, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), the neutrophil to lymphocyte ratio (NLR), the lymphocyte to CRP ratio (LCR) and the leukocyte-CRP ratio (LeCR).

ResultsThe duration of hospital stay for all three groups was nearly equivalent. There was no mortality of the subjects in any of the groups. Intermittent oxygen was administered from day of admission for up to four to five days with mask (two to four Lpm) to two subjects in Gr. 2 and one subject in Gr. 3. None of the subjects required ventilation. The D-Dimer values in Gr. 1, which was on average 751 ng/ml at baseline, decreased to 143.89 ng/ml on day 15, but increased to 202.5 ng/ml on day 30, which in groups 2 and 3 decreased on day 15 and continued to remain at normal levels until day 30. IL-6 levels decreased on day 15 from an average of 7.395 pg/ml to 3.16 pg/ml in the control, 26.18 pg/ml to 6.94 pg/ml in Gr. 2 and 6.25 pg/ml to 5.22 pg/ml in Gr. 3. However, when measured on day 30, in Gr. 1, the IL-6 increased to 55.37 pg/ml while there was only slight marginal increase in Gr. 2 but within normal range, and the levels further decreased to less than 0.5 pg/ml in Gr. 3. The same trend was observed with ESR. LCR and LeCR increased significantly in Gr. 3. NLR decreased significantly in groups 2 and 3. There was no difference in CRP within the groups.

ConclusionIn this exploratory study, consumption of Aureobasidium pullulans produced beta glucans for thirty days, results in a significant control of IL6, D-Dimer and NLR, a significant increase in LCR, LeCR and marginal control of ESR in COVID-19 patients. As these beta glucans are well known food supplements with decades of a track record for safety, based on these results, we recommend larger multi-centric clinical studies to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.


title: The impact of seasonal factors on the COVID-19 pandemic waves

abstract: The daily number of new COVID-19 cases per capita is an important characteristic of the pandemic dynamics indicating the appearance of new waves (e.g., caused by new coronavirus strains) and indicate the effectiveness of quarantine, testing and vaccination. Since this characteristic is very random and demonstrates some weekly period, we will use the 7-days smoothing. The second year of the pandemic allows us to compare its dynamics in the spring and the summer of 2020 with the same period in 2021 and investigate the influence of seasonal factors. We have chosen some northern countries and regions: Ukraine, EU, the UK, USA and some countries located in tropical zone and south semi-sphere: India, Brazil, South Africa and Argentina. The dynamics in these regions was compared with COVID-19 pandemic dynamics in the whole world. Some seasonal similarities are visible only for EU and South Africa. In 2020, the southern countries demonstrated the exponential growth, but northern regions showed some stabilization trends.


title: International Completeness of Death Registration 2015-2019

abstract: Death registration completeness, the share of deaths captured by countries vital registration systems, vary substantially across countries. Estimates of completeness, even recent ones, are outdated or contradictory for many countries. In this short paper, I utilize the annual amount of deaths registered in 139 vital registration systems around the world to provide the most up-to-date estimates of death-registration completeness from 2015 to 2019.


title: DECREASED BREADTH OF THE ANTIBODY RESPONSE TO THE SPIKE PROTEIN OF SARS-CoV-2 AFTER VACCINATION

abstract: The rapid development of vaccines to prevent infection by SARS-CoV-2 virus causing COVID-19 makes necessary to compare the capacity of the different vaccines in terms of development of a protective humoral response. Here, we have used a highly sensitive and reliable flow cytometry method to measure the titers of antibodies of the IgG1 isotype in blood of healthy volunteers after receiving one or two doses of the vaccines being administered in Spain. We took advantage of the multiplexed capacity of the method to measure simultaneously the reactivity of antibodies with the S protein of the original strain Wuhan and the variants B.1.1.7 (Alpha), B.1.617.2 (Delta) and B.1.617.1 (Kappa). We found significant differences in the titer of anti-S antibodies produced after a first dose of the vaccines ChAdOx1 nCov-19/AstraZeneca, mRNA-1273/Moderna, BNT162b2/Pfizer-BioNTech and Ad26.COV.S/Janssen. Most important, we found a relative reduction in the reactivity of the sera with the Alpha, Delta and Kappa variants, versus the Wuhan one, after the second boosting immunization. These data allow to make a comparison of different vaccines in terms of anti-S antibody generation and cast doubts about the convenience of repeatedly immunizing with the same S protein sequence.


title: DECREASED BREADTH OF THE ANTIBODY RESPONSE TO THE SPIKE PROTEIN OF SARS-CoV-2 AFTER REPEATED VACCINATION


title: Gender Distribution of Organizing Committees and Invited Speakers at the International Conferences on Emergency Medicine

abstract:
BackgroundIt has been documented that women are under-represented as speakers at emergency medicine conferences globally. This lack of opportunity is likely contributing to the gender gap of women in academic and leadership positions.

MethodsThe Gender-Specific Issues Special Interest Group (GSI-SIG) of the International Federation of Emergency Medicine (IFEM) has analyzed the gender distribution of invited speakers, plenary speakers, and organizing committees from its last three International Conferences on Emergency Medicine in 2016, 2018, and 2019.

ResultsMen comprised 75% (range 57-92%) of organizing committees, 69% (67-70%) of plenary speakers, and 78% (range 75-81%) of invited speakers.

ConclusionThe percentage of women speakers at IFEMs International Conferences on Emergency Medicine is low; even below the percentage of women emergency medicine physicians. By understanding these data and their consequences, changes can be made to close this gender gap and create more equitable opportunities for women and their career advancement.

Strengths and Limitations of this studyO_LIThe gender breakdown of local organizing committee members and invited speakers at three consecutive International Conferences on Emergency Medicine heavily favoured men over women.
C_LIO_LIHaving women on the host countrys local organizing committee had no effect on the gender distribution of speakers.
C_LIO_LIAs these conferences draw speakers and participants from a diverse, international audience, the results are generalizable.
C_LIO_LIThe organizing committee and speakers backgrounds (MD, RN, paramedic) were not delineated, and may have skewed the results.
C_LIO_LIGender non-conforming individuals were not identified.
C_LI

category: emergency medicine


title: The influence of SARS-CoV-2 variants of concern on national case fatality rates

abstract:
BackgroundDuring 2021 several new variants of the SARS-CoV-2 virus appeared with both increased levels of transmissibility and virulence with respect to the original wild variant. The Delta (B.1.617.2) variation, first seen in India, dominates COVID-19 infections in several large countries including the United States and India. Most recently, the Lambda variant of interest with increased resistance to vaccines has spread through much of South America.

ObjectiveThis research explores the degree to which new variants of concern 1) generate spikes and waves of fluctuations in the daily case fatality rates (CFR) across countries in several regions in the face of increasing levels of vaccination of national populations and 2) may increase the vulnerability of persons with certain comorbidities.

MethodsThis study uses new, openly available, epidemiological statistics reported to the relevant national and international authorities for countries across the Americas, Europe, Africa, Asia and the Middle East. Daily CFRs and correlations of fatal COVID-19 infections with potential cofactors are computed for the first half of 2021 that has been dominated by the wide spread of several "variants of concern" as denoted by the World Health Organization.

ResultsThe analysis yields a new quantitative measure of the temporal dynamics of mortality due to SARS-CoV-2 infections in the form of variations of a proxy case fatality rate compared on a country to-country basis in the same region. It also finds minimal variation of correlation between the cofactors based on WHO data and on the average apparent case fatality rate.


title: Savor the flavor - a randomized double-blind study on taste-enhanced placebo analgesia in healthy volunteers

abstract: We conducted a randomized, double-blind, between-group study to investigate how the taste of oral medication affects placebo analgesia. Over three sub-studies, 318 healthy volunteers (297 included) were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste-neutral (water), bitter (quinine), sweet (saccharine), or no placebo drops. Pain ratings indicated that taste enhances placebo analgesia. This effect was small but accounted for a substantial portion of the overall placebo effect and was comparable to WHO stage 1 analgesic effects. Moreover, placebo treatments were associated with an increase in peak heart rate response to cold water. Adverse effects were minimal. These results indicate that added taste may be an easy-to-implement, cost-effective, and safe way to optimize treatment outcomes and that taste-neutral preparations may reduce placebo-related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.

category: pain medicine


title: Rapid initiation of nasal saline irrigation: hospitalizations in COVID-19 patients randomized to alkalinization or povidone-iodine compared to a national dataset

abstract:
ImportanceSARS-CoV-2 enters the nasopharynx to replicate; nasal irrigation soon after diagnosis could reduce viral load and inhibit furin cleavage necessary for cell entry, thereby reducing morbidity and mortality.

ObjectiveTo determine whether initiating nasal irrigation after COVID-19 diagnosis reduces hospitalizations and death in high-risk outpatients, and whether irrigant composition impacts severity.

DesignUnblinded randomized clinical trial of two nasal irrigation protocols in older outpatients PCR positive for SARS-CoV-2, with an observational arm using laboratory-confirmed cases in the CDC COVID-19 Case Surveillance dataset.

SettingSingle-lab community testing facility associated with the emergency department (ED) in Augusta, GA.

ParticipantsA consecutive sample of high-risk adults were enrolled within 24 hours of a positive COVID-19 test between September 24 and December 21 of 2020. Patients aged 55 and older were remotely consented. Among 826 screened, 321 of 694 eligible patients were unable to be reached, 294 refused participation, and 79 participants were enrolled.

InterventionsParticipants were randomly assigned adding 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days.

Main Outcomes and MeasuresThe primary outcome was hospitalization or death from COVID-19 within 28 days of enrollment by daily self-report confirmed with phone calls and hospital records, compared to the CDC Surveillance Dataset covering the same time. Secondary outcomes compared symptom resolution by irrigant additive.

ResultsSeventy-nine high-risk participants were enrolled (mean [SD] age, 64 [8] years; 36 [46%] women; 71% Non-Hispanic White), with mean BMI 30.3. Analyzed by intention-to-treat, by day 28, COVID-19 symptoms resulted in one ED visit and no hospitalizations in 42 irrigating with alkalinization, one hospitalization of 37 in the povidone-iodine group, (1.27%) and no deaths. Of nearly three million CDC cases, 9.47% were known to be hospitalized, with an additional 1.5% mortality in those without hospitalization data. The total risk of hospitalization or death (11%) was 8.57 times that of enrolled patients (SE=2.74; P=.006). 62 completed daily surveys (78%), averaging 1.8 irrigations/day. Eleven had irrigation complaints, and four discontinued. There were no significant differences by additive.

ConclusionSARS-CoV-2+ participants initiating nasal irrigation were over 8 times less likely to be hospitalized than the national rate.

Trial RegistrationClinicalTrial.gov Identifier: NCT04559035

Author ApprovalAll authors have filled out ICMJE and approved submission.

Conflict of Interest StatementMaterials were provided by Neilmed Inc. and Rhinosystems Inc. The study was supported by funding from the Bernard and Anne Gray Donor Advised Fund Community Foundation for Greater Atlanta, Neilmed Inc., and Rhinosystems. No authors have conflict of interest.

Key PointsO_ST_ABSQuestionC_ST_ABSAfter testing positive for COVID-19, will rapidly initiating nasal irrigation reduce the risk of morbidity and mortality compared to a national dataset?

FindingsA consecutive sample of 79 high-risk adults (mean age 64, BMI 30.3) were randomized to initiate one of two nasal irrigation protocols within 24 hours of a positive COVID-19 test. Compared to a CDC COVID-19 National Dataset observational arm, 1.27% of participants initiating twice daily nasal irrigation were hospitalized or died, compared to 11%, a significant difference.

MeaningIn high-risk outpatients testing positive for SARS-CoV-2 who initiated nasal irrigation rapidly after diagnosis, risk of hospitalization or death was eight times lower than national rates reported by the CDC.


title: Rapid initiation of nasal saline irrigation to reduce morbidity and mortality in COVID+ outpatients: a randomized clinical trial compared to a national dataset


title: Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients: a randomized clinical trial compared to a national dataset observational arm


title: Leveraging sequences missing from the human genome to diagnose cancer

abstract: Cancer diagnosis using cell-free DNA (cfDNA) can significantly improve treatment and survival but has several technical limitations. Here, we show that tumor-associated mutations create neomers, DNA sequences 11-18bp in length that are absent in the human genome, that can accurately detect cancer subtypes and features. We show that we can detect twenty-one different tumor-types with higher accuracy than state-of-the-art methods using a neomer-based classifier. Refinement of this classifier via supervised learning identified additional cancer features with even greater precision. We also demonstrate that neomers can precisely diagnose cancer from cfDNA in liquid biopsy samples. Finally, we show that neomers can be used to detect cancer-associated non-coding mutations affecting gene regulatory activity. Combined, our results identify a novel, sensitive, specific and straightforward cancer diagnostic tool.

category: oncology


title: Immunogenicity and safety of inactivated whole virion Coronavirus vaccine with CpG (VLA2001) in healthy adults aged 18 to 55: a randomised phase 1 /2 clinical trial

abstract:
BackgroundWe assessed the safety, tolerability and immunogenicity of VLA2001 is a whole-virion inactivated SARS-CoV-2 vaccine adsorbed to alum with a toll-like receptor 9 agonist adjuvant in healthy volunteers aged 18-55.

MethodsThe first 15 participants were enrolled, in groups of 5, to receive two doses, separated by 21 days, of one of three dose concentrations, administered intramuscularly. 138 further participants were randomised 1:1:1 to receive the same 3 dose concentrations, in a double blinded manner. Primary outcomes were solicited adverse reactions 7 days after each vaccination and neutralising antibody geometric mean titres (GMT) against SARS-CoV-2, 2 weeks after the second vaccination (day 36), measured by live microneutralisation assay against wild-type virus (MNA50). Secondary outcomes included unsolicited adverse events, and humoral and cellular responses at day 36, measured by IgG ELISA against Spike protein and interferon-{gamma} secreting T-cells by ELISpot stimulated with multiple SARS-CoV-2 antigens. (ClinicalTrials.gov NCT04671017, ISRCTN 82411169)

FindingsBetween December 16, 2020 and January 21, 2021, 153 participants were enrolled and randomised evenly between the dose groups. The rates of solicited reactions were similar after the first and second doses and between the three dose groups. The most frequent local reactions were tenderness (58{middle dot}2%) and pain (41{middle dot}8%) and systemic reactions were headache (46%) and fatigue (39{middle dot}2%).

In the high dose group, two weeks following the second dose, the geometric mean titres were 530.4 (95% CI: 421{middle dot}49, 667{middle dot}52) for neutralizing antibodies and 2147{middle dot}9 (95% CI: 1705{middle dot}98, 2704{middle dot}22) for S-binding antibodies. There was a dose dependent response with 90{middle dot}0% (95% CI:78{middle dot}0%.,97{middle dot}0%) seroconversion (4-fold rise) at day 36 in the high dose group, which was significantly higher than rates in both the medium (73.5%; 95% CI: 59%,85%), CIs) and low dose (51%; 95%CI: 37%,65%) rate, CIs) groups (both p < 0.001). Antigen-specific interferon-{gamma} T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49% of high dose recipients, respectively.

InterpretationVLA2001-201 was well tolerated and produced both humoral and cellular immune responses, with a clear dose-response effect.

FundingThis study was funded by the Department of Health and Social Care, UK

The funder had no role in the study design, implementation or analysis.


title: Efficacy and Safety of Ayurveda Intervention AYUSH 64 as add-on therapy for patients with COVID 19 infections: An open labelled, Parallel Group, Randomized controlled clinical trial

abstract: The authors have withdrawn this manuscript because they found a serious issue in data-analysis which leads to wrong interpretation of the results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.


title: Clinical Metagenomic Sequencing for Species Identification and Antimicrobial Resistance Prediction in Orthopaedic Device Infection

abstract:
BackgroundDiagnosis of orthopaedic device-related infection is challenging, and causative pathogens may be difficult to culture. Metagenomic sequencing can diagnose infections without culture, but attempts to detect antimicrobial resistance (AMR) determinants using metagenomic data have been less successful. Human DNA depletion may maximise the amount of microbial DNA sequence data available for analysis.

MethodsHuman DNA depletion by saponin was tested in 115 sonication fluid samples generated following revision arthroplasty surgery, comprising 67 where pathogens were detected by culture and 48 culture-negative samples. Metagenomic sequencing was performed on the Oxford Nanopore Technologies GridION platform. Filtering thresholds for detection of true species versus contamination or taxonomic misclassification were determined. Mobile and chromosomal genetic AMR determinants were identified in Staphylococcus aureus-positive samples.

ResultsOf 114 samples generating sequence data, species-level sensitivity of metagenomic sequencing was 49/65 (75%; 95%CI 63-85%) and specificity 103/114 (90%; 95%CI 83-95%) compared with culture. Saponin treatment reduced the proportion of human bases sequenced in comparison to 5{micro}m filtration from a median (IQR) 98.1% (87.0%-99.9%) to 11.9% (0.4%-67.0%), improving reference genome coverage at 10-fold depth from 18.7% (0.30%-85.7%) to 84.3% (12.9%-93.8%). Metagenomic sequencing predicted 13/15 (87%) resistant and 74/74 (100%) susceptible phenotypes where sufficient data were available for analysis.

ConclusionsMetagenomic nanopore sequencing coupled with human DNA depletion has the potential to detect AMR in addition to species detection in orthopaedic device-related infection. Further work is required to develop pathogen-agnostic human DNA depletion methods, improving AMR determinant detection and allowing its application to other infection types.


title: Seasonal betacoronavirus antibodies expansion post BNT161b2 vaccination associates with reduced SARS-CoV-2 VoCs neutralization

abstract: SARS-CoV-2 vaccination is known to induce antibodies that recognize also variants of concerns (VoCs) of the virus. However, epidemiological and laboratory evidences indicate that these antibodies have a reduce neutralization ability against VoCs. We studied binding and neutralizing antibodies against the Spike RBD and S2 domains of the Wuhan-Hu-1 virus and its alpha and beta VoCs and of seasonal betacoronaviruses (HKU1 and OC43) in a cohort of 31 health care workers vaccinated with BNT162b2-Comirnaty and prospectively followed post-vaccination. The study of sequential samples collected up to 64 days post-vaccination showed that serological assays measuring IgG against Wuhan-Hu-1 antigens were a poor proxy for VoCs neutralization. In addition, in subjects who had asymptomatic or mild COVID-19 prior to vaccination the loss of nAbs following disease can be rapid and protection from re-infection post-vaccination is often no better than in naive subjects. Interestingly, in health care workers naive for SARS-CoV-2 infection, vaccination induced a rapid and transient reactivation of pre-existing seasonal coronaviruses IgG responses that was associated with a subsequent reduced ability to neutralize some VoCs.


title: Cost-effectiveness analysis of Intravascular Temperature Management after cardiac arrest in England

abstract:
BackgroundAlthough there is recognized that Targeted Temperature Management (TTM) can improve neurological outcomes and survival in patients resuscitated from out of hospital cardiac arrest, the cost-effectiveness of multiple methods of TTM is still uncertain.

ObjectiveThis study aimed to evaluate the cost-effectiveness of Intravascular Temperature Management (IVTM) through Thermogard XP in targeted temperature management compared to surface cooling method after cardiac arrest in England.

MethodsWe developed a multi-state Markov model that compared intravascular temperature management through Thermogard XP and the surface cooling method through two different devices including Blanketrol III and Arctic Sun 5000, over a short-term and lifetime horizon. Model input parameters were obtained from the literature and local databases. We assumed hypothetical cohort of 1,000 patients who need TTM after cardiac arrest per year in England. The outcomes were costs (in 2019 {pound}) and quality-adjusted life-years (QALYs), discounted at 3.5% annually. Deterministic and probabilistic analyses were undertaken to examine the effect of alternative assumptions and uncertainty in model parameters on the results.

ResultsIn a simulated cohort of 1,000 patients who need TTM, the Thermogard XP resulted in direct cost savings of {pound}2,339 and {pound}2,925 (per patient) when compared with Blanketrol III and Arctic Sun 5000 respectively, and a gain of 0.98 QALYs over the patient lifetime. Total cost saving considering cohort of 1,000 patients is {pound}2,339,479 and {pound} 2,925,109 when using IVTM through Thermogard XP compared with Blanketrol III and Arctic Sun 5000 respectively in life-time horizon. Results were robust against alternative assumptions, changes in values of input parameters, and alternative time horizons.

ConclusionImplementation of intravascular temperature management using Thermogard XP can lead to cost-savings and improvement in patients quality of life versus surface cooling methods.

category: health economics


title: Cardiac Inflammation after COVID-19 mRNA Vaccines: A Global Pharmacovigilance Analysis

abstract:
BackgroundTo counter the COVID-19 pandemic, mRNA vaccines, namely tozinameran and elasomeran, have been authorized in several countries. These next generation vaccines have shown high efficacy against COVID-19 and demonstrated a favorable safety profile. As widespread vaccinations efforts are taking place, incidents of myocarditis and pericarditis cases following vaccination have been reported. This safety signal has been recently confirmed by the European Medicine Agency and the U.S. Food and Drug Administration.

This study aimed to investigate and analyze this safety signal using a dual pharmacovigilance database analysis.

MethodsThis is as an observational study of reports of inflammatory heart reactions associated with mRNA COVID-19 vaccines reported in the World Health Organizations global individual case safety report database (up to June 30th 2021), and in the U.S. Vaccine Adverse Event Reporting System (VAERS, up to May 21st 2021). Cases were described, and disproportionality analyses using reporting odds-ratios (ROR) and their 95% confidence interval (95%CI) were performed to assess relative risk of reporting according to patient sex and age.

ResultsAt a global scale, the inflammatory heart reactions most frequently reported were myocarditis (1241, 55%) and pericarditis (851, 37%), the majority requiring hospitalization (n=796 (64%)). Overall, patients were young (median age 33 [21-54] years). The main age group was 18-29 years old (704, 31%), and mostly males (1555, 68%). Pericarditis onset was delayed compared to myocarditis with a median time to onset of 8 [3-21] vs. 3 [2-6] days, respectively (p=0.001). Regarding myocarditis, an important disproportionate reporting in males (ROR, 9.4 [8.3-10.6]) as well as in adolescents (ROR, 22.3 [19.2-25.9]) and 18-29 years old (ROR, 6.6 [5.9-7.5]) compared to older patients were observed.

ConclusionsThe inflammatory heart reactions, namely myocarditis and pericarditis, have been reported world-wide shortly following COVID-19 mRNA vaccination. An important disproportionate reporting among adolescents and young adults, particularly in males, was observed especially for myocarditis. Guidelines must take this specific risk into account and to optimize vaccination protocols according to sex and age. While the substantial benefits of COVID-19 vaccination still prevail over risks, clinicians and the public should be aware of these reactions and seek appropriate medical attention.

category: pharmacology and therapeutics


title: Predicting Future Cognitive Impairment in De Novo Parkinson's Disease Using Clinical Data and Structural MRI

abstract:
BACKGROUNDParkinsons disease is the second most common neurodegenerative condition and associated with increasing cognitive dysfunction as the disease progresses. However, subtle cognitive deficits can be detected at diagnosis in 42% of individuals, suggesting that damage may already be present. Our aim was to determine clinical and structural differences in those recently diagnosed with PD who later develop cognitive impairment, and whether these changes predict future cognitive decline.

METHODSClinical and imaging data was acquired from the Parkinsons Progression Markers Initiative for 318 individuals with a diagnosis of Parkinsons disease and baseline 3T T1-weighted MRI. The cohort was divided according to cognitive status over follow-up, with 9 individuals developing Parkinsons disease dementia, 102 developing mild cognitive impairment and 207 remaining cognitively unaffected.

FINDINGSAt baseline, those who went on to develop cognitive impairment (mild cognitive impairment or dementia) were older with more severe motor and non-motor symptoms (anosmia, rapid eye movement sleep behaviour disorder, depression). Grey matter loss was present in those destined for Parkinsons disease dementia in the precuneus, hippocampi, primary olfactory cortex, lingual gyrus, temporal cortex and cerebellum. Those who later developed mild cognitive impairment had an attenuated but similar pattern of grey matter loss in the temporal lobe, lingual gyrus and cerebellum. Using support vector machines with a feature selection step, future cognitive impairment could be predicted using 11 clinical variables (AUC = 0.81), structural imaging (AUC = 0.72) or a combination of these two modalities (AUC = 0.85). These models more accurately predicted those who developed dementia (subgroup sensitivity 100%).

INTERPRETATIONSignificant abnormalities in cortical structure is present at least three years before dementia manifests in Parkinsons disease, with associated differences in clinical profiles. Combining this data provides a technique to accurately identify future cognitive impairment, providing a non-invasive way to stratify individuals early on.


title: Early Reduction of SARS-CoV-2 Replication in Bronchial Epithelium by Kinin B2 Receptor Antagonism

abstract:
BackgroundSARS-CoV2 has evolved to enter the host via the ACE2 receptor which is part of the Kinin-kallirein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV2 infection and epithelial mechanisms of the kinin-kallikrein system at the kinin B2 receptor level in SARS-CoV-2 infection that is of direct translational relevance.

MethodsFrom acute SARS-CoV-2-positive patients and -negative controls, transcriptomes of nasal brushings were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo.

ResultsHere, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive patients. A B2R antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero E6 cells. B2R antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2 in vitro and in a murine airway inflammation model in vivo. In addition, it suppressed gene expression broadly, particularly genes involved in G-protein-coupled-receptor signaling and ion transport.

ConclusionsIn summary, this study provides evidence that treatment with B2R antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R antagonists, like icatibant, in the treatment of early-stage COVID-19.


title: Performance and safety of induced sputum procedure in young children in Malawi: a prospective study

abstract:
BackgroundCollecting sputum specimens are a challenge in infants and young children. We assessed performance and safety of induced sputum (IS) collection in this population, embedded in a prospective study evaluating respiratory cryptosporidiosis in Malawian children with diarrheal disease.

MethodsWe assessed sputum quality and correlation with detection of cryptosporidium, and evaluated safety and adverse events in 162 children.

ResultsAmong 159 stool specimens tested, 34 (21%, 95% CI 15.0 - 28%) were positive for Cryptosporidium spp. There were160 IS and 161 nasopharyngeal (NP) specimens collected. The majority of IS specimens 122/147 (83%) were clear in appearance, and 132/147 (90%) were of good quality. Among the respiratory specimens tested, 10 (6.3%, 95% CI 2.5 - 10) IS and 4 (3% (95% CI 0 - 5)) NP were positive for Cryptosporidium spp. When stool cryptosporidium PCR was the gold standard, IS PCR sensitivity was higher (29 %, 95% CI 22 - 37) compared to NP PCR (12%, 95% CI 7 - 17) for detection of Cryptosporidium spp. One (0.4%) adverse event occurred, a drop in oxygen saturations at 30-minute post procedure evaluation. Consciousness - level, median respiratory rate and oxygen saturations were unchanged, before or after IS.

ConclusionsIS provides good quality specimens, is more sensitive than NP specimens for diagnosis of respiratory cryptosporidiosis, and collection can be done safely in children hospitalized with diarrheal disease.


title: A third COVID-19 vaccine shot markedly boosts neutralizing antibody potency and breadth

abstract:
COVID-19 (coronavirus disease 2019) vaccines have been rapidly developed and deployed globally as a measure to combat the disease. These vaccines have been demonstrated to confer significant protection, but there have been reports of temporal decay in antibody titer. Furthermore, several variants have been identified with variable degrees of antibody resistance. These two factors suggest that a booster vaccination may be worthy of consideration. While such a booster dose has been studied as a series of three homologous vaccines in healthy individuals, to our knowledge, information on a heterologous regimen remains unreported, despite the practical benefits of such a scheme. Here, in this observational study, we investigated the serological profile of four healthy individuals who received two doses of the BNT162b2 vaccine, followed by a third booster dose with the Ad26.COV2.S vaccine. We found that while all individuals had spike-binding antibodies at each of the timepoints tested, there was an appreciable drop in titer by four months following the second vaccination. The third vaccine dose robustly increased titers beyond that of two vaccinations, and these elicited antibodies had neutralizing capability against all SARS-CoV-2 strains tested in both a recombinant vesicular stomatitis virus-based pseudovirus assay and an authentic SARS-CoV-2 assay, except for one individual against B.1.351 in the latter assay. Thus, a third COVID-19 vaccine dose in healthy individuals promoted not just neutralizing antibody potency, but also induced breadth against dominant SARS-CoV-2 variants.

SignificanceCOVID-19 vaccines confer protection from symptomatic disease, but the elicited antibody titer has been found to decrease with time. Furthermore, SARS-CoV-2 variants with relative resistance against antibody neutralization have been identified. To overcome such issues, a third vaccine dose applied as a booster vaccine may be necessary. We studied four healthy individuals who received a heterologous booster dose as a third vaccine. All of these individuals had heightened neutralizing antibody titer following the booster vaccination, and could neutralize nearly all variants tested. Thus, a heterologous third COVID-19 vaccine dose may be a mechanism to both heighten and broaden antibody titers, and could be an additional strategy for controlling the SARS-CoV-2 pandemic.


title: Adjusting for time of infection or positive test when estimating the risk of a post-infection outcome in an epidemic

abstract: When comparing the risk of a post-infection binary outcome, e.g. hospitalisation, for two variants of an infectious pathogen, it is important to adjust for calendar time of infection to avoid the confounding that would occur if the relative incidence of the two variants and the variant-specific risks of the outcome both change over time. Infection time is typically unknown and time of positive test used instead. Likewise, time of positive test may be used instead of infection time when assessing how the risk of the binary outcome changes over calendar time. Here we show that if mean time from infection to positive test is correlated with the outcome, the risk conditional on positive test time depends on whether incidence of infection is increasing or decreasing over calendar time. This complicates interpretation of risk ratios adjusted for positive test time. We also propose a simple sensitivity analysis that indicates how these risk ratios may differ from the risk ratios adjusted for infection time.


title: Whole Genome Sequencing Analysis of Spike D614G Mutation Reveals Unique SARS-CoV-2 Lineages of B.1.524 and AU.2 in Malaysia

abstract: The SARS-CoV-2 has spread throughout the world since its discovery in China, and Malaysia is no exception. WGS has been a crucial approach in studying the evolution and genetic diversity of SARS-CoV-2 in the ongoing pandemic, and while an exceptional number of SARS-CoV-2 complete genomes have since been submitted to GISAID and NCBI, there is a scarcity of data from Malaysia. This study aims to report new Malaysian lineages responsible for the sustained spikes in COVID-19 cases during the third wave of the pandemic. Patients whose nasopharyngeal and oropharyngeal swabs were confirmed positive by real-time RT-PCR with Ct-value < 25 were chosen for WGS. The 10 SARS-CoV-2 isolates obtained were then sequenced, characterized and analyzed, including 1356 sequences of the dominant lineages of D614G variant currently circulating throughout Malaysia. The prevalence of clade GH and G formed strong ground of the discovery of two Malaysian lineages that caused sustained spikes of cases locally. Statistical analysis on the association of gender and age group with Malaysian lineages revealed a significant association (p < 0.05). Phylogenetic analysis revealed dispersion of 41 lineages, for which 22 lineages are still active. Mutational analysis observed unique G1223C missense mutation in Transmembrane Domain of Spike protein. Thus, calls for the large-scale WGS analysis of strains found around the world for greater understanding of viral evolution and genetic diversity especially in addressing the question of the effect of deleterious substitution mutation in transmembrane region of Spike protein.


title: Estimating data-driven COVID-19 mitigation strategies for safe university reopening

abstract: After one pandemic year of remote or hybrid instructional modes, universities in the United States are now planning for an in-person fall semester in 2021. However, it is uncertain what the vaccination rate will look like after students, faculty, and staff return to campus. To help inform university-reopening policies, we collected survey data on social contact patterns and developed an agent-based model to simulate the spread of COVID-19 in university settings. In this paper, we aim to identify the immunity threshold that, if exceeded, would lead to a relatively safe on-campus experience for the university population. With relaxed non-pharmaceutical interventions, we estimated that immunity in at least 60% of the university population is needed for safe university reopening. Still, attention needs to be paid to extreme events that could lead to huge infection size spikes. At an immune level of 60%, continuing non-pharmaceutical interventions, such as wearing masks, could lead to an 89% reduction in the maximum cumulative infection, which reflects the possible non-negligible infection size from extreme events.


title: Genome Wide Analysis Across Alzheimer's Disease Endophenotypes: Main Effects and Stage Specific Interactions

abstract:
IntroductionGenetic association analysis of key Alzheimers disease (AD) endophenotypes may provide insight into molecular mechanisms and genetic contributions.

MethodsMajor AD endophenotypes based on the A/T/N (Amyloid-{beta}, Tau, and Neurodegeneration) biomarkers and cognitive performance were selected from Alzheimers Disease Neuroimaging Initiative (ADNI) in up to 1,565 subjects. Genome-wide association analysis of quantitative phenotypes was performed using a main SNP effect and a SNP by Diagnosis interaction (SNPxDX) model to identify stage specific genetic effects.

ResultsSixteen novel or replicated loci were identified in the main effect model, with six (SRSF10, MAPT, XKR3, KIAA1671, ZNF826P, and LOC100507506) meeting study significance thresholds with the A/T/N biomarkers. The SNPxDX model identified three study significant genetic loci (BACH2, EP300, PACRG-AS1) associated with a neuroprotective effect in later AD stage endophenotypes.

DiscussionAn endophenotype approach identified novel genetic associations and new insights into the associations that may otherwise be missed using conventional case-control models.

category: genetic and genomic medicine


title: Associations of Telemedicine vs. In-Person Ambulatory Care Visits on Cancellation Rates and 30-Day Follow-Up Hospitalizations and Emergency Department Visits

abstract:
ImportanceStudies have shown that telemedicine use in specific conditions can promote continuity of care, decreases healthcare costs, and can potentially improve clinical outcomes. The COVID-19 pandemic forced many healthcare systems to expand access for patients using telemedicine, but little is known about cancellation frequencies in telemedicine vs. in-person appointments and its impact on clinical outcomes.

ObjectiveCompare ambulatory clinic cancellation rates, 30-day inpatient hospitalizations rates, and 30-day emergency department visit rates between in-person and video telemedicine appointments, and examine differences in cancellation rates by age, race/ethnicity, gender, and insurance.

DesignA retrospective cohort study.

SettingThe largest academic healthcare system in the state of Georgia with ambulatory clinics in urban, suburban and rural settings.

ParticipantsAdults scheduled for an ambulatory clinic appointment from June 2020 to December 2020 were included. Each appointment was identified as either a video telemedicine or in-person clinic appointment. Demographics including age, race, ethnicity, gender, primary insurance, and comorbidities were extracted from the electronic medical record.

Main Outcomes and MeasuresThe primary process outcome was ambulatory clinic cancellation rates. The primary clinical outcomes were 30-day hospitalization rates and 30-day emergency department visit rates. Multivariable logistic regression was used to assess differences in the clinical outcomes between appointment types.

ResultsA total of 1,652,623 ambulatory clinic appointments were scheduled during the study period. Ambulatory appointment cancellations rates were significantly lower among telemedicine appointments compared to in-person appointments (20.5% vs. 31.0%, p <.001). Cancellation rates were significantly lower for telemedicine appointments than in-person appointments regardless of gender, age, race, ethnicity, primary insurance, or specialty (p <.05 for all sub-groups). Telemedicine appointments was associated with lower 30-day hospitalization rates compared to in-person appointments (2.1% vs. 2.8%; aOR: 0.72, 95% CI: 0.71 to 0.74). There was no difference in 30-day emergency department visit rates between telemedicine and in-person appointment patients (2.6% vs. 2.6%: aOR: 1.00, 95% CI: 0.98 to 1.02)

Conclusions and RelevanceOur findings suggest that there are fewer barriers to attending an ambulatory care visit via telemedicine relative than in-person. Moreover, using telemedicine was not associated with any more frequent adverse clinical events compared with in-person visits.


title: A systematic review of the impact of the Alpha and Gamma variants of concern on hospitalization and symptomatic rate of SARS-CoV-2

abstract: The hospitalization and symptomatic rates of Severe Acute Respiratory Syndrome Coronavirus Disease 2019 (SARS-CoV-2) are key epidemiological parameters affecting risk analyses conducted for the Canadian Armed Forces (CAF) during the Coronavirus Disease-19 (COVID-19) pandemic. As one of the criteria of a variant of concern (VOC) is that it affects disease severity, the authors sought to understand whether the Alpha and Gamma VOCs are significantly different in these two parameters than the original wildtype of SARS-CoV-2, the most prevalent in relevant areas of Canada as of study initiation. Searches for studies were conducted in Scopus and PubMed, and located through following citations and receiving studies from daily literature scans. For the hospitalization outcome, effect ratios relative to original wildtype were included. For the symptomatic ratio, the ratio itself for each variant was used. Analysis of age-related effects was of particular value, as CAF members are primarily adults under the age of 60. The firmest conclusion of this review is that the Alpha VOC comes with a higher relative risk of hospitalization compared to the original wildtype, most likely above 1.4, while unlikely to be above 2, with the balance of evidence being that the relative risk is not significantly modified by age. The evidence for Gamma is more limited, but the odds ratio may be above 2, and potentially much greater than that, especially for those 20-39 years of age. For both VOCs reports on symptomatic ratio differed on whether there was an effect, as well as its potential direction.


title: Bean extract-based gargle for efficient diagnosing COVID-19 at early-stage using rapid antigen tests: a clinical, prospective, diagnostic study

abstract:
ImportanceThe antigen-based rapid diagnostic test (Ag-RDT), using saliva specimens, is fast, non-invasive and suitable for SARS-CoV-2 self-testing, unlike nasopharyngeal swab (NPS) testing.

ObjectiveTo assess the diagnostic sensitivity of a novel Beanguard gargle (BG)-based virus detection method for early diagnosis of COVID-19.

DesignThis clinical trial was conducted at Gunsan Medical Center, Namwon Medical Center, and Jeonbuk National University Hospital, between May 7 and July 7, 2021.

SettingPaired NPS and BG-based saliva specimens collected from COVID-19 patients and healthy individuals were analyzed using NPS-RT-PCR, BG-RT-PCR, and BG-Ag-RDTs.

ParticipantsThe study comprised 102 COVID-19-positive patients hospitalized after governmental screening process and 100 healthy individuals. Forty-five COVID-19 patients were sampled within 6 days of illness and 57 within 7-15 days; 27 were categorized as asymptomatic and 75, as symptomatic. Eight and 2 patients carried the SARS-CoV-2 Alpha and Delta variants, respectively.

InterventionThe diagnostic performances of BG-Ag-RDT, BG-RT-PCR, and NPS-RT-PCR for detecting SARS-CoV-2 were compared.

Main outcomesThe sensitivities of BG-Ag-RDT and BG-RT-PCR towards salivary viral detection were highly concordant, with no discrimination between symptomatic, asymptomatic, or SARS-CoV-2 variant cases.

ResultsAmong total participants (mean age, 43.7 years), 51% were women. BG-Ag-RDTs showed high sensitivity (97.8%, [95% CI, 88.4% to 99.6%]) and specificity (100%, [95% CI, 96.3% to 100%) in 45 patients within 6 days of illness and could detect all cases of SARS-CoV-2 Alpha and Delta variants. In 11 asymptomatic early-stage cases, both BG-Ag-RDTs and BG-RT-PCR showed excellent sensitivity and specificity of 100% (95% CI, 74.1% to 100% and 95% CI, 20.7% to 100%, respectively). The interaction between SARS-CoV-2 spike proteins and truncated canavalin, an active ingredient from bean extract (BE) and the ultrastructural features of SARS-CoV-2 particles coated with BE were observed. The detachment of the SARS-CoV-2 receptor-binding domain from hACE2 increased as the BE concentration increased, allowing the release of the virus from hACE2 for early diagnosis.

Conclusions and RelevanceUsing BG-based saliva remarkably enhances the Ag-RDT diagnostic performance as an alternative to NPS and enables rapid and accurate COVID-19 self-testing and mass screening, supporting efficient COVID-19 management.

Trial RegistrationKCT0006438

Key PointsO_ST_ABSQuestionC_ST_ABSHow can we collect SARS-CoV-2 from oral cavity to improve the sensitivity of antigen-based rapid diagnostic test (Ag-RDT)?

FindingsIn this clinical study involving 102 hospitalized COVID-19 patients, the Ag-RDT test using Beanguard gargle-based saliva specimens showed significantly enhanced sensitivity and specificity towards detection of SARS-CoV-2 along with Alpha and Delta variants in all patients tested within 6 days of illness.

MeaningOur self-testing method represents an attractive alternative to nasopharyngeal swab RT-PCR for the early diagnosis of symptomatic and asymptomatic COVID-19 cases.


title: Robust SARS-CoV-2-specific and heterologous immune responses after natural infection in elderly residents of Long-Term Care Facilities

abstract:
Long term care facilities (LTCF) provide residential and/or nursing care support for frail and elderly people and many have suffered from a high prevalence of SARS-CoV-2 infection. Although mortality rates have been high in LTCF residents there is little information regarding the features of SARS-CoV-2-specific immunity after infection in this setting or how this may influence immunity to other infections. We studied humoral and cellular immunity against SARS-CoV-2 in 152 LTCF staff and 124 residents over a prospective 4-month period shortly after the first wave of infection and related viral serostatus to heterologous immunity to other respiratory viruses and systemic inflammatory markers. LTCF residents developed high levels of antibodies against spike protein and RBD domain which were stable over 4 months of follow up. Nucleocapsid-specific responses were also elevated in elderly donors but showed waning across all populations. Antibodies showed stable and equivalent levels of functional inhibition against spike-ACE2 binding in all age groups with comparable activity against viral variants of concern. SARS-CoV-2 seropositive donors showed high levels of antibodies to other beta-coronaviruses but serostatus did not impact humoral immunity to influenza or RSV. SARS-CoV-2-specific cellular responses were equivalent across the life course but virus-specific populations showed elevated levels of activation in older donors. LTCF residents who are survivors of SARS-CoV-2 infection thus show robust and stable immunity which does not impact responses to other seasonal viruses. These findings augur well for relative protection of LTCF residents to re-infection. Furthermore, they underlie the potent influence of previous infection on the immune response to Covid-19 vaccine which may prove to be an important determinant of future vaccine strategy.

One sentence summeryCare home residents show waning of nucleocapsid specific antibodies and enhanced expression of activation markers on SARS-CoV-2 specific cells


title: Gut microbiome activity predicts risk of type 2 diabetes and metformin control in a large human cohort

abstract: Recognizing and treating the early stages of type 2 diabetes (T2D) is the most cost effective way to decrease prevalence, before heart disease, renal disease, blindness, and limb amputation become inevitable. In this study, we employ high resolution gut microbiome metatranscriptomic analysis of stool samples from 53,970 individuals to identify predictive biomarkers of type 2 diabetes progression and potential for diagnosis and treatment response. The richness of the metatranscriptomic data enabled us to develop a T2D risk model to delineate individuals with glycemic dysregulation from those within normal glucose levels, with ROC-AUC of 0.83+/-0.04. This risk score can predict the probability of having insulin dysregulation before detecting high glycated hemoglobin (HbA1c), the standard-of-care marker for prediabetes and diabetes. Additionally, a machine learning model was able to distinguish novel metatranscriptomic features that segregate patients who receive metformin and are able to control their HbA1c from those who do not. These discoveries set the stage for developing multiple therapeutic avenues for prevention and treatment of T2D.

category: endocrinology


title: EXCESS DEATHS FROM ALL CAUSES AND BY COVID-19 IN BRAZIL IN 2020

abstract:
ObjectiveTo estimate the 2020 all-cause and COVID-19 excess mortality according to sex, age, race/color, and state, and to compare mortality rates by selected causes with that of the five previous years in Brazil.

MethodsData from the Mortality Information System were used. Expected deaths for 2020 were estimated from 2015 to 2019 data using a negative binomial log-linear model.

ResultsExcess deaths in Brazil in 2020 amounted to 13.7%, and the ratio of excess deaths to COVID-19 deaths was 0.90. Reductions in deaths from cardiovascular diseases (CVD), respiratory diseases, and external causes, and an increase in ill-defined causes were all noted. Excess deaths were also found to be heterogeneous, being higher in the Northern, Center-Western, and Northeastern states. In some states, the number of COVID-19 deaths was lower than that of excess deaths, whereas the opposite occurred in others. Moreover, excess deaths were higher in men, in those aged 20 to 59, and in black, yellow, or indigenous individuals. Meanwhile, excess mortality was lower in women, individuals aged 80 years or older, and in whites. Additionally, deaths among those aged 0 to 19 were 7.2% lower than expected, with reduction in mortality from respiratory diseases and external causes. There was also a drop in mortality due to external causes in men and in those aged 20 to 39 years. Furthermore, reductions in deaths from CVD and neoplasms were noted in some states and groups.

ConclusionThere is evidence of underreporting of COVID-19 deaths and of the possible impact of restrictive measures in the reduction of deaths from external causes and respiratory diseases. The impacts of COVID-19 on mortality were heterogeneous among the states and groups, revealing that regional, demographic, socioeconomic, and racial differences expose individuals in distinct ways to the risk of death from both COVID-19 and other causes.


title: A sensitive and rapid wastewater test for SARS-COV-2 and its use for the early detection of a cluster of cases in a remote community

abstract: Throughout the COVID-19 pandemic, wastewater surveillance has been used to monitor trends in SARS-CoV-2 prevalence in the community. A major challenge in establishing wastewater surveillance programs, especially in remote areas, is the need for a well-equipped laboratory for sample analysis. Currently, no options exist for rapid, sensitive, mobile, and easy-to-use wastewater tests for SARS-CoV-2. The performance of the GeneXpert System, which offers cartridge-based, rapid molecular clinical testing for SARS-CoV-2 in a portable platform, was evaluated using wastewater as the input. The GeneXpert demonstrated a SARS-CoV-2 limit of detection in wastewater below 32 copies/mL with a sample processing time of less than an hour. Using wastewater samples collected from multiple sites across Canada during February and March 2021, a high overall agreement (97.8%) was observed between the GeneXpert assay and laboratory-developed tests regarding the presence or absence of SARS-CoV-2. Additionally, with the use of centrifugal filters the detection threshold of the GeneXpert system was improved to <10 copies/mL in wastewater. Finally, to support on-site wastewater surveillance, GeneXpert testing was implemented in Yellowknife, a remote community in Northern Canada where its use successfully alerted public health authorities to undetected transmission of COVID-19. The identification of SARS-CoV-2 in wastewater triggered clinical testing of recent travelers and identification of new COVID-19 cases/clusters. Taken together, these results suggest the GeneXpert is a viable option for surveillance of SARS-CoV-2 in wastewater in locations that do not have access to established testing laboratories.


title: Association between interruption to medical care and sickness presenteeism during the COVID-19 pandemic: a cross-sectional study in Japan

abstract:
ObjectivesThis study examined the relationship between interruption to routine medical care during the coronavirus disease 2019 pandemic and sickness presenteeism among workers in Japan.

MethodsA cross-sectional study using data obtained from an internet monitor questionnaire was conducted. Interruption to medical care was defined based on the response "I have not been able to go to the hospital or receive treatment as scheduled." The fraction of sickness presenteeism days in the past 30 days was employed as the primary outcome. A fractional logit model was used for analysis to treat bounded data.

ResultsOf the 27,036 participants, 17,526 (65%) were workers who did not require routine medical care, 8,451 (31%) were using medical care as scheduled, and 1,059 (4%) experienced interrupted medical care. The adjusted odds ratio (aOR) of sickness presenteeism was significantly higher among workers who experienced interrupted medical care (3.44; 95% confidence interval [CI]: 3.04-3.89) than those who did not require routine medical care. In terms of symptoms, the highest aOR was observed among workers with mental health symptoms (aOR: 5.59, 95%CI: 5.04-6.20).

ConclusionsThis study suggests the importance of continuing necessary treatment during a pandemic to prevent presenteeism.

category: occupational and environmental health


title: Treatment interruption is a risk factor for sickness presenteeism: a large-scale cross-sectional study during the COVID-19 pandemic


title: Prostate cancer risk stratification improved across multiple ancestries with new polygenic hazard score

abstract:
IntroductionProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.

MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry--the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.

ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.

ConclusionWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.


title: Longitudinal changes in age and race of patients with SARS-CoV-2 in a multi-hospital health system

abstract:
BackgroundThe COVID-19 pandemic continues to affect the United States and the world. Media reports have suggested that the wave of the alpha variant in the Spring of 2021 in the US caused more cases among younger patients and racial and ethnic subgroups.

ApproachWe analyzed electronic health record data from a multihospital health system to test whether younger patients accounted for more cases and more severe disease, and whether racial disparities are widening. We compared demographics, patient characteristics, and hospitalization variables for patients admitted from November 2020 through January 2021 to those admitted in March and April 2021.

ResultsWe analyzed data for 37, 502 unique inpatients and outpatients at 21 hospitals from November 1, 2020 to April 30, 2021. Compared to patients from November through January, those with positive tests in March and April were younger and less likely to die. Among patients under age 50, those with positive tests in March and April were three times as likely to be hospitalized and twice as likely to require ICU admission or mechanical ventilation. Individuals identified as Black represented a greater proportion of cases and hospitalizations in March and April as compared to November through January.

ConclusionsWe found that relative COVID-19 hospitalization rates for younger individuals and individuals identified as Black were rising over time. These findings have important implications for ongoing public health measures to mitigate the impact of the pandemic.