title: Home Monitoring for Fever: An Inexpensive Screening Method to Prevent Household Spread of COVID-19

abstract:
The COVID-19 pandemic surge has exceeded testing capacities in many parts of the world. We investigated the effectiveness of home temperature monitoring for early identification of COVID-19 patients.

Study DesignWe compared home temperature measurements from a convenience sample of 1180 individuals who reported being test positive for SARS-CoV-2 to an age, sex, and location matched control group of 1249 individuals who had not tested positive.

MethodsAll individuals monitored their temperature at home using an electronic smartphone thermometer that relayed temperature measurements and symptoms to a centralized cloud based, de-identified data bank.

ResultsIndividuals varied in the number of times they monitored their temperature. When temperature was monitored for over 72 hours fever (> 37.6{degrees}C or 99.7{degrees}F or a change in temperature of > 1{degrees}C or 1.8{degrees}F) was detected in 73% of test positive individuals, a sensitivity comparable to rapid SARS-CoV-2 antigen tests. When compared our control group the specificity of fever for COVID-19 was 0.70. However, when fever was combined with complaints of loss of taste and smell, difficulty breathing, fatigue, chills, diarrhea, or stuffy nose the odds ratio of having COVID-19 was sufficiently high as to obviate the need to employ RTPCR or antigen testing to screen for and isolate coronavirus infected cases.

ConclusionsOur findings suggest that home temperature monitoring could serve as an inexpensive convenient screen for the onset of COVID-19, encourage earlier isolation of potentially infected individuals, and more effectively reduce the spread of infection in closed spaces.


title: Risk of Myopericarditis following COVID-19 mRNA vaccination in a Large Integrated Health System: A Comparison of Completeness and Timeliness of Two Methods

abstract:
PurposeHow completely do hospital discharge diagnoses identify cases of myopericarditis after an mRNA vaccine?

MethodsWe assembled a cohort 12 to 39 years old patients, insured by Kaiser Permanente Northwest, who received at least one dose of an mRNA vaccine (Pfizer-BioNTech or Moderna) between December 2020 and October 2021. We followed them for up to 30 days after their second dose of an mRNA vaccine to identify encounters for myocarditis, pericarditis or myopericarditis. We compared two identification methods: A method that searched all encounter diagnoses using a brief text description (e.g., ICD-10-CM code I40.9 is defined as  acute myocarditis, unspecified). We searched the text description of all inpatient or outpatient encounter diagnoses (in any position) for "myocarditis" or "pericarditis." The other method was developed by the Centers for Disease Control and Preventions Vaccine Safety Datalink (VSD), which searched for emergency department visits or hospitalizations with a select set of discharge ICD-10-CM diagnosis codes. For both methods, two physicians independently reviewed the identified patient records and classified them as confirmed, probable or not cases using the CDCs case definition.

ResultsThe encounter methodology identified 14 distinct patients who met the confirmed or probable CDC case definition for acute myocarditis or pericarditis with an onset within 21 days of receipt of COVID-19 vaccination. Three of these 14 patients had an ICD-10 code of I51.4 "Myocarditis, Unspecified" which was overlooked by the VSD algorithm. The VSD methodology identified 11 patients who met the CDC case definition for acute myocarditis or pericarditis. Seven (64%) of the eleven patients had initial care for myopericarditis outside of a KPNW facility and their diagnosis could not be ascertained by the VSD methodology until claims were submitted (median delay of 33 days; range of 12-195 days). Among those who received a second dose of vaccine (n=146,785), we estimated a risk as 95.4 cases of myopericarditis per million second doses administered (95% CI, 52.1 to 160.0).

ConclusionWe identified additional valid cases of myopericarditis following an mRNA vaccination that would be missed by the VSDs search algorithm, which depends on select hospital discharge diagnosis codes. The true incidence of myopericarditis is markedly higher than the incidence reported to US advisory committees. The VSD should validate its search algorithm to improve its sensitivity for myopericarditis.

Key PointsO_LIWe identified a higher estimate of myopericarditis following COVID-19 mRNA vaccine by searching encounter text description compared with the Vaccine Safety Datalink (VSD) methodology
C_LIO_LIAn incomplete list of ICD-10 codes and delays in hospital claims data were responsible for the difference
C_LIO_LIWe estimated a risk of 95.4 cases of myopericarditis per million second doses administered in patients age 12-39 which is higher than the incidence reported to US advisory committees
C_LIO_LIWe encourage other VSD sites to validate the case ascertainment of current VSD methodology
C_LI

category: infectious diseases


title: Transmission of SARS-CoV-2 among children and staff in German daycare centers: results from the COALA study

abstract:
BackgroundWhereas the majority of children under 6 years of age attend daycare centers in Germany, evidence on the role of daycare centers in the transmission of SARS-CoV-2 is scarce.

AimsThis study aims to investigate the transmission risk in daycare centers among children and staff and the spread of infections to associated households.

Methods30 daycare groups with at least one recent laboratory-confirmed SARS-CoV-2 case (child or staff) were enrolled in the study (10/2020-06/2021). Close contacts within the daycare group and households were examined over a 12-day period (repeated SARS-CoV-2 PCR tests, genetic sequencing of viruses, documentation of symptoms). Households, local health authorities and daycare staff were interviewed to gain comprehensive information on each outbreak. We determined primary cases for all daycare groups.

ResultsThe number of secondary cases varied considerably between daycare groups. The pooled secondary attack rate (SAR) across all 30 daycare centers was 9.6%. The SAR tended to be higher in daycare centers in which the Alpha variant of the virus was detected (15.9% vs. 5.1% with evidence of wild type). The SAR in households was 53.3%. Exposed children were less likely to get infected with SARS-CoV-2 in daycare centers, compared to adults (7.7% vs. 15.5%).

ConclusionContainment measures in daycare programs are critical and become increasingly important with highly transmissible new variants to reduce SARS-CoV-2 transmission, especially to avoid spread to associated households. Virus variants may modify transmission dynamics in daycare programs.


title: Controlling the worldwide chaotic spreading of COVID-19 through vaccinations

abstract: The striking differences and similarities between the  Spanish-flu of 1918 and the Coronavirus disease of 2019 (COVID-19) are analyzed. Progress in medicine and technology and in particular the availability of vaccines has decreased the death probability from about 2% for the Spanish-flu, to about 10-4 in the UK and 10-3 in Italy, USA, Canada, San Marino and other countries for COVID-19. The logistic map reproduces most features of the disease and may be of guidance for predictions and future steps to be taken in order to contrast the virus. We estimate 6.4 x 107 deceases worldwide without the vaccines, this value decreases to 2.4 x 107 with the current vaccination rate. In November 2021, the number of deceased worldwide was 5.1 x 106. To reduce the fatalities further, it is imperative to increase the vaccination rate worldwide to at least 120 millions/day and the AstraZeneca vaccine due to its efficacity and cost is a possible route to accomplish this.


title: Antibody therapy reverses biological signatures of COVID-19 progression

abstract: Understanding who is at risk of progression to severe COVID-19 is key to effective treatment. We studied correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of SARS-CoV-2 infection. Several laboratory parameters identified study participants at greater risk of severe disease, including a high neutrophil-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test and whole blood transcriptome profiles. Sotrovimab treatment in these groups was associated with normalization of NLR and the transcriptomic profile, and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provided the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identified a 10-gene signature with similar predictive accuracy. In summary, we identified markers of risk for disease progression and demonstrated that normalization of these parameters occurs with antibody treatment of established infection.


title: Reliably Assessing Duration of Protection for COVID-19 Vaccines

abstract: Decision-making about booster dosing for COVID-19 vaccine recipients hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also more reliably detects plateaus in protective effectiveness as compared with the traditional method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines where rapid and reliable understanding of vaccine effectiveness over time is desired.


title: Immunosequencing and epitope mapping reveal substantial preservation of the T cell immune response to Omicron generated by SARS-CoV-2 vaccines

abstract: The Omicron SARS-CoV-2 variant contains 34 mutations in the spike gene likely impacting protective efficacy from vaccines. We evaluated the potential impact of these mutations on the cellular immune response. Combining epitope mapping to SARS-CoV-2 vaccines that we have determined from past experiments along with T cell receptor (TCR) repertoire sequencing from thousands of vaccinated or naturally infected individuals, we estimate the abrogation of the cellular immune response in Omicron. Although 20% of CD4+ T cell epitopes are potentially affected, the loss of immunity mediated by CD4+ T cells is estimated to be slightly above 30% as some of the affected epitopes are relatively more immunogenic. For CD8+ T cells, we estimate a loss of approximately 20%. These reductions in T cell immunity are substantially larger than observed in other widely distributed variants. Combined with the expected substantial loss of neutralization from antibodies, the overall protection provided by SARS-CoV-2 vaccines could be impacted adversely. From analysis of prior variants, the efficacy of vaccines against symptomatic infection has been largely maintained and is strongly correlated with the T cell response but not as strongly with the neutralizing antibody response. We expect the remaining 70% to 80% of on-target T cells induced by SARS-CoV-2 vaccination to reduce morbidity and mortality from infection with Omicron.


title: High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron

abstract:
The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period.

These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.


title: The Canadian COVID-19 Experiences Survey: Study Protocol

abstract:
IntroductionVaccine hesitancy and inconsistent mitigation behavior performance have been significant challenges throughout the COVID-19 pandemic. In Canada, despite relatively high vaccine availability and uptake, willingness to accept booster shots and maintain mitigation behaviors in the post-acute phase of COVID-19 remain uncertain. The aim of the Canadian COVID-19 Experiences Project (CCEP) is two-fold: 1) to identify social-cognitive and neurocognitive correlates of vaccine hesitancy and mitigation behaviors, and 2) to identify optimal communication strategies to promote vaccination and mitigation behaviors into the post-acute phase of the pandemic.

Methods and analysesThe CCEP is comprised of two components: a conventional population survey (Study 1) and a functionally interconnected laboratory study (Study 2). Study 1 will involve 3 waves of data collection. Wave 1, completed between 28 September and 21 October, 2021, recruited 1,958 vaccine-hesitant (49.8%) and fully vaccinated (50.2%) adults using quota sampling to ensure maximum statistical power. Measures included a variety of social cognitive (e.g., beliefs, intentions) and neurocognitive (e.g., delay discounting) measures, followed by an opportunity to view and rate a set of professionally produced COVID-19 public service announcement (PSA) videos for perceived efficacy. Study 2 employs the same survey items and PSAs but coupled with lab-based eye tracking and functional brain imaging to directly quantify neural indicators of attention capture and self-reflection in a smaller community sample. In the final phase of the project, subjective impressions and neural indicators of PSA efficacy will be compared and used to inform recommendations for construction of COVID-19 PSAs into the post-acute phase of the pandemic.

Ethics and disseminationThe CCEP has received ethical review and approval by the University of Waterloo Office of Research Ethics. Findings will be disseminated through peer-reviewed publications and presentations at scientific meetings.


title: The Canadian COVID-19 Experiences Project: Design and Protocol


title: BNT162b2 boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19

abstract: Reports suggest that COVID-19 vaccine effectiveness is decreasing, either due to waning immune protection, emergence of new variants of concern, or both. Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) appeared to be superior in inducing protective immunity, and large scale second booster vaccination is ongoing. However, data comparing declining immunity after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. We longitudinally monitored immunity in ChAd/ChAd (n=41) and ChAd/BNT (n=88) vaccinated individuals and assessed the impact of a second booster with BNT in both groups. The second booster greatly augmented waning anti-spike IgG but only moderately increased spike-specific CD4+ and CD8+ T cells in both groups to cell frequencies already present after the boost. More importantly, the second booster efficiently restored neutralizing antibody responses against Alpha, Beta, Gamma, and Delta, but neutralizing activity against B.1.1.529 (Omicron) stayed severely impaired. Our data suggest that inferior SARS-CoV-2 specific immune responses after homologous ChAd/ChAd vaccination can be cured by a heterologous BNT vaccination. However, prior heterologous ChAd/BNT vaccination provides no additional benefit for spike-specific T cell immunity or neutralizing Omicron after the second boost.


title: Durability of Response to a Third BNT162b2 Vaccine in Adults >=60 Years

abstract:
BackgroundAge/frailty are strong predictors of COVID-19 mortality. After the second BNT162b2 dose, immunity wanes faster in older ([≥]65 years) versus younger adults. The durability of response after the third vaccine is unclear.

MethodsThis prospective cohort study included healthcare workers/family members[≥]60 years who received a third BNT162b2 dose. Blood samples were drawn immediately before (T0), 10{square}19 (T1), and 74{square}103 (T2) days after the third dose. Anti-spike IgG titers were determined using a commercial assay, seropositivity was defined as[≥]50 AU/mL. Neutralising antibody titres were determined at T2. Adverse events, COVID-19 infections, and clinical frailty scale (CFS) levels were documented.

FindingsThe analysis included 97 participants (median age, 70 years [IQR, 66{square}74], 58% CFS level 2). IgG titres, which increased significantly from T0 to T1 (medians, 440 AU/mL [IQR, 294{square}923] and 25,429 [14203{square}36114] AU/mL, respectively; p<0{middle dot}001), decreased significantly by T2, but all remained seropositive (median, 8306 AU/mL [IQR, 4595{square}14701], p<0{middle dot}001 vs T1). In a multivariable analysis, only time from the first vaccine was significantly associated with lower IgG levels at T2 (p=0{middle dot}004). At T2, 60 patients were evaluated for neutralising antibodies; all were seropositive (median, 1294 antibody titre [IQR, 848{square}2072]). Neutralising antibody and anti-spike IgG levels were correlated (R=0{middle dot}6, p<0{middle dot}001). No major adverse events or COVID-19 infections were reported.

InterpretationAnti-spike IgG and neutralising antibody levels remain adequate 3 months after the third BNT162b2 vaccine in healthy adults[≥]60 years, although the decline in IgG is concerning. A third vaccine dose in this population should be top priority.

FundingNo external funding.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on Aug 1, 2021, for published research articles with no date restrictions, using the search terms of "SARS-Cov-2", "COVID-19", "vaccine", "dose", "antibody response", and "adults" with English as a filter. Several studies were identified that investigated waning of immunity in healthy adults. It is well established through epidemiology and serology studies that in healthy adults, the protection conferred by the BNT162b2 messenger RNA (mRNA) vaccine (Pfizer/BioNtech) wanes significantly after several months. Studies have also shown that the immune response to the vaccine varies with age, and that after the second dose of the BNT162b2 vaccine, the older adult population (65-85 years of age) typically has a lower immune response (as reflected in an analysis of anti-spike IgG antibodies and neutralising antibody titres), than younger adults (18-55 years of age), and that the immunity wanes in all age groups within several months.

Added value of this studyThis is, to our knowledge, the first study that examined anti-spike IgG and neutralising antibody titres three months after the third BNT162b2 vaccine dose. The study has demonstrated that three months after that dose, participants, who were healthy adults aged 60 years and older, remained anti-spike IgG seropositive, although a significant decrease in anti-spike IgG titres was observed (compared to two weeks after the third dose). In addition, a statistically significant correlation was observed between the neutralising antibody titres and the anti-spike IgG titres, and all participants were seropositive for neutralising antibodies three months after the third dose. Also, no major adverse events or COVID-19 infections were reported.

Implications of all the available evidenceAs our data suggest that a third dose of the BNT162b2 vaccine is effective in maintaining adequate immune response against COVID-19 for at least several months in healthy adults aged 60 years and older, and as it is well established that older adults are at higher risk of severe COVID-19 disease and COVID-19 mortality, providing a third dose to this population should be a top priority. Our data also highlight that understanding the waning of the immune response in other age groups is key for making evidence-based policies regarding booster vaccinations for the population at large.


title: Detection of the omicron variant virus with the Abbott BinaxNow SARS-CoV-2 Rapid Antigen Assay

abstract: The US Centers for Disease Control and Prevention recommends rapid testing for SARS-CoV-2 infection as a key element of epidemic control. The Abbott BinaxNow is in widespread use in the United States for self-testing and as part of public health screening campaigns, but has not been evaluated for use with the omicron variant of SARS-CoV-2. We recruited individuals testing positive for COVID-19 PCR at an academic medical center. Anterior nasal swabs were stored in viral transport media and evaluated by viral load quantification and whole genome sequencing. We created serial dilutions from 2.5x103-2.5x105 viral copies/specimen for two delta and omicron specimens, respectively, and tested each with the BinaxNow assay per manufacturer instructions. Results were interpreted by three readers, blinded to the specimen variant and concentration. All omicron and delta specimens with concentrations of 100,000 copies/swab or greater were positive by the BinaxNow Assay, a concentration similar to previously reported limits of detection for this assay. Assay sensitivity diminished below that. This study demonstrates that Omicron variant SARS-CoV-2 infections are detected by the BinaxNow rapid antigen assay. Additional laboratory and clinical validation assessments are needed to better determine their limits of detection and performance in real-world settings.


title: Effectiveness of CoronaVac, ChAdOx1, BNT162b2 and Ad26.COV2.S among individuals with prior SARS-CoV-2 infection in Brazil

abstract:
BackgroundCOVID-19 vaccines have proven highly effective among SARS-CoV-2 naive individuals, but their effectiveness in preventing symptomatic infection and severe outcomes among individuals with prior infection is less clear.

MethodsUtilizing national COVID-19 notification, hospitalization, and vaccination datasets from Brazil, we performed a case-control study using a test-negative design to assess the effectiveness of four vaccines (CoronaVac, ChAdOx1, Ad26.COV2.S and BNT162b2) among individuals with laboratory-confirmed prior SARS-CoV-2 infection. We matched RT-PCR positive, symptomatic COVID-19 cases with RT-PCR-negative controls presenting with symptomatic illnesses, restricting both groups to tests performed at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity, and the odds of hospitalization or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines.

FindingsAmong individuals with prior SARS-CoV-2 infection, vaccine effectiveness against symptomatic infection [≥] 14 days from vaccine series completion was 39.4% (95% CI 36.1-42.6) for CoronaVac, 56.0% (95% CI 51.4-60.2) for ChAdOx1, 44.0% (95% CI 31.5-54.2) for Ad26.COV2.S, and 64.8% (95% CI 54.9-72.4) for BNT162b2. For the two-dose vaccine series (CoronaVac, ChAdOx1, and BNT162b2), effectiveness against symptomatic infection was significantly greater after the second dose compared with the first dose. Effectiveness against hospitalization or death [≥] 14 days from vaccine series completion was 81.3% (95% CI 75.3-85.8) for CoronaVac, 89.9% (95% CI 83.5-93.8) for ChAdOx1, 57.7% (95% CI -2.6-82.5) for Ad26.COV2.S, and 89.7% (95% CI 54.3-97.7) for BNT162b2.

InterpretationAll four vaccines conferred additional protection against symptomatic infections and severe outcomes among individuals with previous SARS-CoV-2 infection. Provision of a full vaccine series to individuals following recovery from COVID-19 may reduce morbidity and mortality.

FundingBrazilian National Research Council, Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro, Oswaldo Cruz Foundation, JBS S.A., Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Generalitat de Catalunya.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and SSRN for articles published from January 1, 2020 until December 15, 2021, with no language restrictions, using the search terms "vaccine effectiveness" AND "previous*" AND ("SARS-CoV-2" OR "COVID-19"). We found several studies evaluating ChAdOx1 and BNT162b2, and one additionally reporting on mRNA-1273 and Ad26.COV2.S, which found that previously infected individuals who were vaccinated had lower risk of symptomatic SARS-CoV-2 infection. One study found that risk of hospitalization was lower for previously infected individuals after a full series of BNT162b2 or mRNA-1273. Limited evidence is available comparing effectiveness of one versus two doses among individuals with prior infection. No studies reported effectiveness of inactivated vaccines among previously infected individuals.

Added value of this studyWe used national databases of COVID-19 case surveillance, laboratory testing, and vaccination from Brazil to investigate effectiveness of CoronaVac, ChAdOx1, Ad26.COV2.S and BNT162b2 among individuals with a prior, laboratory-confirmed SARS-CoV-2 infection. We matched >22,000 RT-PCR-confirmed re-infections with >145,000 RT-PCR-negative controls using a test-negative design. All four vaccines were effective against symptomatic SARS-CoV-2 infections, with effectiveness from 14 days after series completion ranging from 39-65%. For vaccines with two-dose regimens, the second dose provided significantly increased effectiveness compared with one dose. Effectiveness against COVID-19-associated hospitalization or death from 14 days after series completion was >80% for CoronaVac, ChAdOx1and BNT162b2.

Implications of all the available evidenceWe find evidence that four vaccines, using three different platforms, all provide protection to previously infected individuals against symptomatic SARS-CoV-2 infection and severe outcomes, with a second dose conferring significant additional benefits. These results support the provision of a full vaccine series among individuals with prior SARS-CoV-2 infection.


title: Premature Ventricular Contractions During the Recovery Phase of Exercise Are Only Associated with Increased Cardiovascular Mortality when Present Together with Echocardiographic Abnormalities

abstract:
BackgroundPremature ventricular contractions (PVCs) during recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with echocardiographic abnormalities, and their combined prognostic performance.

MethodsEchocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and PVCs during recovery ([≥]1/min) were identified among patients having undergone echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables.

ResultsAmong included patients (n=3,106), PVCs during recovery were found in 1,327 (43%) patients, among which the prevalence of echocardiographic abnormalities was increased (58% vs. 44%, p<0.001). Overall, PVCs during recovery were associated with increased cardiovascular mortality (219 total events, 7.9 [5.4-11.1] years follow-up; adjusted hazard ratio (HR [95% confidence interval]) 1.6 [1.2-2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery were associated with increased risk when such were present (HR 3.3 [1.9-5.5], p<0.001) but not when absent (HR 1.5 [0.8-2.8], p=0.22), in reference to those with neither.

ConclusionPVCs during recovery were associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. Our findings provide mechanistic insights to the increased CV risk reported in patients with PVCs during recovery.

category: cardiovascular medicine


title: Prognostic implications of structural heart disease and premature ventricular contractions in recovery of exercise


title: Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: a prospective case-cohort study

abstract:
BackgroundEpidemiological investigations implied that inter-individual variations of mitochondrial DNA copy number (mtDNAcn) could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain.

MethodsWe conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n=278), gastric cancer (GC, n=138), and esophageal cancer (EC, n=72) as well as a random subcohort (n=1173), who were followed up from baseline to the end of 2018. Baseline blood mtDNAcn was determined with quantitative PCR assay, and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models.

ResultsSignificant U-shaped associations were observed between mtDNAcn and risks of CRC, GC, EC, and total GICs. Compared to subjects within the 2nd quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3) and 4th (Q4) quartile subgroups showed increased risks of CRC [HR(95%CI)=2.27(1.47-3.52), 1.65(1.04-2.62), and 2.81(1.85-4.28), respectively] and total GICs [HR(95%CI)=1.84(1.30-2.60), 1.47(1.03-2.10), and 2.51(1.82-3.47), respectively], and those within Q4 subgroup present elevated GC and EC risks [HR(95%CI)=2.16(1.31-3.54) and 2.38(1.13-5.02), respectively]. Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, and smoking status. Notably, there were joint effects of age and smoking status with mtDNAcn on CRC and total GICs risks.

ConclusionsThis prospectively case-cohort study showed U-shaped associations between mtDNAcn and incident risks of GICs, but further researches are needed to confirm these results and uncover underlying biological mechanisms.

category: epidemiology


title: Dying from COVID-19 or with COVID-19: a definitive answer through a retrospective analysis of mortality in Italy

abstract:
BackgroundCOVID-19 mortality was associated with several reasons, including conspiracy theories and infodemic phenomena. However, little is known about the potential endogenous reasons for the increase in COVID-19 associated mortality in Italy.

ObjectiveThis study aimed to search the potential endogenous reasons for the increase in COVID-19 mortality recorded in Italy during the year 2020 and evaluate the statistical significance of the latter.

MethodsWe analyzed all the trends in the timelapse 2011-2019 related to deaths by age, sex, region, and cause of death in Italy and compared them with those of 2020. Ordinary least squares (OLS) linear regressions and ARIMA (p, d, q) models were applied to investigate the predictions of death in 2020 as compared to death reported in the same year. Grubbs and Iglewicz-Hoaglin tests were used to identify the statistical differences between the predicted and observed deaths. The relationship between mortality and predictive variables was assessed using OLS multiple regression models.

ResultsBoth ARIMA and OLS linear regression models predicted the number of deaths in Italy during 2020 to be between 640,000 and 660,000 (95% confidence intervals range: 620,000 - 695,000) and these values were far from the observed deaths reported (above 750,000). Significant difference in deaths at national level (P = 0.003), and higher male mortality than women (+18% versus +14%, P < 0.001 versus P = 0.01) was observed. Finally, higher mortality was strongly and positively correlated with latitude (R = 0.82, P < 0.001).

ConclusionsOur findings support the absence of historical endogenous reasons capable of justifying the increase in deaths and mortality observed in Italy in 2020. Together with the current knowledge on the novel coronavirus 2019, these findings provide decisive evidence on the devastating impact of COVID-19 in Italy. We suggest that this research be leveraged by government, health, and information authorities to furnish proof against conspiracy hypotheses. Moreover, given the marked concordance between the predictions of the ARIMA and OLS regression models, we suggest that these models be exploited to predict mortality trends.


title: Wastewater sequencing uncovers early, cryptic SARS-CoV-2 variant transmission

abstract: As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing/sequencing capacity, which can also introduce biases. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here, we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We develop and deploy improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detect emerging variants of concern up to 14 days earlier in wastewater samples, and identify multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.


title: Understanding the impact of the COVID-19 pandemic on a socially deprived UK coastal town: a preliminary exploratory analysis of health and socioeconomic data

abstract:
IntroductionIn addition to the direct impact of COVID-19 infections on health and mortality, a growing body of literature indicates there are wide-ranging indirect impacts of the COVID-19 pandemic and associated public health measures on population health and wellbeing. Exploring these indirect impacts in the context of a socially deprived UK coastal town will help identify priority areas to focus COVID-19 recovery efforts on.

MethodsData on primary care diagnosis, hospital admissions, and several socioeconomic outcomes between 2016 and Spring 2021 in the UK town of Fleetwood were collected and analysed in an exploratory analysis looking at pre- and post-COVID-19 patterns in health and social outcomes. Weekly and monthly trends were plotted by time and differences between periods examined using Chi-squared and t-tests.

ResultsInitial falls in hospital admissions and diagnoses of conditions in primary care in March 2020 were followed by sustained changes to health service activity for specific diagnostic and demographic groups, including for chronic kidney disease and young people. Increases in the number of people receiving Universal Credit and children eligible for free school meals appear to be greater for those in the least deprived areas of the town.

DiscussionThese exploratory findings provide initial evidence of the sustained impact of the pandemic across several health and social outcomes. Examining these trends in multivariate analyses will further test these associations and establish the strength of the medium term impact of the pandemic on the population of this coastal town. Advanced modelling of this data is ongoing and will be published shortly.


title: Use of Baricitinib in Treatment of COVID-19: A Systematic Review

abstract:
ObjectivesTo assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19.

MethodsSystematic literature search was conducted in the WHO COVID-19 Coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1st 2019 and September 30th 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, and relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools.

ResultsA total of 267 articles were found to be eligible after primary screening of title and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add on to standard therapy, either alone or in combination with other drugs, was found to have favourable outcomes in moderate to severe hospitalised patients with COVID-19. Furthermore, ongoing trials indicate that drug is being extensively studied across the world for its safety and efficacy in COVID-19.

ConclusionBaricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia and further evidence may establish the drug as a standard treatment among such patients.

category: respiratory medicine


title: The Health Effects of Chunga Dumpsite on surrounding communities in Lusaka, Zambia.

abstract:
BackgroundDumpsites in low and middle income countries (LMICs) are commonly used for solid waste disposal as opposed to landfills. However, these are naturally unsanitary hence provide ideal conditions for breeding of disease transmitting agents and become predisposing factors for spread of diseases and infections to surrounding communities. This study aimed at determining the Health Effects of Chunga Dumpsite on surrounding communities in Lusaka, Zambia.

Design and MethodsThis was a mixed method design and employed a cross sectional approach and case study conducted concurrently. Communities were stratified by distance into Stratum One (within 250 meters radius) and Two (above 250 to 500 meters). Quantitative data were collected from total 200 households thus 100 households from each stratum by using self-administered questionnaires. Qualitative data were collected from Two Key informants from the Local Authority and 15 participants using semi-structured interview guide. Both data were collected from December 22nd, 2018 to February 18th, 2019.

ResultsResults revealed that smoke and various gasses emitted from burning and decomposing waste compromised quality of air in surrounding communities. Communities were infested with flies, mosquitoes and vermin. Consequently, (73.5%) complained of persistent coughing, (65.1%) suffered from malaria, (72.6%) complained of persistent headaches and (62.2%) had frequent diarrhoea cases in stratum one. Respiratory problems were more pronounced at night possibly due to high humidity which hindered pollutants to easily escape. However, these cases reduced drastically in stratum two.

ConclusionsUnsanitary dumpsites in LMICs including Zambia are commonly used as solid waste disposal facilities as opposed to sanitary landfills and become predisposing factors for spread of diseases. Short proximities to dumpsites by unplanned human settlements cause serious environmental challenges leading to public health risks to surrounding communities.

category: occupational and environmental health


title: Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications.

abstract:
Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICI) remain limited to a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetics and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveals a highly prevalent patient molecular profiles predictive of response to PD-(L)1 immune checkpoint inhibitors. A clinical blood test based on the set of 8 3D genomic biomarkers has been developed and validated on several independent cancer patient cohorts to predict response to PD-(L)1 immune checkpoint inhibition. The predictive 8 biomarker set is derived from prospective observational clinical trials, representing 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in diverse indications: melanoma, non-small cell lung, urethral, hepatocellular, bladder, prostate cancer, head and neck, vulvar, colon, breast, bone, brain, lymphoma, larynx cancer, and cervix cancers.

The 3D genomic 8 biomarker panel for response to immune checkpoint therapy achieved high accuracy up to 85%, sensitivity of 93% and specificity of 82%. This study demonstrates that a 3D genomic approach could be used to develop a predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients.

category: oncology


title: NATIONAL SCALE REAL-TIME SURVEILLANCE OF SARS-COV-2 VARIANTS DYNAMICS BY WASTEWATER MONITORING IN ISRAEL

abstract:
In this report, we describe a national-scale monitoring of the SARS-COV-2 (SC-2) variant dynamics in Israel, using multiple-time sampling of twelve wastewater treatment plants. We used a combination of inclusive and selective quantitative PCR assays that specifically identify variants A19 or B.1.1.7 and tested each sample for the presence and relative viral RNA load of each variant. We show that between December-2020 and March-2021, a complete shift in the SC-2 variant circulation was observed, where the B.1.1.7 replaced the A19 in all examined test points. We further show that the normalized viral load (NVL) values and the average new cases per week reached a peak in January 2021, and then decreased gradually in almost all test points, in parallel with the progression of the national vaccination campaign, during February-March 2021. This study demonstrates the importance of monitoring SC-2 variant dynamics on a national scale through wastewater sampling. It also provides a proof-of-concept methodology for continuous surveillance by using a combination of inclusive and selective PCR tests, which is far more amendable for high throughput monitoring compared with sequencing. This approach may be useful for real-time dynamics surveillance of current and future variants, such as the Omicron (BA.1) variant.

SynopsisThis study describes the continuous monitoring of the SARS CoV-2 variant B.1.1.7 circulation in wastewater in Israel using a positive/negative quantitative PCR assay.


title: Can individuals with low antibody responses to vaccines against other viruses acquire adequate SARS-CoV-2 antibody after vaccination with the BNT162b2 mRNA vaccine?

abstract:
ObjectiveIn Japan, healthcare workers (HCWs) are vaccinated against contagious viruses (measles, rubella, chickenpox, mumps, and hepatitis B) to prevent nosocomial infection; however, some do not produce sufficient antibodies (suboptimal responders). Whether suboptimal responders to live attenuated viruses or inactivated viruses vaccines can produce adequate antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines remains to be elucidated.

MethodsIn this prospective cohort study, SARS-CoV-2 anti-spike antibodies were measured 11 times, from before the first BNT162b2 vaccination to 5 months after the second vaccination. Antibody titers of suboptimal and normal responders were compared. SARS-CoV-2 neutralizing antibody activity was measured twice in suboptimal responders, 1 week to 1 month, and 5 months after the second vaccination.

PatientsThis study included 50 HCWs who received two doses of mRNA BNT162b2 vaccine 3 weeks apart.

ResultsAfter vaccination, the SARS-CoV-2 anti-spike antibody was detectable in the samples from suboptimal and normal responders at each timepoint. The median SARS-CoV-2 anti-spike antibody titer was higher in suboptimal responders than in normal responders 1 week after receiving the second dose of BNT162b2 vaccine (3721.0 vs. 2251.5, P=0.029). Suboptimal responders had SARS-CoV-2 neutralizing antibody activity 1 week to 1 month, and 5 months after the second vaccination, which exceeded the positive threshold 5 months after the second vaccination.

ConclusionAfter BNT162b2 vaccination, suboptimal responders acquired adequate SARS-CoV-2 anti-spike and SARS-CoV-2 neutralizing antibodies to prevent SARS-CoV-2. These results suggest that vaccination with mRNA vaccine against SARS-CoV-2 should also be recommended for suboptimal responders to conventional vaccines.


title: Can individuals with low antibody responses to conventional antiviral vaccines acquire adequate antibody by the SARS-CoV-2 mRNA vaccine?


title: Can individuals with suboptimal antibody responses to conventional antiviral vaccines acquire adequate antibodies from SARS-CoV-2 mRNA vaccination?


title: Disease severity related to VOC dominance in unvaccinated SARS-CoV-2 positive adults without risk factors in Sweden

abstract:
Although the emerging SARS-CoV-2 variants of concern (VOC) have shown increasing transmissibility, their role for causing severe disease has not been fully clarified. Here, we studied changes in rates of hospitalisation and severe illness (subjection to high-flow nasal oxygen or admission to an intensive care unit during hospital stay) among all (n=685 891) unvaccinated SARS-CoV-2 positive adults without risk factors in Sweden from November 2020 to September 2021.

After adjustment for age, sex, and socio-economic factors, and with November 2020 (non-VOC period) as reference, the odds ratios (OR) for hospitalisation were 1.6-1.7 in March-May 2021 (Alpha VOC dominance) and 2.4-3.0 in June-September 2021 (Delta VOC dominance), and the ORs for severe illness were 1.8-2.1 in March-May 2021 and 3.1-4.7 in June-September 2021. This study shows that unvaccinated adults without risk factors, have had a gradually increased risk for hospital admission and severe illness when infected with the Alpha and Delta VOCs, respectively.


title: SARS-CoV-2 Omicron VOC Transmission in Danish Households

abstract:
1The Omicron variant of concern (VOC) is a rapidly spreading variant of SARS-CoV-2 that is likely to overtake the previously dominant Delta VOC in many countries by the end of 2021.

We estimated the transmission dynamics following the spread of Omicron VOC within Danish households during December 2021. We used data from Danish registers to estimate the household secondary attack rate (SAR).

Among 11,937 households (2,225 with the Omicron VOC), we identified 6,397 secondary infections during a 1-7 day follow-up period. The SAR was 31% and 21% in households with the Omicron and Delta VOC, respectively. We found an increased transmission for unvaccinated individuals, and a reduced transmission for booster-vaccinated individuals, compared to fully vaccinated individuals. Comparing households infected with the Omicron to Delta VOC, we found an 1.17 (95%-CI: 0.99-1.38) times higher SAR for unvaccinated, 2.61 times (95%-CI: 2.34-2.90) higher for fully vaccinated and 3.66 (95%-CI: 2.65-5.05) times higher for booster-vaccinated individuals, demonstrating strong evidence of immune evasiveness of the Omicron VOC.

Our findings confirm that the rapid spread of the Omicron VOC primarily can be ascribed to the immune evasiveness rather than an inherent increase in the basic transmissibility.


title: The changing epidemiology of human monkeypox - a potential threat? A systematic review

abstract:
Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. Since monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the Congo (DRC), it has spread to other regions of Africa (primarily West and Central), and cases outside Africa have emerged in recent years. We conducted a systematic review of peer-reviewed and grey literature on how monkeypox epidemiology has evolved, with particular emphasis on the number of confirmed, probable, and/or possible cases, age at presentation, mortality, and geographical spread. The review is registered with PROSPERO (CRD42020208269). We identified 48 peer-reviewed articles and 18 grey literature sources for data extraction. The number of human monkeypox cases has been on the rise since the 1970s, with the most dramatic increases occurring in the DRC. The median age at presentation has increased from 4 (1970s) to 21 years (2010-2019). There was an overall case fatality rate of 8.7%, with a significant difference between clades -- Central African 10.6% (95% CI: 8.4% - 13.3%) vs. West African 3.6% (95% CI: 1.7% - 6.8%). Since 2003, import- and travel-related spread outside of Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. Our review shows an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.

Author SummaryMonkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. We conducted a systematic review to assess how monkeypox epidemiology has evolved since it was first diagnosed in 1970 in the Democratic Republic of the Congo. In total, human monkeypox has now appeared in 10 African countries and 4 countries elsewhere. Examples include Nigeria, where the disease re-emerged in the last decade after a 40-year hiatus, and the United States, where an outbreak occurred in 2003. The number of cases has increased at a minimum of 10-fold and median age at presentation has evolved from young children (4 years old) in the 1970s to young adults (21 years old) in 2010-2019. This may be related to the cessation of smallpox vaccinations, which provided some cross-protection against monkeypox. The case fatality rate for the Central African clade was 10.6% versus 3.6% for the West African clade. Overall, monkeypox is gradually evolving to become of global relevance. Surveillance and detection programs are essential tools for understanding the continuously changing epidemiology of this resurging disease.


title: Pandemic-related decline in injuries related to women wearing high-heeled shoes: Analysis of U.S. data for 2016-2020

abstract:
BackgroundWearing high-heeled shoes is associated with injury risk. During the COVID-19 pandemic, changes in work and social behavior may have reduced womens use of such footwear.

MethodsThis study assessed the trend in high-heel related injuries among U.S. women, using 2016-2020 data from the U.S. Consumer Product Safety Commissions National Electronic Injury Surveillance System (NEISS).

ResultsIn 2020 there were an estimated 6,290 high-heel related emergency department visits involving women ages 15-69, down from 16,000 per year in 2016-2019. The 2020 decline began after the start of the COVID-19 shutdowns on March 15. There was no significant change in the percentage of fractures or hospital admissions.

ConclusionsThe COVID-19 pandemic was associated with a decline in reported injuries related to high-heeled shoes among US women. If this resulted from fewer women wearing such shoes, and such habits influence future behavior, the result may be fewer injuries in the future.

category: public and global health


title: Direct, Indirect and Mixed Methods of Health Education By Nurse and Its Impact on Type 2 Diabetes Patients: A Literature review

abstract:
BackgroundDiabetes Mellitus (DM) is one of the chronic non-communicable diseases that has currently been very common, in particular Diabetes Mellitus type 2 that threatens public health. It has been included in the category of the six biggest causes of worldwide death, but self-control of treatment and obedience to self-care is still low. One of the influencing factors is related to the lack of knowledge. Providing ongoing health education is one of the solutions or efforts to strengthen knowledge in type 2 diabetes. The aim was to identify the various health education methods currently used by nurses and their impacts on type 2 DM. The method used is a literature review. The literature was searched on data based on Scopus, Web of Science, SAGE, CINAHL with the keywords "methods" or "interventions", "education", "health", "nursing", and "type 2 diabetes melitus. Fifteen (15) pieces of literature were considered to meet the criteria inclusion.

ResultsThree (3) types of health education methods used by nurses were identified: 1). Direct health education refers to providing education by nurses to patients through training, coaching, interviews, Focus Group Discussion (FGD) and home visits; 2). Indirect Health Education - using mobile phones; 3). The mixed of direct health education and the use of mobile phone-based applications is carried out with the application of mobile health technology and nurse health coaching. The impact of providing health education by nurses to type 2 diabetic patients: increasing of knowledge, behavioral change on preventing diabetes complications, increasing self-efficacy, increasing self-care activities (diet management, physical activity, monitoring blood sugar levels, and foot care).

Conclusionvarious methods of health education carried out by nurses currently have a positive impact on improving and increasing self-care management and efforts to prevent complications in type 2 diabetes.


title: Omicron infection enhances neutralizing immunity against the Delta variant

abstract: Omicron variant (B.1.1.529) infections are rapidly expanding worldwide, often in settings where the Delta variant (B.1.617.2) was dominant. We investigated whether neutralizing immunity elicited by Omicron infection would also neutralize the Delta variant and the role of prior vaccination. We enrolled 23 South African participants infected with Omicron a median of 5 days post-symptoms onset (study baseline) with a last follow-up sample taken a median of 23 days post-symptoms onset. Ten participants were breakthrough cases vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV2.S. In vaccinated participants, neutralization of Omicron increased from a geometric mean titer (GMT) FRNT50 of 28 to 378 (13.7-fold). Unvaccinated participants had similar Omicron neutralization at baseline but increased from 26 to only 113 (4.4-fold) at follow-up. Delta virus neutralization increased from 129 to 790, (6.1-fold) in vaccinated but only 18 to 46 (2.5-fold, not statistically significant) in unvaccinated participants. Therefore, in Omicron infected vaccinated individuals, Delta neutralization was 2.1-fold higher at follow-up relative to Omicron. In a separate group previously infected with Delta, neutralization of Delta was 22.5-fold higher than Omicron. Based on relative neutralization levels, Omicron re-infection would be expected to be more likely than Delta in Delta infected individuals, and in Omicron infected individuals who are vaccinated. This may give Omicron an advantage over Delta which may lead to decreasing Delta infections in regions with high infection frequencies and high vaccine coverage.


title: Omicron infection of vaccinated individuals enhances neutralizing immunity against the Delta variant


title: SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron

abstract: The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations that contribute to escape from the neutralizing antibody responses, and reducing vaccine protection from infection. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, and in unvaccinated convalescent COVID-19 patients (n = 70). We found that 70-80% of the CD4 and CD8 T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to that of the Beta and Delta variants, despite Omicron harbouring considerably more mutations. Additionally, in Omicron-infected hospitalized patients (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those found in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). These results demonstrate that despite Omicrons extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell response, induced by vaccination or natural infection, cross-recognises the variant. Well-preserved T cell immunity to Omicron is likely to contribute to protection from severe COVID-19, supporting early clinical observations from South Africa.


title: Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in Japanese patients after allogeneic stem cell transplantation.

abstract: Patients who have undergone hematopoietic stem cell transplantation (HSCT) for hematological disease experience high mortality when infected by coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccine in HSCT patients remains to be investigated. We prospectively evaluated the safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine (Pfizer BioNTech) in 25 Japanese allogeneic HSCT patients in comparison with 19 healthy volunteers. While anti-S1 antibody titers in almost all healthy volunteers after the second dose were higher than the cut-off value reported previously, levels in HSCT patients after the second dose were diverse. Nineteen patients (76%) got seroconversion of anti-S1 IgG. Median optical density of antibody levels in HSCT patients with low IgG levels (< 600 mg/dL), steroid treatment, or low lymphocytes (< 1000 /L) was significantly lower than that in the other HSCT patients. There were no serious adverse events (> Grade 3), no new development or exacerbation of graft-versus-host disease after vaccination. We concluded BNT162b2 mRNA vaccine is safe and effective in Japanese allogeneic HSCT patients.

category: hematology


title: SARS-CoV-2 Omicron variant: healthcare workers' perceptions and beliefs of vaccine effectiveness and advocacy: a national survey during the first week of the World Health Organization variant alert

abstract:
BackgroundAs the SARS-CoV2 Omicron variant spreads in several countries, healthcare workers (HCWs) perceptions and worries regarding vaccine effectiveness and boosters warrant reassessment.

MethodsAn online questionnaire among HCWs in Saudi Arabia (KSA) was distributed from Dec 1st to 6th 2021 to assess their perceptions, vaccine advocacy to the Omicron variant, and their perception of the effectivness of infection prevention measures and vaccination to prevent its spread, their Omicron variant related worries in comparison to the other variants, and their agreement with mandatory vaccination in general for adults.

ResultsAmong the 1285 HCW participants, two-thirds were female, 49.8 % were nurses, 46.4% were physicians, and 50.0% worked in tertiary care hospitals. 66.9% considered vaccination to be the most effective way to prevent the spread of the Omicron variant and future variants. The respondents however perceived social distancing (78.0%), universal masking (77.8%), and avoiding unnecessary travel (71.4%) as slightly superior to vaccination to prevent the spread of SARS-CoV-2 variants. HCWs aging 55 or older agreed singficanlty with vaccine ineffictivness to control Omicron spread, while those who believed in non-pharmacolgical infection prevention measures agreed signifcantly with vaccination for that purpose. Male HCWs had a significant agreement with mandatory vaccination of all eligible adult populations. On the other hand, unwilling HCWs to receive the vaccine had strong disagreements with mandatory vaccination.

ConclusionsThe current study in the first week of Omicron showed that only two-thirds of HCWs felt that vaccination was the best option to prevent the spread of the Omicron variant, indicating the need for further motivation campaigns for vaccination and booster dose. HCWs had a strong belief in infection prevention measures to contain the spread of SARS-CoV-2 variants that should be encouraged and augmented.


title: SARS-CoV-2 Omicron variant: exploring healthcare workers' awareness and perception of vaccine effectiveness: a national survey during the first week of WHO variant alert


title: Effects of statin therapy on coronary plaque volume by decreasing CRP/hsCRP levels: A meta-regression of randomized controlled trials

abstract:
Background and aimsSeveral clinical trials have indicated that statins stabilize and reverse atherosclerotic plaque. However, different studies have provided inconsistent findings regarding mechanisms and influencing factors of plaque regression under statin therapy. In this study, meta-analysis and meta-regression were used to determine the effects of statin medications on coronary plaque volume as determined by intravenous ultrasound. Meanwhile, the impact of CRP/hsCRP reduction during statin therapy on plaque regression was investigated.

MethodsUp to May 28, 2021, a systematic PubMed, EMBASE, and Cochrane search was performed for randomized controlled trials that assessed treatment effect using total atheroma volume (TAV), percent atheroma volume (PAV), or plaque volume (PV). Only CRP/hsCRP and LDL-C values reported before and after treatment were considered.

Results12 studies fulfilled the inclusion criteria and were included in the systematic review. A meta-analysis of 15 statin-treated arms reported a significant reduction in change of TAV/PV (standardized mean difference [SMD]: -0.27, 95% confidence intervals [CI]: -0.42, -0.12), compared with the control arms. Another meta-analysis of 7 trials also found that patients in the intervention group had a significant reduction in change of PAV (SMD: -0.16, 95% CI: -0.29, -0.03), compared with those in the control group. Meta-regression analysis revealed the percent change of CRP/hsCRP statistically influences SMD in change of TAV/PV after adjusting for percent change of LDL-C, age and gender. Meta-regression analysis showed that percent change of CRP/hsCRP statistically influences SMD in change of PAV.

ConclusionIn conclusion, statin therapy is beneficial for plaque regression. Statins promote plaque regression through their anti-inflammatory ability.


title: Risk of Cardiovascular Events after Covid-19: a double-cohort study

abstract:
ObjectiveTo determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular events and all-cause mortality.

MethodsWe conducted a retrospective double-cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection [COVID-19(+) cohort] and its documented absence [COVID-19(-) cohort]. The study investigators drew a simple random sample of records from all Oregon Health & Science University (OHSU) Healthcare patients (N=65,585) with available COVID-19 test results, performed 03.01.2020 - 09.13.2020. Exclusion criteria were age < 18y and no established OHSU care. The primary outcome was a composite of cardiovascular morbidity and mortality. All-cause mortality was the secondary outcome.

ResultsThe study population included 1355 patients (mean age 48.7{+/-}20.5 y; 770(57%) female, 977(72%) white non-Hispanic; 1072(79%) insured; 563(42%) with cardiovascular disease (CVD) history). During a median 6 months at risk, the primary composite outcome was observed in 38/319 (12%) COVID-19(+) and 65/1036 (6%) COVID-19(-) patients (p=0.001). In Cox regression adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk of the primary composite outcome (HR 1.71; 95%CI 1.06-2.78; p=0.029). Inverse-probability-weighted estimation, conditioned for 31 covariates, showed that for every COVID-19(+) patient, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19(-): average treatment effect on the treated -65.5 (95%CI -125.4 to -5.61) days; p=0.032.

ConclusionsEither symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes and has causal effect on all-cause mortality in a late post-COVID-19 period.

ClinicalTrials.gov Identifier: NCT04555187

Key messagesO_ST_ABSWhat is already known about this subjectC_ST_ABSO_LIAcute, symptomatic COVID-19 can cause acute cardiovascular manifestations.
C_LIO_LIPost-acute or "long" COVID-19 can be a debilitating disease following acute infection with a heterogenous presentation.
C_LI

What might this study add?O_LIEither symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes.
C_LIO_LIEither symptomatic or asymptomatic SARS-CoV-2 infection has causal effect on all-cause mortality in a late post-COVID-19 period.
C_LI

How might this impact on clinical practice?O_LIAs we begin to care for more survivors of COVID-19, we will need to better understand not only how to care for their acute symptoms and complications following infection, but also recognize future cardiovascular risk and mitigate such risk with appropriate screening and preventative measures.
C_LI


title: Trends and country-level variation in age at first sex in sub-Saharan Africa among birth cohorts entering adulthood between 1985 and 2020

abstract:
BackgroundDebuting sexual intercourse marks exposure to pregnancy or fatherhood and sexually transmitted infections (STIs), including HIV. In sub-Saharan Africa (SSA), sexual debut varies according to cultural, religious, and economic factors, and encouraging delay has been a longstanding component of behavioural HIV prevention strategies. Age at first sex (AFS) is routinely collected in national household surveys, but data are affected by reporting biases, limiting utility to monitor trends and guide sexual health interventions.

MethodsWe collated individual-level data from nationally-representative household surveys to analyse timing and national trends in AFS in 42 SSA countries. We used a log-skew-logistic distribution to characterize the time to AFS in a Bayesian spatio-temporal model, providing estimates of the sexual debut rate by sex, age, time, and country. We statistically adjusted for reporting biases by comparing AFS reported by the same birth cohorts in multiple survey rounds, allowing different reporting biases by sex and country.

ResultsMedian AFS in 2015 ranged from 15.8 among Angolan women to 25.3 among men in Niger. AFS was younger for women than men in 37/40 countries. The gap was largest for Sahel region countries and minimal in southern African countries. The distribution of female AFS was asymmetric with half debuting sex in an age range of 3.9 years [IQR 3.4-5.0 across countries]. Median AFS increased slightly between 1985 and 2020, ranging 0.84 years [IQR 0.11-1.55] and 0.79 [IQR -0.23-1.98] for females and males, respectively. The gender gap changed little over time in most countries. Female teens often reported higher AFS compared to when asked in their late twenties while male teens reported lower AFS; both sexes recalled a higher AFS in older ages compared to their thirties.

ConclusionsAFS increased slightly in most SSA countries, but changes were modest relative to large and persistent variation between countries and sexes, indicating relatively entrenched socio-cultural practices around sexual debut. Sexual health, family planning, and HIV/STI prevention services should adapt to local practices rather than focusing interventions to change AFS. These estimates for rates of sexual debut provide data to guide programmatic prioritization and implementation of sexual health services.


title: A preliminary study of commercially available general-purpose chest radiography artificial intelligence-based software for detecting airspace opacity lesions in COVID-19 patients

abstract:
PurposeTo validate commercially available general-purpose artificial intelligence (AI)-based software for detecting airspace opacity in chest radiographs (CXRs) of COVID-19 patients.

Materials and MethodsWe used the ieee8023-covid-chestxray-dataset to validate commercial AI software capable of detecting "Nodule/Mass" and "Airspace opacity" as regions of interest with probability scores. From this dataset, we excluded computed tomography images and CXR images taken using an anteroposterior spine view and analyzed CXR images tagged with "Pneumonia/Viral/COVID-19" and "no findings." A radiologist then reviewed the images and rated them on a 3-point opacity score for the presence of airspace opacity. The maximum probability score of airspace opacity for each image was calculated using this software. The difference in each maximum probability for each opacity score was evaluated using Wilcoxons rank sum test. The threshold of the probability score was determined by receiver operator characteristic curve analysis for the presence or absence of COVID-19, and the true positive rate (TPR) and false positive rate (FPR) were determined for the individual and overall opacity scores.

ResultsImages from 342 patients with COVID-19 and 15 normal images were included. Opacity scores of 1, 2, and 3 were observed in 44, 70, and 243 images, respectively, of which 33 (75%), 66 (94.2%), and 243 (100%), respectively, were from COVID-19 patients. The overall TPR and FPR were 0.82 and 0.13, respectively, at an area under the curve of 0.88 and a threshold of 0.06, while the FPR for opacity score 1 was 0.18 and the TPR for score 3 was 0.97.

ConclusionUsing a public database containing CXR images of COVID-19 patients, commercial AI software was shown to be able to detect airspace opacity in severe pneumonia.

SummaryCommercially available AI software was capable of detecting airspace opacity in CXR images of COVID-19 patients in a public database.

category: radiology and imaging


title: Vitamin D Status & Latitude Predict Brain Lesions in Adrenoleukodystrophy

abstract: A subset of boys with X-linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating brain lesions. Risk factors are largely undefined. We used two independent cohorts to assess whether low vitamin D status predicts lesion development. In our first cohort, we measured 25-hydroxyvitamin D in 53 plasma samples from 20 pre-lesional ALD boys followed at two centers; half subsequently developed lesions. In our second cohort, we measured latitude (using home ZIP code) among 230 ALD boys in a database of 51 US pediatric hospitals; over half developed lesions. In regression models, low plasma vitamin D and northerly latitudes independently predicted ALD brain lesions.

category: neurology


title: Effects of COVID-19 on the human central olfactory system: a natural pre-post experiment

abstract: Reduced olfactory function is the symptom with the highest prevalence in COVID-19 with nearly 70% of individuals with COVID-19 experiencing partial or total loss of their sense of smell at some point during the disease. The exact cause is not known but beyond peripheral damage, studies have demonstrated insults to both the olfactory bulb and central olfactory brain areas. However, these studies often lack both baseline pre-COVID-19 assessments and a control group and could therefore simply reflect preexisting risk factors. Right before the COVID-19 outbreak, we completed an olfactory focused study including structural MR brain images and a full clinical olfactory test. Opportunistically, we invited participants back one year later, including 9 participants who had experienced mild to medium COVID-19 (C19+) and 12 that had not (C19-), thereby creating a pre-post controlled natural experiment with a control group. Despite C19+ participants reporting subjective olfactory dysfunction, few showed signs of objectively altered function one year later. Critically, all but one individual in the C19+ group had reduced olfactory bulb volume with an average volume reduction of 14.3%, but this did not amount to a significant between group difference compared to the control group (2.3% reduction) using inference statistics. No morphological differences in cerebral olfactory areas were found but we found stronger functional connectivity between olfactory brain areas in the C19+ croup at the post measure. Taken together, these data suggest that COVID-19 might cause a long-term reduction in olfactory bulb volume but with no discernible differences in cerebral olfactory regions.


title: A Pilot Basket Study to Evaluate Multi-Analyte Liquid Biopsies for Personalized Treatments in Advanced Refractory Cancers

abstract:
PurposeThe selection of safe and efficacious anticancer regimens for treatment of broadly refractory patients with metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling in peripheral blood can identify a majority of drug targets that can guide the selection of efficacious combination regimens.

Patients and MethodsLIQUID IMPACT was a pilot clinical study where patients with advanced refractory cancers received combination anticancer treatment regimens based on multi-analyte liquid biopsy (MLB) profiling of circulating tumor biomarkers; this study design was based on the findings of prior feasibility analysis to determine the abundance of targetable variants in blood specimens from 1299 real-world cases of advanced refractory cancers.

ResultsAmong the 29 patients in the intent to treat (ITT) cohort of the trial, 26 were finally evaluable as per study criteria out of whom 12 patients showed Partial Response (PR) indicating an Objective Response Rate (ORR) of 46.2% and 11 patients showed Stable Disease (SD) indicating the Disease Control Rate (DCR) to be 88.5%. The median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 4.3 months (95% CI: 3.0 - 5.6 months) and 8.8 months (95% CI: 7.0 - 10.7 months), respectively. Toxicities were manageable and there were no treatment-related deaths.

ConclusionThe study findings suggest that MLB could be used to assist treatment selection in heavily pretreated patients with advanced refractory cancers.


title: Multi-Analyte Liquid Biopsies for Molecular Pathway Guided Personalized Treatment Selection in Advanced Refractory Cancers: A Clinical Utility Pilot Study


title: Validation of a Pancreatic Cancer Detection Test in New-Onset Diabetes Using Cell-Free DNA 5-Hydroxymethylation Signatures

abstract:
BACKGROUNDPancreatic cancer (PaC) has poor (10%) 5-year overall survival, largely due to predominant late-stage diagnosis. Patients with new-onset diabetes (NOD) are at a six-to eightfold increased risk for PaC. We developed a pancreatic cancer detection test for the use in a clinical setting that employs a logistic regression model based on 5-hydroxymethylcytosine (5hmC) profiling of cell-free DNA (cfDNA).

METHODScfDNA was isolated from plasma from 89 subjects with PaC and 596 case-control non-cancer subjects, and 5hmC libraries were generated and sequenced. These data coupled with machine-learning, were used to generate a predictive model for PaC detection, which was independently validated on 79 subjects with PaC, 163 non-cancer subjects, and 506 patients with non-PaC cancers.

RESULTSThe area under the receiver operating characteristic curve for PaC classification was 0.93 across the training data. Training sensitivity was 58.4% (95% confidence interval [CI]: 47.5- 68.6) after setting a classification probability threshold that resulted in 98% (95% CI: 96.5-99) specificity. The independent validation dataset sensitivity and specificity were 51.9% (95% CI: 40.4-63.3) and 100.0% (95% CI: 97.8-100.0), respectively. Early-stage (stage 1 and 2) PaC detection was 47.6% (95% CI: 23%-58%) and 39.4% (95% CI: 32%-64%) in the training and independent validation datasets, respectively. Sensitivity and specificity in NOD patients were 55.2% [95% CI: 35.7-73.6] and 98.4% [95% CI: 91.3-100.0], respectively. The PaC signal was identified in intraductal papillary mucinous neoplasm (64%), pancreatitis (56%), and non-PaC cancers (17%).

CONCLUSIONSThe pancreatic cancer detection assay showed robust performance in the tested cohorts and carries the promise of becoming an essential clinical tool to enable early detection in high-risk NOD patients.

category: genetic and genomic medicine


title: Replacement of the Gamma by the Delta variant in Brazil: impact of lineage displacement on the ongoing pandemic

abstract: The COVID-19 epidemic in Brazil was driven mainly by the spread of Gamma (P.1), a locally emerged Variant of Concern (VOC) that was first detected in early January 2021. This variant was estimated to be responsible for more than 96% of cases reported between January and June 2021, being associated with increased transmissibility and disease severity, a reduction in neutralization antibodies and effectiveness of treatments or vaccines, as well as diagnostic detection failure. Here we show that, following several importations predominantly from the USA, the Delta variant rapidly replaced Gamma after July 2021. However, in contrast to what was seen in other countries, the rapid spread of Delta did not lead to a large increase in the number of cases and deaths reported in Brazil. We suggest that this was likely due to the relatively successful early vaccination campaign coupled with natural immunity acquired following prior infection with Gamma. Our data reinforces reports of the increased transmissibility of the Delta variant and, considering the increasing concern due to the recently identified Omicron variant, argues for the necessity to strengthen genomic monitoring on a national level to quickly detect and curb the emergence and spread of other VOCs that might threaten global health.


title: Relationship between temperature and relative humidity on the initial spread of COVID-19 cases and deaths in Brazil

abstract:
IntroductionClimate conditions may have influence on the transmission of COVID-19. Thus, this study aims to evaluate the impact of temperature and relative humidity on COVID-19 cases and deaths during the initial phase of the epidemic in Brazil.

MethodologyThis is an ecological study based on secondary data. Daily data on new COVID-19 cases and deaths and on climate indicators was collected from February 20th to April 18th, 2020 (n=59 days), for all state capital cities in Brazil and the Federal District (Brasilia). The studied climate indicators included mean temperature, temperature amplitude, mean relative humidity, relative humidity amplitude, and percentage of days with mean relative humidity less than or equal to 65%. Correlation and multiple linear regression analysis were performed for all cities and was also stratified by quintiles of the COVID-19 incidence rate.

ResultsMean daily temperature was positively correlated with the number of days until the first COVID-19 case was reported. A lower mean relative humidity was correlated with lower number of cases and deaths in Brazil, especially when the relative humidity was less than or equal to 65%. Higher temperatures and humidity amplitudes were correlated with lower COVID-19 mortality. Additionally, after controlling for humidity, cumulative cases of COVID-19 were inversely associated with temperature in cities with mean temperatures less than 25.8 {degrees}C.

ConclusionsOur findings indicate that variations in temperature and humidity across the Brazilian territory may have influenced the spread of the novel coronavirus during the initial phase of the epidemic in the country.


title: Mechanically ventilated patients shed high titre live SARS-CoV2 for extended periods from both the upper and lower respiratory tract

abstract:
BackgroundSARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection control measures both within healthcare settings and the public domain.

MethodsWe examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (sub-glottic aspirate), or lower respiratory tract (non-directed bronchoalveolar lavage (NBL) or bronchoalveolar lavage (BAL)) and analyzed by both qPCR and plaque assay.

Results117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types, however live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titres of live virus were higher in subglottic aspirates (4.5x107) than in saliva (2.2x106) or BAL/NBAL (8.5x106), and reached >108 PFU/ml in some samples. The longest duration of shedding was 98 days, while the majority of patients (14/25) shed live virus for 20 days or longer.

ConclusionsIntensive care unit patients infected with SARS-CoV-2 can shed high titres of virus both in the upper and lower respiratory tract, and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of PPE, and undertaking potential aerosol generating procedures.

SummaryPatients on intensive therapy infected with SARS-CoV-2 tend to be prolonged shedders, excreting virus for far beyond the time periods specified in current guidelines, and live virus titres can be extremely high in both the upper and lower respiratory tracts.


title: Topological data analysis identifies distinct biomarker phenotypes during the inflammatory phase of COVID-19

abstract:
OBJECTIVESThe relationships between baseline clinical phenotypes and the cytokine milieu of the peak  inflammatory phase of coronavirus 2019 (COVID-19) are not yet well understood. We used Topological Data Analysis (TDA), a dimensionality reduction technique to identify patterns of inflammation associated with COVID-19 severity and clinical characteristics.

DESIGNExploratory analysis from a multi-center prospective cohort study.

SETTINGEight military hospitals across the United States between April 2020 and January 2021.

PATIENTSAdult ([≥]18 years of age) SARS-CoV-2 positive inpatient and outpatient participants were enrolled with plasma samples selected from the putative  inflammatory phase of COVID-19, defined as 15-28 days post symptom onset.

INTERVENTIONSNone.

MEASUREMENTS AND MAIN RESULTSConcentrations of 12 inflammatory protein biomarkers were measured using a broad dynamic range immunoassay. TDA identified 3 distinct inflammatory protein expression clusters. Peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated with logistic regression for associations with each cluster. The study population (n=129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct clusters were found that differed by peak disease severity (p <0.001), age (p <0.001), BMI (p<0.001), and CCI (p=0.001).

CONCLUSIONSExploratory clustering methods can stratify heterogeneous patient populations and identify distinct inflammation patterns associated with comorbid disease, obesity, and severe illness due to COVID-19.


title: Prediction of SARS-CoV-2 Omicron Variant Immunogenicity, Immune Escape and Pathogenicity, through Analysis of Spike Protein-specific Core Unique Peptides

abstract: The recently discovered Omicron variant of the SARS-CoV-2 corona virus has raised a new, global, awareness, since it is considered as a new variant of concern from all major health organizations, including WHO and ECDC. Omicron variant is characterized by 30 amino acid changes, three small deletions and one small insertion in the Spike protein. In this study, we have identified the Core Unique Peptides (CrUPs) that reside exclusively in the Omicron variant of Spike protein and are absent from the human proteome, thus creating a new dataset of peptides named as C/H-CrUPs. Furthermore, we have analyzed their protein locations and compared them with the respective ones of Alpha and Delta SARS-CoV-2 variants. In Omicron, 115 C/H-CrUPs were generated and 119 C/H-CrUPs were lost, almost four times as many compared to the other two variants. From position 440 to position 508, at the Receptor Binding Motif (RBM), 8 mutations were detected, resulting in the construction of 28 novel C/H-CrUPs. Most importantly, in Omicron variant, new C/H-CrUPs carrying two or three mutant amino acids were produced, as a consequence of the accumulation of multiple mutations in the RBM. Remarkably, these Omicron-derived C/H-CrUPs that bear several mutated amino acids could not be recognized in any other viral Spike variant. We suggest that virus binding to the ACE2 receptor is facilitated by the herein identified C/H-CrUPs in contact point mutations and Spike-cleavage sites, while the immunoregulatory NF9 peptide is not detectably affected. Taken together, our findings indicate that Omicron variant contains intrinsic abilities to escape immune-system attack, while its mutations can mediate strong viral binding to the ACE2 receptor, leading to highly efficient fusion of the virus to the target cell. However, the intact NF9 peptide suggests that Omicron exhibits reduced pathogenicity compared to Delta variant.

category: allergy and immunology


title: Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate

abstract:
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this anti-resorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesion. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved pro-inflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology was predominantly induced by the oral N-BP and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.

Brief SummaryThe targeted removal of legacy bisphosphonate from the jawbone by competitive equilibrium therapy elucidated the pathological mechanism of aberrant oral barrier immunity and bisphosphonate-related osteonecrosis of the jaw (BRONJ)

category: dentistry and oral medicine


title: Control Strategies for the Third wave of COVID-19 infection in India: A Mathematical Model Incorporating Vaccine Effectiveness

abstract: The waning effectiveness of the COVID-19 vaccines and the emergence of a new variant Omicron has given rise to the possibility of another outbreak of the infection in India. COVID-19 has caused more than 34 million reported cases and 475 thousand deaths in India so far, and it has affected the country at the root level, socially as well as economically. After going through different control measures, mass vaccination has been achieved to a large extent for the highly populous country, and currently under progress. India has already been hit by a massive second wave of infection in April-June, 2021 mainly due to the delta variant, and might see a third wave in the near future that needs to be controlled with effective control strategies. In this paper, we present a compartmental epidemiological model with vaccinations incorporating the dose-dependent effectiveness. We study a possible sudden outbreak of SARS-CoV2 variants in the future, and bring out the associated predictions for various vaccination rates and point out optimum control measures. Our results show that for transmission rate 30% higher than the current rate due to emergence of new variant or relaxation of social distancing conditions, daily new cases can peak to 250k in March 2022, taking the second dose effectiveness dropping to 50% in the future. Combination of vaccination and controlled lockdown or social distancing is the key to tackling the current situation and for the coming few months. Our simulation results show that social distancing measures show better control over the disease spread than the higher vaccination rates.


title: Real-time Estimation of Global CFR Ascribed to COVID-19 Confirmed Cases Applying Machine Learning Technique

abstract:
The COVID-19 is declared as a public health emergency of global concern by World Health Organisation (WHO) affecting a total of 201 countries across the globe during the period December 2019 to January 2021. As of January 25, 2021, it has caused a pandemic outbreak with more than 99 million confirmed cases and more than 2 million deaths worldwide. The crisp of this paper is to estimate the global risk in terms of CFR of the COVID-19 pandemic for seventy deeply affected countries. An optimal regression tree algorithm under machine learning technique is applied which identified four significant features like diabetes prevalence, total number of deaths in thousands, total number of confirmed cases in thousands, and hospital beds per 1000 out of fifteen input features. This real-time estimation will provide deep insights into the early detection of CFR for the countries under study.

CFR[Formula]as suggested by (Boldog et al., 2020, Chakraborty et al. 2019, Russell et al., 2020)

Diabetes Prevalenceproportion of a population who have diabetes in a given period of time.

Stringency Indexit provides a computable parameter to evaluate the effectiveness of the nationwide lock down in a particular country.

GDP Per Capitait is a metric that breaks down a countrys economic output per person and is calculated by [Formula]

Population Densityit is a measurement of population per unit area. It refers to the number of people living in an area per square kilometre.

HDIit is a statistic composite index of life expectancy, education (literacy rate, gross enrolment ratio at different levels and net attendance ratio) and per capita income indicators which are used to rank countries into four tiers of human development.


title: Seroprevalence, waning, and correlates of anti-SARS-CoV-2 IgG antibodies in Tyrol, Austria: Large-scale study of 35,193 blood donors conducted between June 2020 and September 2021

abstract:
BackgroundThere is uncertainty about the seroprevalence of anti-SARS-CoV-2 antibodies in the general population of Austria, and about the extent to which antibodies elicited by vaccination or infection wane over time.

AimTo estimate seroprevalence, waning, and correlates of anti-SARS-CoV-2 IgG antibodies in the Federal State of Tyrol, Austria.

MethodsWe conducted a seroepidemiological study between June 2020 and September 2021, enrolling blood donors aged 18-70 years across Tyrol, Austria (participation rate 84.0%). We analysed serum samples for antibodies against spike or nucleocapsid proteins of SARS-CoV-2 with Abbott SARS-CoV-2 IgG assays.

ResultsWe performed 47,363 serological tests among 35,193 individuals (median age 43.1 years [IQR: 29.3-53.7], 45.3% women, 10.0% with prior SARS-CoV-2 infection). Seroprevalence increased from 3.4% (95% CI: 2.8-4.2%) in June 2020 to 82.7% (95% CI: 81.4-83.8%) in September 2021, largely due to vaccination. Anti-spike IgG seroprevalence was 99.6% (99.4-99.7%) among fully vaccinated individuals, 90.4% (88.8-91.7%) among unvaccinated with prior infection, and 11.5% (10.8-12.3%) among unvaccinated without known prior infection. Anti-spike IgG levels were reduced by 44.0% (34.9-51.7%) at 5-6 months compared to 0-3 months after infection. In fully vaccinated individuals, they decreased by 31.7% (29.4-33.9%) per month. In multivariable adjusted analyses, both seropositivity among unvaccinated and antibody levels among fully vaccinated individuals were higher at young age (<25 years), higher with a known prior infection, and lower in current smokers.

ConclusionSeroprevalence in Tyrol increased to 82.7% in September 2021, with the bulk of seropositivity stemming from vaccination. Antibody levels substantially and gradually declined after vaccination or infection.


title: Characteristics and outcomes of cases of children and adolescents with pediatric inflammatory multisystem syndrome in a tertiary care centre in Mexico City.

abstract:
Backgroundpediatric inflammatory multisystem syndrome (PIMS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that resembles Kawasaki syndrome and places them at high risk of cardiorespiratory instability and/or cardiac damage. This study aims to describe the clinical presentation and outcomes of patients with PIMS in Mexico City.

MethodsThis was an observational study of children hospitalized for PIMS based on the Centers for Disease Control and Prevention case definition criteria, in a single tertiary care pediatric center in Mexico City between May 1, 2020, and September 30, 2021. Demographic characteristics, epidemiological data, medical history, laboratory tests, cardiology evaluations, treatment, and clinical outcomes were analyzed.

ResultsSeventy-five cases fulfilled the case definition criteria for PIMS (median age: 10.9 years, Interquartile range [IQR]: 5.6-15.6). Fifteen (20%) patients had a severe underlying disease, 48 (64%) were admitted to the intensive care unit, 33 (44%) required invasive mechanical ventilation and 39 (52%) received vasopressor support. The patients were clustered through latent class analysis based on identified symptoms: Cluster 1 had rash or gastrointestinal symptoms (n = 60) and cluster 2 were those with predominantly respiratory manifestations (n = 15). Two patients (2.7%) died, and both had severe underlying conditions. Five patients (6.7%), all from cluster 1, developed coronary aneurysms.

ConclusionThere were a high proportion of patients with severe respiratory involvement and positive RT-PCR SARS-CoV-2 and very few cases of coronary aneurysms in our study which suggests that a high proportion of the children had severe acute COVID-19. The clinical manifestations and outcomes are comparable to previously reported international studies.

category: pediatrics