title: SARS-CoV-2 Antibody Response is Associated with Age in Convalescent Outpatients

abstract: COVID-19 has had an unprecedented global impact on human health. Understanding the antibody memory responses to infection is one tool needed to effectively control the pandemic. Among 173 outpatients who had virologically confirmed SARS-CoV-2 infection, we evaluated serum antibody concentrations, microneutralization activity, and enumerated SARS-CoV-2 specific B cells in convalescent blood specimens. Serum antibody concentrations were variable, allowing for stratification of the cohort into high and low responders. Serum antibody concentration was positively associated with microneutralization activity and participant age, with participants under the age of 30 showing the lowest antibody level. Neither participant sex, the timing of blood sampling following the onset of illness, nor the number of SARS-CoV-2 spike protein specific B cells correlated with serum antibody concentration. These data suggest that young adult outpatients did not generate as robust antibody memory, compared with older adults. Further, serum antibody concentration or neutralizing activity trended but did not significantly correlate with the number of SARS-CoV-2 memory B cells. These findings have direct implications for public health policy and current vaccine efforts. Knowledge gained regarding antibody memory following infection will inform the need for vaccination in those previously infected and allow for a better approximation of population-wide protective immunity.


title: Defining the determinants of under-vaccination in migrant populations in Europe to improve routine and COVID-19 vaccine uptake: a systematic review

abstract: Diverse migrant populations in Europe are at risk of under-immunisation and have recently shown lower levels of COVID-19 vaccination intent and uptake. Understanding the determinants of vaccine uptake in migrants is critical to address immediate COVID-19 vaccination inequities, and longer-term will help improve coverage for routine vaccinations, aligning with the goals of the new Immunisation Agenda 2030. We did a systematic review following PRISMA guidelines and using a PICOS framework (PROSPERO CRD42020219214; MEDLINE, CINAHL, PsycINFO databases, 1 January 2000 - 14 September 2021) exploring barriers and facilitators to vaccine uptake and determinants of under-vaccination in migrants in the EU/EEA, UK, and Switzerland. We categorised barriers/facilitators using the  5As Determinants of Vaccine Uptake Taxonomy. 5259 data sources were screened, with 67 studies included from 16 countries, representing 366,529 migrants. Access barriers were most commonly reported (language, literacy and communication barriers; practical and legal barriers to accessing/delivering vaccination services; service barriers, including lack of specific guidelines and knowledge of healthcare professionals) for key vaccines including MMR, DTP, HPV, influenza, polio, COVID-19 vaccines. Acceptance barriers were mostly reported in Eastern European and Muslim communities for HPV, measles, and influenza vaccines. We identified 23 determinants of under-vaccination in migrants, including geographical origin (where 25/26 (96%) studies showed significance) - particularly African/Eastern European origin; recent migration; being a refugee/asylum seeker; higher income; parental education level; no healthcare contact in the past year; and lower language skills. Facilitators of migrants vaccine uptake included tailored vaccination messaging, community outreach and  nudging interventions. Migrants barriers to accessing healthcare are already well documented, and this review confirms their role in limiting vaccine uptake. These data hold immediate relevance to strengthening vaccination programmes in high-income countries, including for COVID-19. Our findings suggested that targeted, evidence-informed strategies are needed to address access and acceptance barriers to vaccination in migrants, including the development of migrant-sensitive and adaptable vaccination services and systems, unambiguous public health messaging, and coproduction of tailored interventions.

category: public and global health


title: Analysis of Corticosteroids in Immune Checkpoint Inhibitor(ICE)Induced Myocarditis-A Systematic Review of 352 Screened Articles

abstract:
IntroductionImmune Checkpoint Inhibitors (ICI) are used as a single agent or as a combination therapies for early or late-stage malignancies. The common malignancies that ICI targets include the following: melanoma, lung cancer, renal cell carcinoma, and hematological malignancies such as Hodgkins lymphoma. ICI use is associated with many immune-related adverse events, and ICI-induced myocarditis is one of the rare and most severe AE with a high mortality rate. There are no consensus evidence-based treatment guideline; the expert recommendation is to use high-dose steroids. We aim in this review to assess the effectiveness of steroids in treating ICI-induced myocarditis.

MethodsWe searched the following database Pubmed, Scopus, Cinhale, and Google Scholar, using the following keywords: ICI-induced myocarditis, treatment, steroid. We included articles in the English language, case reports, case series, and published in the last five years.

Results352 articles were screened using PRISMA guidelines. After excluding the articles that were duplicate, irrelevant, and did not meet inclusion criteria, 35 articles with a total number of 50 patients were included. All patients treated with ICI either as a single or combination regimen. The onset of symptoms post initiation varied from one day to a year. 46 out of the 50 cases received high doses of Intravenous steroids as a loading dose followed by an oral or intravenous maintenance dose. Out of 50 patients 14 patients (28 %) died but 34 (68 %) patients survived, and 2 (4 %) patients data were not available. The mean age of the patients was 66.31 {+/-} 14.071 (range 23-88 years), 29 were male (58%), 21 were female (42%). Most of the cases were from the USA (42%), followed by Australia (20 %), Japan (14%), Germany, France, and China (4%), Switzerland, Canada, and Spain (2%), and for (6%) cases. A total of 23 patients had cardiovascular comorbidities (46%), which were HTN (14 patients, 60.87%), hyperlipidemia (5 patients, 21.73%), and less than 1 % of patients had myocardial ischemia, congestive heart failure, atrial fibrillation, and peripheral vascular disease. While 26 patients (52%) had normal basal cardiac status.

ConclusionOur results showed that high doses of steroids were effective in controlling cardiac myocyte inflammation and mortality by 28%. Race was not included in the analysis as it was not reported. More in - depth studies are needed to provide a broader representation of steroids in myocarditis.

category: urology


title: Genetic Contributions to Early and Late Onset Ischemic Stroke

abstract:
ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).

MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.

ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).

ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

category: neurology


title: Association between long working hours and psychological distress: The effect of sick leave criteria in the workplace during the COVID-19 pandemic

abstract:
ObjectiveThis study investigated the effect of sick leave criteria on the association between long working hours and psychological distress.

MethodsWe conducted a cross-sectional survey in December 2020, and 27,032 workers completed the questionnaire. First, after testing the interaction effect of overtime work hours and sick leave criteria on psychological distress, we conducted stratified analyses using sick leave criteria.

ResultsA significant interaction effect was found. When we conducted stratified analyses, the odds ratios increased with longer working hours, both with and without sick leave criteria groups; however, the risk was greater in the without sick leave criteria group, compared with the criteria group.

ConclusionWe revealed that working without sick leave criteria could strengthen the association between long working hours and psychological distress during the COVID-19 pandemic.

Clinical significanceWorkers working without sick leave criteria had a significantly higher risk of psychological distress due to long working hours than those who worked with the criteria. Our findings contribute to preventing the deterioration of mental health during the COVID-19 pandemic.

category: occupational and environmental health


title: Preventing the Transmission of COVID-19 in Older Adults Aged 60 Years and Above Living in Long-Term Care: Rapid Review Update

abstract:
ObjectivesThe objective of this study was to examine the effect of measures of control and management of COVID-19, Middle East Respiratory Syndrome (MERS), and severe acute respiratory syndrome (SARS) in adults 60 years or above living in long-term care facilities. This is an update of previous work done by Rios et al.

MethodsA rapid review was conducted in accordance with the Rapid Review Guide for Health Policy and Systems Research. Literature search of databases MEDLINE, Cochrane library, and pre-print servers (biorxiv/medrxiv) was conducted from July 31, 2020 to October 9, 2020. EMBASE was searched from July 31, 2020 until October 18, 2020. Titles and abstracts from public archives were identified for screening using Gordon V. Cormack and Maura R. Grossmans Continuous Active Learning(R) ("CAL(R)") tool, which uses supervised machine learning.

ResultsFive observational studies and one clinical practice guideline were identified. Infection prevention measures identified in this rapid review included: social distancing and isolation, personal protective equipment (PPE) use and hygiene practices, screening, training and staffing policies. The use of PPE, laboratory screening tests, sick pay to staff, self-confinement of staff within the LTCFs for 7 or more days, maintaining maximum residents occupancy, training and social distancing significantly reduced the prevalence of COVID-19 infection among residents and/or staff of LTCFs (p<0.05). Practices such as hiring of temporary staff, not assigning staff to care separately for infected and uninfected residents, inability to isolate sick residents and infrequent cleaning of communal areas significantly increased the prevalence of infection among residents and/or staff of LTCFs (p<0.05).

ConclusionThe available studies are limited to only three countries despite the global nature of the disease. The majority of these studies showed that infection control measures such as favourable staffing policies, training, screening, social distancing, isolation and use of PPE significantly improved residents and staff related outcomes. More studies exploring the effects infection prevention and control practices in long term care facilities are required.

O_TEXTBOXKey MessagesO_LIThis is an update of a previous rapid review.
C_LIO_LILiterature search of databases MEDLINE, Cochrane library, and pre-print servers (biorxiv/medrxiv) was conducted from July 31, 2020 to October 9, 2020. EMBASE was searched from July 31, 2020 until October 18, 2020.
C_LIO_LIFive observational studies and one clinical practice guideline were identified.
C_LIO_LIInfection prevention measures identified in this rapid review included: social distancing and isolation, PPE use and hygiene practices, screening, training and staffing policies.
C_LIO_LIThe use of PPE, laboratory screening tests, sick pay to staff, self-confinement of staff within the LTCFs for 7 or more days, maintaining maximum residents occupancy, training and social distancing significantly reduced the prevalence of COVID-19 infection among residents and/or staff of LTCFs (p<0.05).
C_LIO_LIPractices such as hiring of temporary staff, not assigning staff to care separately for infected and uninfected residents, inability to isolate sick residents and infrequent cleaning of communal areas significantly increased the prevalence of infection among residents and/or staff of LTCFs (p<0.05).
C_LI

C_TEXTBOX

category: infectious diseases


title: Transmission of Acute Respiratory Infections during Aerosol Generating Medical Procedures (AGMPs): An Updated Review

abstract:
1ObjectivesTo review the literature from 2011 until March 31st, 2020 to identify the risk of transmission of ARIs to healthcare workers caring for patients undergoing AGMPs compared with the risk of transmission when caring for patients not undergoing AGMPs.

ResultsOnly two prospective cohort studies were identified meeting inclusion criteria. One found that performance or assistance with AGMP during the previous week was significantly associated with symptomatic influenza (adjusted OR: 2.29, 95% CI: 1.3 to 4.2). The second study found that performance of AGMP was significantly associated with clinical respiratory infections (RR 2.9, 95% CI 1.42-5.87, p<0.01), laboratory-confirmed virus or bacteria (RR 2.9, 95% CI 1.37-6.22, p=0.01), and laboratory-confirmed virus (RR 3.3, 95% CI 1.01-11.02, p=0.05). Further evidence is needed regarding what constitutes an AGMP and the risk of ARI transmission during presumed AGMPs. Organizations need to interpret these findings with caution when establishing AGMP lists requiring airborne precautions.


title: SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2

abstract:
IntroductionThe humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the long-term chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine.

MethodsWe performed serological, neutralization, and T cell assays among 100 hospital workers aged 22-73 years who received the vaccine. We conducted seven surveys up to eight months after the second vaccination dose.

ResultsSARS-CoV-2 spike protein-specific IgG (IgG-S) titers and T cell responses increased significantly following the first vaccination dose. The highest titers were observed on day 29 and decreased gradually until the end of the follow-up period. There was no correlation between IgG-S and T cell responses. Notably, T cell responses were detected on day 15, earlier than the onset of neutralizing activity.

ConclusionsThis study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These immune responses are sustained for approximately six-ten weeks but not for seven months or later following the second vaccination, indicating the need for the booster dose (i.e., third vaccination).


title: SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2: A 9 months longitudinal study


title: A need of COVID19 vaccination for children aged <12 years: Comparative evidence from the clinical characteristics in patients during a recent Delta surge (B.1.617.2)

abstract:
ObjectiveTo evaluate the necessity of Covid-19 vaccination in children aged < 12 y by comparing the clinical characteristics in unvaccinated children aged < 12 y with vaccinated patients aged [≥] 12y during the Delta surge (B.1.617.2) in Putian, Fujian, China.

MethodsA total of 226 patients with SARS-Cov-2 Delta variant (B.1.167.2; confirmed by Realtime PCR positive and sequencing) were enrolled from Sep 10th to Oct 20th, 2021, including 77 unvaccinated children (aged < 12y) and 149 people aged [≥] 12y, mostly vaccinated. The transmission route was explored and the clinical data of two groups were compared; the effect factors for the time of the nucleic acid negativization (NAN) were examined by R statistical analysis.

ResultsThe Delta surge in Putian spread from children in schools to factories, mostly through family contact. Compared with those aged [≥] 12y, patients aged < 12y accounted for 34.07% of the total and showed milder fever, less cough and fatigue; they reported higher peripheral blood lymphocyte counts [1.84(1.32,2.71)x10^9/L vs. 1.31(0.94,1.85)x10^9/L; p<0.05), higher normal CRP rate (92.21% vs. 57.72%), lower IL-6 levels [5.28(3.31,8.13) vs. 9.10(4.37,15.14); p< 0.05]. Upon admission, their COVID19 antibodies (IgM and IgG) and IgG in convalescence were lower [0.13(0.00,0.09) vs. 0.12(0.03,0.41), p<0.05; 0.02(0.00,0.14) vs. 1.94(0.54,6.40), p <0.05; 5.46(2.41,9.26) vs. 73.63 (54.63,86.55), p<0.05, respectively], but longer NAN time (18 days vs. 16 days, p=0.13).

ConclusionChildren aged < 12y may be critical hidden spreaders, which indicates an urgent need of vaccination for this particular population.


title: Immunogenicity and adverse events of priming with inactivated whole SARS-CoV-2 vaccine (CoronaVac) followed by boosting the ChAdOx1 nCoV-19 vaccine

abstract:
BackgroundResponding to SARS-CoV-2 Delta variants escaped the vaccine-induced immunity and waning immunity from the inactivated whole virus vaccine, Thailand recently proposed a heterologous inactivated whole virus vaccine (CoronaVac) viral vector vaccine (ChAdOx1 nCoV-19) prime-boost vaccine regimen(I/V). This study aims to evaluate the immunogenicity and adverse events of this regimen by comparison with homologous CoronaVac, ChAdOx1 nCoV-19, and convalescent serum.

MethodImmunogenicity was evaluated by the level of IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein (S1 subunit) (anti-S RBD). At 2 weeks following the second dosage, a selection of random samples was tested for plaque reduction neutralisation (PRNT) and Pseudotype-Based Microneutralization test (PVNT) against SARS-CoV-2 variants of concern (VOCs). The safety profile of heterologous CoronaVac-ChAdOx1 nCoV-19 prime-boost vaccine regimen was described by interviewing at the 1-month visit.

ResultBetween April to August 2021,426 participants were included in the study, with 155 obtaining CoronaVac-ChAdOx1 nCoV-19(I/V),32 obtaining homologous CoronaVac(I/I),47 obtaining homologous ChAdOx1 nCoV-19(V/V),169 with history covid-19 infection. Geometric mean titers (GMTs) of anti-S RBD level in the I/V group compare 2wks and 4 wks (873.9 vs 639,p=0.00114).At 4 wks, GMTs of anti-S RBD level in I/V group was 639, 95% CI 63-726,and natural infection group 177.3, 95% CI 42-221, and V/V group 211.1, 95% CI 77-152, and I/I group 108.2, 95% CI 77-152; all p<0.001).At 2 wks, The GMTs of 50%PRNT of 19 sampling from the I/V group is 434.5, 95% CI 326-579, against wild type and 80.4, 95% CI 56-115, against alpha and 67.4, 95% CI 48-95, against delta and 19.8, 95% CI 14-30, against beta; all p<0.001. At 2 wks, The GMTs of 50%PVNT of 15 sampling from the I/V group is 597.8, 95% CI 368-970, against wild type and 163.9, 95% CI 89-301, against alpha and 157.7, 95% CI 66-378, against delta. The AEs in the I/V schedule were well tolerated and generally unremarkable.

ConclusionThe I/V vaccination is a mixed regimen that induced higher immunogenicity and shall be considered for responding to Delta Variants when only inactivated whole virus vaccine and viral vector vaccine was available.


title: Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: A cohort study from OpenSAFELY

abstract:
BackgroundWhile the vaccines against COVID-19 are considered to be highly effective, COVID-19 vaccine breakthrough is likely and a small number of people will still fall ill, be hospitalised, or die from COVID-19, despite being fully vaccinated. With the continued increase in numbers of positive SARS-CoV-2 tests, describing the characters of individuals who have experienced a COVID-19 vaccine breakthrough could be hugely important in helping to determine who may be at greatest risk.

MethodWith the approval of NHS England we conducted a retrospective cohort study using routine clinical data from the OpenSAFELY TPP database of fully vaccinated individuals, linked to secondary care and death registry data, and described the characteristics of those experiencing a COVID-19 vaccine breakthrough.

ResultsAs of 01st November 2021, a total of 15,436,455 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: 107-179). From within this population, a total of 577245 (<4%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate was 98.02 (95% CI 97.9-98.15). There were 16,120 COVID-19-related hospital admissions, 1,100 COVID-19 critical care admission patients and 3,925 COVID-19-related deaths; corresponding incidence rates of 2.72 (95% C 2.7-2.74), 0.19 (95% C 0.18-0.19) and 0.66 (95% C 0.65-0.67), respectively. When broken down by the initial priority group, higher rates of hospitalisation and death were seen in those in care homes and those over 80 years of age. Comorbidities with the highest rates of breakthrough COVID-19 included chronic kidney disease, dialysis, transplant, haematological malignancy, and immunocompromised.

ConclusionThe majority of COVID-19 vaccine breakthrough cases in England were mild with relatively few fully vaccinated individuals being hospitalised or dying as a result. However, some concerning differences in rates of breakthrough cases were identified in several clinical and demographic groups. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the continued increase in numbers of positive SARS-CoV-2 tests are concerning. As numbers of fully vaccinated individuals increases and follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, aimed at identifying individuals at higher risk, are therefore required.

category: epidemiology


title: National and subnational short-term forecasting of COVID-19 in Germany and Poland, early 2021

abstract: We report on the second and final part of a pre-registered forecasting study on COVID-19 cases and deaths in Germany and Poland. Fifteen independent research teams provided forecasts at lead times of one through four weeks from January through mid-April 2021. Compared to the first part (October-December 2020), the number of participating teams increased, and a number of teams started providing subnational-level forecasts. The addressed time period is characterized by rather stable non-pharmaceutical interventions in both countries, making short-term predictions more straightforward than in the first part of our study. In both countries, case counts declined initially, before rebounding due to the rise of the B.1.1.7 variant. Deaths declined through most of the study period in Germany while in Poland they increased after a prolonged plateau. Many, though not all, models outperformed a simple baseline model up to four weeks ahead, with ensemble methods showing very good relative performance. Major trend changes in reported cases, however, remained challenging to predict.


title: Ranking the Effectiveness of Non-Pharmaceutical Interventions to Counter COVID-19 in UK Universities with Vaccinated Population

abstract: Several universities around the world have resumed in-person teaching after successful vaccination campaigns have covered 70/80% of the population. In this study, we combine a new compartmental model with an optimal control formulation to discover, among different non-pharmaceutical interventions, the best prevention strategy to maximize on-campus activities while keeping spread under control. Composed of two interconnected Susceptible-Exposed-Infected-Quarantined-Recovered (SEIQR) structures, the model enables staff-to-staff infections, student-to-staff cross infections, student-to-student infections, and environment-to-individual infections. Then, we model input variables representing the implementation of different non-pharmaceutical interventions and formulate and solve optimal control problems for four desired scenarios: minimum number of cases, minimum intervention, minimum non-quarantine intervention, and minimum quarantine intervention. Our results reveal the particular significance of mask wearing and social distancing in universities with vaccinated population (with proportions according to UK data). The study also reveals that quarantining infected students has a higher importance than quarantining staff. In contrast, other measures such as environmental disinfection seems to be less important.


title: Public engagement and crowdfunding for health research: A global qualitative evidence synthesis and TDR pilot

abstract:
BackgroundMany low-and middle-income country (LMIC) researchers have disadvantages when applying for research grants. Crowdfunding may help LMIC researchers to fund their research. Crowdfunding organizes large groups of people to make small contributions to support a research study. This manuscript synthesizes global qualitative evidence and describes a TDR crowdfunding pilot for LMIC-based researchers.

MethodsOur global systematic review and qualitative evidence synthesis searched six databases for qualitative data. We used a thematic synthesis approach and assessed our findings using the GRADE-CERQual approach. Building on the review findings, we organized a crowdfunding pilot to support LMIC researchers and use crowdfunding. The pilot provided an opportunity to assess the feasibility of crowdfunding for infectious diseases of poverty research in resource-constrained settings.

ResultsNine studies were included in the qualitative evidence synthesis and we identified seven themes. Seven studies demonstrated that strong public engagement facilitated crowdfunding for research. Other themes included the correlates of crowdfunding success, risks of crowdfunding, and risk mitigation strategies. Our pilot data suggest that crowdfunding is feasible in diverse LMIC settings. Three researchers launched crowdfunding campaigns, met their goals and received substantial monetary (raising a total of $26,546 across all five campaigns) and non-monetary contributions. Two researchers are still preparing for campaign launch due to COVID-19 related difficulties.

ConclusionPublic engagement provides a foundation for effective crowdfunding for health research. Our evidence synthesis and pilot data provide practical strategies for LMIC researchers to engage the public and use crowdfunding. A practical guide was created alongside to facilitate these activities across multiple settings.

What is already known?Crowdfunding has been used to fund health causes, technology start-ups, creative projects, and more recently, scientific research. Although crowdfunding has been used for research funding in high-income settings, there is less evidence from LMIC settings. In addition, previous reviews of crowdfunding have not focused on public engagement strategies that may be important for developing effective crowdfunding campaigns.

What are the new findings?- Our qualitative evidence synthesis finds that crowdfunding research focuses on creators and backers in high-income settings, neglecting LMIC researchers.
- The TDR pilot programme suggests that crowdfunding is feasible for LMIC researchers. Three of the five pilot finalists exceeded their crowdfunding goals and received substantial non-monetary contributions.


title: Crowdfunding for health research: A global systematic review, qualitative evidence synthesis and TDR pilot for LMIC researchers


title: Age and disc degeneration in low back pain: automated analysis enables a magnetic resonance imaging comparison of large cross-sectional cohorts of symptomatic and asymptomatic subjects.

abstract:
ObjectivesWe aimed to improve understanding of the role of imaging in diagnosis of low back pain by determining the prevalence of age-related disc degeneration in asymptomatic and symptomatic subjects. Spinal MRIs of symptomatic and asymptomatic subjects were re-annotated onto the same objective grading system and prevalence of degenerative changes compared.

MethodsIn an exploratory cross-sectional study, we compared the prevalence of disc degeneration between two large groups of anonymised females, 30-80yrs, viz a symptomatic group with chronic back pain (724) and an asymptomatic (701) group. We used a verified automated MRI annotation system to re-annotate their spinal MRIs and report degeneration on the Pfirrmann (1-5) scale, and other degenerative changes (herniation, endplate defects, marrow signs, spinal stenosis) as binary present/absent.

ResultsSevere degenerative changes were significantly more prevalent in discs of symptomatics than asymptomatics in the lower (L4-S1) but not the upper (L1-L3) lumbar discs in subjects <60years. We found high co-existence of several degenerative features in both populations. Degeneration was minimal in around 30% of symptomatics < 50years.

ConclusionsAutomated MRI provides a valuable means of rapidly comparing large MRI datasets. Here, through directly comparing MRI annotations on the same objective scales it enabled us to detect significant age and spinal-level related differences in the prevalence of degenerative features between asymptomatic and symptomatic populations. By distinguishing between symptomatics whose discs have structural defects, and symptomatics with minimal degenerative changes, MRI could provide a means of clinical stratification, and provide a useful pathway to investigate possible pain sources.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIEven though intervertebral disc degeneration, and degenerative changes such as disc herniations, are strongly associated with low back pain, the importance of disc degeneration in development of low back pain is questioned because these degenerative changes are seen in both those with and those without low back pain; spinal MRIs are thus thought to be of little clinical value.
C_LI

What does this study add?O_LIThe study provides the first data on age-related degeneration in those without pain and shows the significant differences in prevalence between age-related and symptom-related disc degeneration.
C_LIO_LIThe study provides definitive data showing that severe disc degeneration is directly implicated in a significant proportion of those with chronic low back pain, with the association with pain strongly dependent on age and spinal level
C_LI

How might this impact on clinical practice or future developments?O_LIThe study shows that even though severe disc degeneration is strongly associated with low back pain, 30% of younger (<50yrs) chronic low back pain patients have no evident disc degeneration detected by MRI, which is important information (currently not used) for clinicians in directing treatments (and perhaps a clearer reason for the proper use of scans).
C_LIO_LIThe study provides important information for those working on mechanisms, as it enables stratification between pathways of pain arising from structural defects in the disc, and those pain pathways in discs with no such structural change.
C_LI

category: orthopedics


title: Signal from the Noise: A Mixed Methods Process Mining Approach to Evaluate Care Pathways.

abstract:
ObjectiveMapping real-world practice patterns vs. deviations from intended guidelines and protocols is necessary to identify and improve the quality of care for emergent medical conditions like stroke. We propose a process mining algorithm applied to Electronic Health Record (EHR) event log data as a unique opportunity to more easily identify and compare real-world care processes.

MaterialsData was obtained from the event log of a major EHR vendor (Epic) for Stanford Health Care Hospital patients aged 18 years and older presenting to the ED from January 1, 2010 through December 31, 2018 and receiving tPA within 4.5 hours of presentation. Our algorithm was built using the Python programming language.

MethodsAn unsupervised process-mining algorithm was developed and used to create a process map for our cohort. This map was then used to identify the most common path as well as individual and average conformity to this path across all encounters.

ResultsOur automatically generated process mining graph, specifically its most common path, mimicked our institutions recommended "code stroke" clinical pathway. The average conformity score for our cohort was 0.36 with a range from high of 0.64 and low of 0.20.

DiscussionThis method allows for greater detail into common process measures to be more easily illustrated to evaluate the quality of care at a given institution. It may be extended to other, similarly well-defined processes or those which currently lack standardized clinical pathways.

ConclusionOur mixed methods approach represents an essential data analysis step to improve complex care processes by automatically generating a qualitative and quantitative process measures from existing event log data which can then be used to target quality improvement initiatives.

category: health systems and quality improvement


title: Effect of the Neutralizing SARS-CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial

abstract:
ImportanceOlder patients and those with underlying comorbidities infected with SARS-CoV-2 may be at increased risk of hospitalization and death from COVID-19. Sotrovimab is a neutralizing antibody designed for treatment of high-risk patients to prevent COVID-19 progression.

ObjectiveTo evaluate the efficacy and safety of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease.

DesignRandomized, double-blind, multicenter, placebo-controlled, phase 3 study.

Setting57 centers in 5 countries.

ParticipantsNonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for disease progression.

InterventionPatients were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo.

Main Outcomes and MeasuresThe primary efficacy outcome was the proportion of patients with COVID-19 progression, defined as all-cause hospitalization longer than 24 hours for acute illness management or death through day 29. Key secondary outcomes included the proportion of patients with COVID-19 progression, defined as emergency room visit, hospitalization of any duration, or death, and proportion of patients developing severe/critical respiratory COVID-19 requiring supplemental oxygen.

ResultsAmong 1057 patients randomized (sotrovimab, 528; placebo, 529), all-cause hospitalization longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) by 79% (95% CI, 50% to 91%; P<.001). Secondary outcome results further demonstrated the effect of sotrovimab in reducing emergency room visits, hospitalization of any duration, or death, which was reduced by 66% (95% CI, 37% to 81%; P<.001), and severe/critical respiratory COVID-19, which was reduced by 74% (95% CI, 41% to 88%; P=.002). No patients receiving sotrovimab required high-flow oxygen, oxygen via nonrebreather mask, or mechanical ventilation compared with 14 patients receiving placebo. The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified.

Conclusions and RelevanceAmong nonhospitalized patients with mild to moderate COVID-19, a single 500-mg intravenous dose of sotrovimab prevented progression of COVID-19, with a reduction in hospitalization and need for supplemental oxygen. Sotrovimab is a well-tolerated, effective treatment option for patients at high risk for severe morbidity and mortality from COVID-19.

Trial RegistrationClinicalTrials.gov Identifier: NCT04545060


title: Surveillance of COVID-19 in a Vaccinated Population: A Rapid Literature Review

abstract:
ObjectivesWith the availability of COVID-19 vaccines, public health focus is shifting to post-vaccination surveillance to identify breakthrough infections in vaccinated populations. Therefore, the objectives of these reviews are to identify scientific evidence and international guidance on surveillance and testing approaches to monitor the presence of the virus in a vaccinated population.

MethodWe searched Ovid MEDLINE(R), including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, EBM Reviews - Cochrane Central Register of Controlled Trials, and EBM Reviews - Cochrane Database of Systematic Reviews. We also searched the Web of Science Core Collection. A grey literature search was also conducted. This search was limited to studies conducted since December 2020 and current to June 13th, 2021. There were no language limitations. COVID-19 surveillance studies that were published after December 2020 but did not specify whether they tested a vaccinated population were also considered for inclusion.

For the international guidance review, a grey literature search was conducted, including a thorough search of Google, websites of international government organizations (e.g., Center for Disease Control and Prevention [CDC], World Health Organization [WHO]), and McMaster Health Forum (CoVID-END). This search was primarily examining surveillance guidance published since December 2020 (to capture guidance specific to vaccinations) and any relevant pre-December 2020 guidance.

ResultsThirty-three studies were included for data synthesis of scientific evidence on surveillance of COVID-19. All the studies were published between April and June 2021. Twenty-one studies were from peer-reviewed journals. Five approaches to monitoring post-vaccination COVID-19 cases and emerging variants of concern were identified, including screening with reverse transcriptase polymerase chain reaction (RT-PCR) and/or a rapid antigen test, genomic surveillance, wastewater surveillance, metagenomics, and testing of air filters on public buses. For population surveillance, the following considerations and limitations were observed: variability in person-to-person testing frequency; lower sensitivity of antigen tests; timing of infections relative to PCR testing can result in missed infections; large studies may fail to identify local variations; and loss of interest in testing by participants in long follow-up studies.

Through comprehensive grey literature searching, 68 international guidance documents were captured for full-text review. A total of 26 documents met the inclusion criteria and were included in our synthesis. Seven overarching surveillance methods emerged in the literature. PCR-testing was the most recommended surveillance method, followed by genomic screening, serosurveillance, wastewater surveillance, antigen testing, health record screening, and syndromic surveillance.

ConclusionEvidence for post-vaccination COVID-19 surveillance was derived from studies in partially or fully vaccinated populations. Population PCR screening, supplemented by rapid antigen tests, was the most frequently used surveillance method and also the most commonly recommended across jurisdictions. Most recent guidance on COVID-19 surveillance is not specific to vaccinated individuals, or it is in effect but has not yet been updated to reflect that. Therefore, more evidence-informed guidance on testing and surveillance approaches in a vaccinated population that incorporates all testing modalities is required.

EXECUTIVE SUMMARYO_ST_ABSObjectivesC_ST_ABSWith the availability of COVID-19 vaccines, public health focus is shifting to post-vaccination surveillance to identify breakthrough infections in vaccinated populations. Therefore, the objectives of these reviews are to: 1) identify scientific evidence on surveillance and testing approaches to monitor the presence of the virus in a vaccinated population and determine how these influence testing strategies; 2) identify international guidance on testing and surveillance for COVID-19 and its variants of concern in a vaccinated population; and 3) identify emerging technologies for surveillance.

DesignA rapid review was conducted to identify scientific evidence on COVID-19 surveillance and testing approaches, and a targeted literature review was conducted on international guidance.

MethodWe searched Ovid MEDLINE(R), including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, EBM Reviews - Cochrane Central Register of Controlled Trials, and EBM Reviews - Cochrane Database of Systematic Reviews. We also searched the Web of Science Core Collection. We performed all searches on June 13, 2021. A grey literature search was also conducted, including: MedRxiv, Google, McMaster Health Forum (COVID-END), and websites of international government organizations (e.g., Center for Disease Control and Prevention [CDC], World Health Organization [WHO]). This search was limited to studies conducted since December 2020 and current to June 13th, 2021. There were no language limitations. COVID-19 surveillance studies that were published after December 2020 but did not specify whether they tested a vaccinated population were also considered for inclusion.

For the international guidance review, a grey literature search was conducted, including a thorough search of Google, websites of international government organizations (e.g., Center for Disease Control and Prevention [CDC], World Health Organization [WHO]), and McMaster Health Forum (CoVID-END). This search was primarily examining surveillance guidance published since December 2020 (to capture guidance specific to vaccinations) and any relevant pre-December 2020 guidance. Although the primary focus was on surveillance guidance in a vaccinated population, guidance that was published after December 2020 but was not vaccine-specific was also considered for inclusion; it was assumed that this guidance was still in effect and was not yet updated. There were no language limitations. A patient partner was engaged during the co-production of a plain language summary for both the rapid review of primary literature and the review of international guidance.

ResultsThirty-three studies were included for data synthesis of scientific evidence on surveillance of COVID-19. All the studies were published between April and June 2021. Twenty-one studies were from peer-reviewed journals. Five approaches to monitoring post-vaccination COVID-19 cases and emerging variants of concern were identified including, screening with reverse transcriptase polymerase chain reaction (RT-PCR) and/or a rapid antigen test, genomic surveillance, wastewater surveillance, metagenomics, and testing of air filters on public buses. Population surveillance with RT-PCR testing and/or rapid antigen testing was utilized in 22 studies, mostly in healthcare settings, but also in long-term care facilities (LTCFs) and in the community. The frequency of testing varied depending on whether there was an outbreak.

For population surveillance, the following considerations and limitations were observed: studies with discretionary access to testing have highly variable person-to-person testing frequency; antigen tests have lower sensitivity, therefore some positive cases may be missed; timing of infections relative to PCR testing as well as the sensitivity of the tests can result in missed infections; large sample sizes from multicentre studies increase generalizability, but fail to identify local variations from individual centres; with electronic database surveillance, it is difficult to confirm whether patients with a breakthrough infection and a previous positive SARS-CoV-2 test result had a true reinfection or had prolonged shedding from the previous infection; and participants lose interest in studies with long follow-up, with decrease in testing rates over time.

Six wastewater surveillance and three genomic surveillance studies were identified in this review. A number of benefits such as, good correlation with clinical data, ability to predict major outbreaks, and rapid turnaround time were observed with wastewater surveillance. However, challenges such as, inconsistencies in variant representation depending on where the samples were taken within the community, differences in the capacity of wastewater to predict case numbers based on the size of the wastewater treatment plants, and cost, were noted. Emerging technologies like viral detection in public transport filters, novel sampling, and assay platforms were also identified.

Through comprehensive grey literature searching, 68 international guidance documents were captured for full-text review. A total of 26 documents met the inclusion criteria and were included in our synthesis. Most were not specific to vaccinated populations but reported on a surveillance method of COVID-19 and were therefore included in the review; it was assumed that they were still in effect but have not yet been updated. Eleven countries/regions were represented, including Australia, Brazil, France, Germany, India, New Zealand, Spain, United Kingdom, United States, Europe, and International. All of the guidance documents included surveillance methods appropriate for community settings. Other settings of interest were healthcare settings, including hospitals and primary care centres, long-term care facilities, points of entry for travel, schools, and other sentinel sites (e.g., prisons and closed settings). Seven overarching surveillance methods emerged in the literature. PCR-testing was the most recommended surveillance method, followed by genomic screening, serosurveillance, wastewater surveillance, antigen testing, health record screening, and syndromic surveillance.

Only one document (published by Public Health England) was identified that provided guidance on surveillance specific to vaccinated populations. The document outlined a plan to surveil and monitor COVID-19 in vaccinated populations through a series of targeted longitudinal studies, routine surveillance, enhanced surveillance, use of electronic health records, surveillance of vaccine failure (including follow-up with viral whole genome sequencing), and sero-surveillance (including blood donor samples, routine blood tests, and residual sera).

ConclusionEvidence for post-vaccination COVID-19 surveillance was derived from studies in partially or fully vaccinated populations. Population PCR screening, supplemented by rapid antigen tests, was the most frequently used surveillance method and also the most commonly recommended across jurisdictions. The selection of testing method and the frequency of testing was determined by the intensity of the disease and the scale of testing. Other common testing methods included wastewater surveillance and genomic surveillance. A few novel technologies are emerging, however, many of these are yet to be utilized in the real-world setting. There is limited evidence-based guidance on surveillance in a vaccinated population. Most recent guidance on COVID-19 surveillance is not specific to vaccinated individuals, or it is in effect but has not yet been updated to reflect that. Therefore, more evidence-informed guidance on testing and surveillance approaches in a vaccinated population that incorporates all testing modalities is required.

Protocol/Topic RegistrationPROSPERO-CRD42021261215.

Key DefinitionsAntigen: a foreign protein which induces an immune response in the body, especially the production of antibodies

Fully vaccinated: refers to individuals who have received complete dosage of a given vaccine

Partially vaccinated: refers to individuals who have received an incomplete dosage of a given vaccine

Sero-surveillance: estimation of antibody levels against infectious diseases

Surveillance: ongoing systematic collection, analysis, and interpretation of health data that are essential to the planning, implementation, and evaluation of public health practice

Variants of Concern: a variant for which there is evidence of an increase in transmissibility and/or more severe disease

Variants: virus with a permanent change in its genetic sequence


title: REGEN-COV for the Treatment of Hospitalized Patients with Covid-19

abstract:
BackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients.

MethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response.

Results1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2-74.0; nominal P = .0032). No safety concerns were noted.

ConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.


title: Casirivimab and imdevimab for the treatment of hospitalized patients with COVID-19


title: Atypical action updating in a dynamic environment associated with adolescent obsessive-compulsive disorder

abstract:
BackgroundComputational research had determined that adults with obsessive-compulsive disorder (OCD) display heightened action updating in response to noise in the environment and neglect meta-cognitive information (such as confidence) when making decisions. These features are proposed to underlie patients compulsions despite knowledge they are irrational. Nonetheless, it is unclear whether this extends to adolescents with OCD as research in this population is lacking. Thus, this study aimed to investigate the interplay between action and confidence in adolescents with OCD.

MethodsTwenty-seven adolescents with OCD and 46 controls completed a predictive-inference task, designed to probe how subjects actions and confidence ratings fluctuate in response to unexpected outcomes. We investigated how subjects update actions in response to prediction errors (indexing mismatches between expectations and outcomes) and used parameters from a Bayesian model to predict how confidence and action evolve over time. Confidence-action association strength was assessed using a regression model. We also investigated the effects of serotonergic medication.

ResultsAdolescents with OCD showed significantly increased learning rates, particularly following small prediction errors. Results were driven primarily by unmedicated patients. Confidence ratings appeared equivalent between groups, although model-based analysis revealed that patients confidence was less affected by prediction errors compared to controls. Patients and controls did not differ in the extent to which they updated actions and confidence in tandem.

ConclusionsAdolescents with OCD showed enhanced action adjustments, especially in the face of small prediction errors, consistent with previous research establishing  just-right compulsions, enhanced error-related negativity, and greater decision-uncertainty in paediatric-OCD. These tendencies were ameliorated in patients receiving serotonergic medication, emphasising the importance of early intervention in preventing disorder-related cognitive deficits. Confidence ratings were equivalent between young patients and controls, mirroring findings in adults OCD research.

category: psychiatry and clinical psychology


title: Ethnicity and outcomes in COVID-19 in the United Kingdom: a systematic review and meta-analysis

abstract: This systematic review and meta-analysis evaluated the clinical outcomes of COVID-19 disease in the ethnic minorities of the UK in comparison to the White ethnic group. Medline, Embase, Cochrane, MedRxiv, and Prospero were searched for articles published between May 2020 to April 2021. PROSPERO ID: CRD42021248117. Fourteen studies (767177 participants) were included in the review. In the adjusted analysis, the pooled Odds Ratio (OR) for the mortality outcome was higher for the Black (1.83, 95% CI: 1.21-2.76), Asian (1.16, 95% CI: 0.85-1.57), and Mixed and Other (MO) groups (1.12, 95% CI: 1.04-1.20) compared to the White group. The adjusted and unadjusted ORs of intensive care admission were more than double for all ethnicities (OR Black 2.32, 95% CI: 1.73-3.11, Asian 2.34, 95% CI: 1.89-2.90, MO group 2.26, 95% CI: 1.64-3.11). In the adjusted analysis of mechanical ventilation need the ORs were similarly significantly raised (Black group 2.03, 95% CI: 1.80-2.29, Asian group 1.84, 95% CI: 1.20-2.80, MO 2.09, 95% CI: 1.35-3.22). This review confirmed that all ethnic groups in the UK suffered from increased disease severity and mortality with regards to COVID-19. This has urgent public health and policy implications to reduce the health disparities.


title: Anti-membrane and anti-spike antibodies are long-lasting and together discriminate between past COVID-19 infection and vaccination

abstract: The consequences of past COVID-19 infection for personal health and long-term population immunity are only starting to be revealed. Unfortunately, detecting past infection is currently a challenge, limiting clinical and research endeavors. Widely available anti-SARS-CoV-2 antibody tests cannot differentiate between past infection and vaccination given vaccine-induced anti-spike antibodies and the rapid loss of infection-induced anti-nucleocapsid antibodies. Anti-membrane antibodies develop after COVID-19, but their long-term persistence is unknown. Here, we demonstrate that anti-membrane IgG is a sensitive and specific marker of past COVID-19 infection and persists at least one year. We also confirm that anti-receptor binding domain (RBD) Ig is a long-lasting, sensitive, and specific marker of past infection and vaccination, while anti-nucleocapsid IgG lacks specificity and quickly declines after COVID-19. Thus, a combination of anti-membrane and anti-RBD antibodies can accurately differentiate between distant COVID-19 infection, vaccination, and naive states to advance public health, individual healthcare, and research goals.


title: A combined polygenic score of 21,293 rare and 22 common variants significantly improves diabetes diagnosis based on hemoglobin A1C levels

abstract: Polygenic scores (PS), constructed from the combined effects of many genetic variants1, have been shown to predict risk or treatment strategies for certain common diseases2-6. As most PS to date are based on common variants7, the benefit of adding rare variation to PS remains largely unknown and methodically challenging. We developed and validated a method for constructing a rare variant PS and applied it to a previously identified clinical scenario, in which genetic variants modify the hemoglobin A1C (HbA1C) threshold recommended for type 2 diabetes (T2D) diagnosis6, 8-10. The resultant rare variant PS is highly polygenic (21,293 variants across 144 genes), depends on ultra-rare variants (72.7% of variants observed in <3 people), and identifies significantly more undiagnosed T2D cases than expected by chance (OR=2.71, p=1.51x10-6). A model combining the rare variant PS with a previously published common variant PS6 is expected to identify 4.9M misdiagnosed T2D cases in the USA, nearly 1.5-fold more than the common variant PS alone. These results provide a method for constructing complex trait PS from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.

category: genetic and genomic medicine


title: Genetics of Myocardial Interstitial Fibrosis in the Human Heart and Association with Disease

abstract: Myocardial interstitial fibrosis is a common thread in multiple cardiovascular diseases including heart failure, atrial fibrillation, conduction disease and sudden cardiac death. To investigate the biologic pathways that underlie interstitial fibrosis in the human heart, we developed a machine learning model to measure myocardial T1 time, a marker of myocardial interstitial fibrosis, in 42,654 UK Biobank participants. Greater T1 time was associated with impaired glucose metabolism, systemic inflammation, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation and conduction disease. In genome-wide association analysis, we identified 12 independent loci associated with native myocardial T1 time with evidence of high genetic correlation between the interventricular septum and left ventricle free wall (r2g = 0.82). The identified loci implicated genes involved in glucose homeostasis (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Transcriptome-wide association studies highlighted the role of expression of ADAMTSL1 and SLC2A12 in human cardiac tissue in modulating myocardial tissue characteristics and interstitial fibrosis. Harnessing machine learning to perform large-scale phenotyping of interstitial fibrosis in the human heart, our results yield novel insights into biologically relevant pathways for myocardial fibrosis and prioritize investigation of pathways for the development of anti-fibrotic therapies.


title: Exploring Associations with Severe Hypoxemic Respiratory Failure in COVID-19 Patients upon Admission: A Model for Severe Hypoxemic Respiratory Failure in 329 Unvaccinated, Hospitalized COVID-19 Patients.

abstract:
ObjectiveThe severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming Coronavirus-Disease-2019 (COVID-19) respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterize COVID-19 patients likely to progress to severe hypoxemic respiratory failure are still needed.

DesignWe conducted a retrospective cohort study to develop a model utilizing demographic and clinical data collected in the first 12-hours admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalized COVID-19 patients.

SettingUniversity based healthcare system including 6 hospitals located in the Galveston, Brazoria and Harris counties of Texas.

ParticipantsAdult patients diagnosed with COVID-19 and admitted to one of six hospitals between March 19th and June 31st, 2020.

Primary outcomeThe primary outcome was defined as reaching a WHO ordinal scale between 6-9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation.

ResultsWe included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), qSOFA score (OR: 2.26), and neutrophil to lymphocyte ratio (OR:1.15) were significant predictors of severe disease. The final model showed an area under curve (AUC) of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies.

ConclusionsOur study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.

STRENGTHS AND LIMITATIONS OF THIS STUDY Our study utilized objective and measurable demographic and clinical information regularly available in healthcare settings even among patients unable to communicate.
 Our primary outcome corresponds to WHO ordinal score which would allow compare our results to other studies and in other settings.
 Our model could serve as an effective point of service tool during early admission to assist in clinical management and allocation of resources to unvaccinated patients.
 Our study is a retrospective study of unvaccinated COVID19 patients, and validation of our prediction model in the rest of our study population is still needed.
 In addition, testing our model in a more recent cohort after emergence of new SARS-CoV-2 variants will be needed to assess its robustness.


title: Prediction of Subsequent Need for Intensive Oxygen Supplementation in Galveston, Texas: A Retrospective Cohort Study and Multivariable Regression Model of Unvaccinated COVID-19 Patients


title: Validation of a rapid and sensitive SARS-CoV-2 screening system developed for pandemic-scale infection surveillance

abstract:
Without any realistic prospect of comprehensive global vaccine coverage and lasting immunity, control of pandemics such as COVID-19 will require implementation of large-scale, rapid identification and isolation of infectious individuals to limit further transmission. Here, we describe an automated, high-throughput integrated screening platform, incorporating saliva-based loop-mediated isothermal amplification (LAMP) technology, that is designed for population-scale sensitive detection of infectious carriers of SARS-CoV-2 RNA. Central to this surveillance system is the "Sentinel" testing instrument, which is capable of reporting results within 25 minutes of saliva sample collection with a throughput of up to 3,840 results per hour. It incorporates continuous flow loading of samples at random intervals to cost-effectively adjust for fluctuations in testing demand. Independent validation of our saliva-based RT-LAMP technology on an automated LAMP instrument coined the "Sentinel", found 98.7% sensitivity, 97.6% specificity, and 98% efficiency against a RT-PCR comparator assay, confirming its suitability for surveillance screening. This Sentinel surveillance system offers a feasible and scalable approach to complement vaccination, to curb the spread of COVID-19 variants, and control future pandemics to save lives.

One-Sentence SummaryDevelopment of a high-throughput LAMP-based automated continuous flow, random access SARS-CoV-2 screening platform with sufficient sensitivity and specificity to enable pandemic-scale population testing of infectious individuals using saliva sampling.


title: Validation of a rapid, saliva-based and ultra-sensitive SARS-CoV-2 screening system for pandemic-scale infection surveillance


title: Validation of a rapid, saliva-based, and ultra-sensitive SARS-CoV-2 screening system for a pandemic-scale infection surveillance


title: Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation

abstract: Acute coronary syndromes (ACS) remain a major cause of worldwide mortality. ACS diagnosis is done by a combination of factors, such as electrocardiogram and plasma biomarkers. These biomarkers, however, lack the power to accurately stratify patients into different risk groups. Instead, we used changes in the circulating cell-free DNA (ccfDNA) methylation profiles to estimate the extent of heart injury and the severity of ACS. Our approach relies on the fact that dying cells in acutely damaged tissue release DNA into the blood, causing an increase in the ccfDNA. In addition, each cell type has a distinct DNA methylation profile. We leverage cell type/state specificity of DNA methylation to deconvolute the cell types of origin for ccfDNA and also find DNA methylation-based biomarkers that stratify patient cohorts. The cohorts consisted of healthy subjects, and patients from three ACS conditions: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). We have used two cohorts of patients - discovery, and validation, both consisting of the same conditions. We have sequenced the ccfDNA from the discovery cohort using Whole Bisulfite Genome Sequencing (WBGS), to obtain an unbiased overview of plasma DNA methylation profiles. We have found a total of 1,614 differential methylated regions (DMRs) in the three ACS groups. Many of the regions are associated with genes involved in cardiovascular conditions and inflammation. Using linear models, we were able to narrow down to 254 DMRs significantly associated with ACS severity. The reduced list of DMRs enabled a more accurate stratification of ACS patients. The predictive power of the DMRs was validated in the confirmation cohort using targeted methylation sequencing of the validation cohort.

category: cardiovascular medicine


title: Three doses of COVID-19 mRNA vaccination are safe based on adverse events reported in electronic health records

abstract: Recent reports on waning of COVID-19 vaccine induced immunity have led to the approval and roll-out of additional dose and booster vaccinations. At risk individuals are receiving additional vaccine dose(s), in addition to the regimen that was tested in clinical trials. The risks and the adverse event profiles associated with these additional vaccine doses are currently not well understood. Here, we performed a retrospective study analyzing vaccine-associated adverse events using electronic health records (EHRs) of individuals that have received three doses of mRNA-based COVID-19 vaccines (n = 47,999). By comparing symptoms reported in 2-week time periods after each vaccine dose and in a 2-week period before the 1st vaccine dose, we assessed the risk associated with 3rd dose vaccination, for both BNT162b2 and mRNA-1273. Reporting of severe adverse events remained low after the 3rd vaccine dose, with rates of pericarditis (0.01%, 0%-0.02% 95% CI), anaphylaxis (0.00%, 0%-0.01% 95% CI), myocarditis (0.00%, 0%-0.01% 95% CI), and cerebral venous sinus thrombosis (no cases), consistent with earlier studies. Significantly more individuals (p-value < 0.05) report low-severity adverse events after their 3rd dose compared with after their 2nd dose, including fatigue (4.92% after 3rd dose vs 3.47% after 2nd dose), lymphadenopathy (2.89% vs 2.07%), nausea (2.62% vs 2.04%), headache (2.47% vs 2.07%), arthralgia (2.12% vs 1.70%), myalgia (1.99% vs 1.63%), diarrhea (1.70% vs 1.24%), fever (1.11% vs 0.81%), vomiting (1.10% vs 0.80%), and chills (0.47% vs 0.36%). Our results show that although 3rd dose vaccination against SARS-CoV-2 infection led to increased reporting of low-severity adverse events, risk of severe adverse events remained comparable to the standard 2-dose regime. This study provides support for the safety of 3rd vaccination doses of individuals that are at high-risk of severe COVID-19 and breakthrough infection.


title: Ethnic Variation and its Association with Malaria Awareness: A Cross-sectional Study in the East Nusa Tenggara Province (Indonesia)

abstract:
ObjectivesThis study aims to investigate ethnic variation and its association with malaria awareness in the East Nusa Tenggara Province (ENTP), Indonesia.

MethodsA community-based cross-sectional study was conducted upon 1495 adults recruited by multi-stage cluster random sampling technique. A malaria awareness related questionnaire was used to collect data alongside a malaria awareness index (MAI). A logistic regression method was applied to quantify the strength of associations of factors associated with the awareness index.

ResultsOf total participants, 33% were from Manggarai, 32.3% were from Atoni, 30.2% from Sumba ethnicity. The level of MAI was significantly different between these groups with the highest in Manggarai ethnicity (65.1%, 95% confidence interval (CI): 59.9 - 70.3) and the lowest in Sumba ethnicity (35%, 95% CI: 27.6 - 42.4). The most prominent factors influencing the MAI in Sumba and Manggarai ethnicity were education level, whilst it was socio-economic status (SES) in Atoni ethnicity. The level of MAI was significantly higher for adults with diploma or above education level (adjusted odds ratio (AOR): 21.4, 95% CI: 3.59 - 127.7-for Manggarai ; AOR: 6.94, 95% CI: 1.81 - 26.6 for Sumba). The level of MAI was significantly higher for adults living in high SES in Atoni (AOR 24.48, 95% CI: 8.79 - 68.21).

ConclusionsPoorer education levels and low SES were more prominent factors contributing to lower levels of MAI in rural ENTP. Interventions should focus on improving malaria awareness to these groups to support the national commitment of the Indonesian government to achieve malaria elimination zone by 2030.


title: Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

abstract:
ObjectiveTo examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways.

MethodsMR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age2, sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.

ResultsA total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes.

ConclusionsHigher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.


title: Association of alcohol consumption and frequency with loneliness: A cross-sectional study among Japanese workers during the COVID-19 pandemic

abstract:
BackgroundThere are increasing concerns that prevention measures against coronavirus disease 2019 (COVID-19) such as social distancing and telework are leading to loneliness and poor lifestyle habits like increased alcohol consumption. The purpose of this study was to assess whether loneliness reported among workers during the COVID-19 pandemic is associated with changes in alcohol consumption.

MethodsThe study comprised a cross-sectional, online survey of 27,036 workers between December 22 and 26, 2020. A questionnaire was used to assess loneliness, usual alcohol consumption and whether that consumption had changed. The odds ratios (ORs) were estimated by logistic regression analysis.

ResultsA total of 2831 (10.5%) workers indicated they had increased alcohol consumption during the pandemic. Increased alcohol consumption was significantly associated with loneliness (OR=1.94, 95%CI 1.70-2.21). This association held true for those who indicated they were drinking two or more days per week (OR=1.98 95%CI 1.71-2.30) and those who drank less than one day per week (OR=1.51 95%CI 0.71-3.25). In contrast, there was no association between increased drinking and loneliness among those who indicated they hardly ever drank (OR=1.22 95%CI 0.55-2.72).

ConclusionsAmong those with a drinking habit, increased alcohol consumption is associated with loneliness.


title: CTKG: A Knowledge Graph for Clinical Trials

abstract: Effective and successful clinical trials are essential in developing new drugs and advancing new treatments. However, clinical trials are very expensive and easy to fail. The high cost and low success rate of clinical trials motivate research on inferring knowledge from existing clinical trials in innovative ways for designing future clinical trials. In this manuscript, we present our efforts on constructing the first publicly available Clinical Trials Knowledge Graph, denoted as CTKG. CTKG includes nodes representing medical entities in clinical trials (e.g., studies, drugs and conditions), and edges representing the relations among these entities (e.g., drugs used in studies). Our embedding analysis demonstrates the potential utilities of CTKG in various applications such as drug repurposing and similarity search, among others.

category: health informatics


title: Third dose vaccine With BNT162b2 and its response on Long COVID after Breakthrough infections

abstract:
BackgroundBreakthrough events are not rare after emerging of Delta variant. On the other hand, long COVID is an unsolved issue where sufferers suffer a lot. Some study has shown that COVID-19 vaccine has improved some clinical and libratory parameters in long COVID. But what will be the possible measures against long COVID after the breakthrough event is still a burning question.

MethodWe have observed the third dose by BNT162b2 in a small group(n=20) who were diagnosed as long COVID after breakthrough infections, in Sheikh Hasina National Institute of Burn & Plastic Surgery Institute, Dhaka, Bangladesh. CRP(C-reactive protein) and Anti S1 RBD IgG responses were measured.

ResultAll 20 participants in the study received both dosage of "ChAdOx1-nCoV-19" in between February 2021 to April 2021 and had breakthrough infection in the same or following month which led to long COVID syndrome. They all received a third dose of "BNT162b2". A before and after 3rd dose (14 days after) CRP from participants serum was measured. A Wilcoxon matched paired signed rank test revealed significant (P value <0.05) reduction of inflammatory marker (CRP) after receiving the 3rd vaccine dose. Pre and post 3rd dose quantitative anti S1-RBD IgG response was measured and compared that revealed significant boosting effect that clearly correlates with the CRP response.

ConclusionCoverage of vaccines all over the world is still not expected level to control this pandemic. WHO has not recommended the use of a third/booster dose of COVID vaccines. Though our results show some sort of hope for the long COVID in breakthrough events after getting the third dose more study is needed to conclude this issue.

category: health policy


title: Illness and Wage Loss: Longitudinal Evidence from India (and Implications for the Universal Health Coverage Agenda)

abstract:
BackgroundA key aim of Universal Health Coverage (UHC) is to protect individuals and households against the financial risk of illness. Large-scale health insurance expansions are therefore a central focus of the UHC agenda. Importantly, however, health insurance does not protect against a key dimension of financial risk associated with illness: forgone wage income (due to short-term disability). In this paper, we quantify the economic burden of illness in India attributable - separately - to wage loss and to medical care spending, as well as differences in them across the socio-economic distribution.

MethodsWe use data from two Indian longitudinal household surveys: (i) the Village Dynamics in South Asia (VDSA) survey (1,350 households surveyed every month for 60 months between 2010 and 2015) and (ii) the Indian Human Development Survey (IHDS) (more than 40,000 households surveyed in 2005 and again in 2011). The VDSA allows us to study the economic dynamics of illness using high-frequency observations, and the IHDS allows us to confirm our findings in a nationally-representative sample. Both contain individual- and household-level information about illness, wage income, and medical spending over time. We use longitudinal variation in illness to estimate regression models of economic burden separately for wage loss and medical care spending across the socio-economic distribution. Our regression models include a series of fixed effects that control for differences in time-invariant household (or individual) characteristics and time-varying factors common across households.

Findings1,184 households (88%) in the VDSA sample reported an episode of illness over 60 months, and 15770 households (40%) in the IHDS reported an illness in the preceding year. In the VDSA sample, on average, a day of illness was associated with a reduction in monthly per capita wage income of Rs 77 [95% CI -99 to -57] and an increase in monthly per capita medical spending of Rs 126 [95% CI 110-142]. Variation across the socio-economic distribution was substantial. Among the poorest households, wage loss due to illness is roughly 15% of total household spending - nearly three times greater than medical spending. Alternatively, among the most affluent households, wage loss is less than 5% of total household spending - and only one-third of medical spending. Put differently, wage loss accounts for more than 80% of the total economic burden of illness among the poorest households, but only about 20% of the economic burden of illness among the most affluent. Estimates from the IHDS sample show that this socio-economic gradient is present in the Indian population generally.

InterpretationWage loss accounts for a substantial share of the total economic burden of illness in India - and disproportionately so among the poorest households. If Universal Health Coverage truly aims to protect households against the financial risk of illness - particularly poor households, the inclusion of wage loss insurance or another illness-related income replacement benefit is needed.

O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Google Scholar for the terms "burden of illness, economic impact of health shock, poor households" and found several systematic reviews of the economic burden of illness in low- and middle-income countries. We then reviewed these articles and the ones that they incorporate. The economic burden of illness among households in low- and middle-income countries is well-established and substantial. However, the vast majority of existing studies focus only on economic burden due to medical care spending, with limited and mixed evidence on wage loss. One systematic review concludes that the economic burden of illness on wage loss is unclear, with some studies showing no effect at all.

Added value of this studyOur paper makes two contributions. First, it directly estimates and compares the magnitude of wage loss and direct medical care expenses due to illness using detailed, high frequency data on wage earnings and illness. Past studies have largely focused on either total economic burden or medical care costs, but our direct comparison informs health policies focused on strengthening financial protection. Our high frequency data allow us to pinpoint precise temporal relationships between illness and its economic burden that have not been possible with other commonly-used longitudinal surveys.

Second, given the large number of longitudinal observations for each household in the data, our paper is the first to produce household-specific estimates of the burden of illness, enabling us to trace-out both wage loss and medical care expenses flexibly across the distribution of household economic status - enabling a more granular analysis of disparities between the poor and more affluent. We show that in India, which accounts for nearly half of those impoverished due to illness globally, wage loss accounts for more than 80% of the total economic burden of illness among the poorest households, but only about 20% of the economic burden of illness among the most affluent ones.

Implications of the available evidenceIn contributing to existing evidence, the findings of this paper suggest that even if successful, the current Universal Health Coverage (UHC) agenda may still not protect poor households in India (and potentially many low- and middle-income countries) from substantial economic burden due to illness. If Universal Health Coverage in countries like India truly aims to protect households against the total economic burden of illness - particularly poor households, wage loss insurance or another health-related income-replacement benefit is required along with health insurance.

C_TEXTBOX


title: Development of a Decision Support Tool for Acute Appendicitis

abstract:
BackgroundMultiple randomized controlled trials have shown that it is safe and effective to treat appendicitis with antibiotics or surgery. There are no tools available to assist surgeons and their patients in choosing the optimal treatment for each individual patient. Here we describe the development of a new decisions support tool (DST) for acute appendicitis and place it in the context of international guidelines for decision aid development.

MethodsThe stakeholder engagement and development process for the DST is described. The DST and its development process are placed in the context of the International Patient Decision Aid Standards (IPDAS) and the DEVELOPTOOLS checklist for a user-centered design process.

ResultsA diverse group of over 60 stakeholders were involved in the needs-assessment, development, and evaluation of the DST. The development process met 11/11 of the scored items on the DEVELOPTOOLS checklist. Of the 34 applicable IPDAS items, the current version of the DST meets 31 of them including 6/6 qualifying criteria, 6/6 certification criteria, and 18/22 quality criteria.

ConclusionsThe novel appendicitis DST was developed with the input of multiple stakeholders. The development process and the tool itself complies with best practices recommended by the IPDAS.


title: Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.

abstract:
AimTo assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19).

MethodsIn this randomized, double-blind, multicenter, phase 3 trial, adults (21-80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS-CoV-2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia.

ResultsIn total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)].

Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup.

Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group], which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group.

ConclusionThe trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.


title: Delta subvariants of SARS-COV-2 in Israel, Qatar and Bahrain: Optimal vaccination as an effective strategy to block viral evolution and control the pandemic

abstract: {delta} variant has rapidly become the predominant pandemic driver and yielded four subvariants ({delta}1, {delta}2, {delta}3 and {delta}4). Among them, {delta}1 has been mainly responsible for the latest COVID-19 waves in India, Southeast Asia, Europe and the USA. A relevant question is how {delta} subvariants may have driven the pandemic in the rest of the world. In both Israel and Qatar, mRNA-based vaccination has been rolled out competitively, but the outcomes are quite different in terms of controlling the recent waves resulting from {delta} variant. This raises the question whether {delta} subvariants have acted differently in Israel and Qatar. In both countries, {delta} variant was first identified in April 2021 and {delta}1 subvariant constituted [~]50% {delta} genomes from April to May 2021. But the situation started to diverge in June 2021: In Israel, {delta}1 variant was encoded by 92.0% {delta} genomes, whereas this fraction was only 43.9% in Qatar. Moreover, a {delta}1 sublineage encoding spike T791I was identified in Israel but not Qatar. This sublineage accounted for 31.8% {delta} genomes sequenced in June 2021 and declined to 13.3% in October 2021. In August 2021, {delta}1 also became dominant in Qatar and a major sublineage encoding spike D1259H emerged. This sublineage has evolved further and acquired additional spike substitutions, including K97E, S255F, I693S, I712S, I1104L, E1258D and/or V1177I, in Qatar and other countries, such as Czech Republic, France and Mexico. Monthly distribution of the above sublineages suggests that the one from Qatar is much more of concern than that from Israel. Different from what was in Israel and Qatar, {delta}2 subvariant has also been important in Bahrain, whereas a {delta}2 sublineage encoding spike V1264L and A1736V of NSP3 was dominant in June 2021, but was gradually taken over by {delta}1 subvariant. These results suggest that {delta}1 and {delta}2 subvariants continue their evolution in different countries. The recent successful pandemic control in Israel, Qatar and Bahrain supports that {delta}1 and {delta}2 subvariants are still sensitive to timed vaccination, thereby urging the use of optimal immunity as a strategy to block SARS-COV-2 evolution and control the pandemic.


title: Humoral immune response to Covid-19 vaccination in diabetes: age-dependent but independent of type of diabetes and glycaemic control-the prospective COVAC-DM cohort study

abstract:
AimsImmune response to COVID-19 vaccination and a potential impact of glycaemia on antibody levels in people with diabetes remains unclear. We investigated the seroconversion following first and second COVID-19 vaccination in people with type 1 and type 2 diabetes in relation to glycaemic control prior to vaccination and analysed the response in comparison to individuals without diabetes.

Materials and MethodsThis prospective, multicenter cohort study analysed people with type 1 and type 2 diabetes, well (HbA1c<7.5% or <58 mmol/mol) or insufficiently (HbA1c[≥]7.5% or [≥]58 mmol/mol) controlled and healthy controls. Roches Elecsys anti-SARS-CoV-2 S was used to quantify anti-spike protein antibodies 7-14 days after the first and 14-21 days after the second vaccination.

Results86 healthy controls and 161 participants with diabetes were enrolled, 150 (75 with type 1 diabetes and 75 with type 2 diabetes) were eligible for the analysis. After the first vaccination, only 52.7% in the type 1 diabetes group and 48.0% in the type 2 diabetes group showed antibody levels above the cut-off for positivity. Antibody levels after the second vaccination were similar in people with type1, type 2 diabetes and healthy controls if adjusted for age, sex and multiple testing (p>0.05). Age (r=-0.45, p<0.001) and glomerular filtration rate (r=0.28, p=0.001) were significantly associated with antibody response.

ConclusionsAnti-SARS-CoV-2 S antibody levels after the second vaccination were comparable in healthy controls, people with type 1 and type 2 diabetes, irrespective of glycaemic control. Age and renal function correlated significantly with the extent of antibody levels.

category: endocrinology


title: Waning of SARS-CoV-2 antibodies targeting the Spike protein in individuals post second dose of ChAdOx1 and BNT162b2 COVID-19 vaccines and risk of breakthrough infections: analysis of the Virus Watch community cohort.

abstract:
BackgroundSARS-CoV-2 vaccines stimulate production of antibodies targeting the spike protein (anti-S). The level of antibodies following vaccination and trajectories of waning may differ between vaccines influencing the level of protection, how soon protection is reduced and, consequently the optimum timing of booster doses.

MethodsWe measured SARS-CoV-2 anti-S titre in the context of seronegativity for SARS-CoV-2 anti-Nucleocapsid (anti-N), in samples collected between 1st July and 24th October 2021 in a subset of adults in the Virus Watch community cohort. We compared anti-S levels after BNT162b2 (BioNTech/Pfizer) or ChAdOx1 (AstraZeneca/Oxford) vaccination using time since second dose of vaccination, age, sex and clinical vulnerability to investigate antibody waning. To investigate the use of anti-S levels as a correlate of protection against SARS-CoV-2 infection, we undertook a survival analysis (Kaplan-Meier and Cox) with individuals entering 21 days after their second dose of vaccine, or first antibody test after 1st July (whichever was latest) and exiting with the outcome of SARS-Cov-2 infection or at the end of follow up 24th October 2021. We also undertook a negative test design case-control analysis of infections occurring after the second vaccine dose (breakthrough infections) to determine whether the type of vaccine affected the risk of becoming infected.

Results24049 samples from 8858 individuals (5549 who received a second dose of ChAdOx1 and 3205 BNT162b2) who remained anti-N negative were included in the analysis of anti-S waning over time. Three weeks after the second dose of vaccine BNT162b2 mean anti-S levels were 9039 (95%CI: 7946-10905) U/ml and ChadOx1 were 1025 (95%CI: 917-1146) U/ml. For both vaccines, waning anti-S levels followed a log linear decline from three weeks after the second dose of vaccination. At 20 weeks after the second dose of vaccine, the mean anti-S levels were 1521 (95%CI: 1432-1616) U/ml for BNT162b2 and 342 (95%CI: 322-365) U/ml for ChadOx1. We identified 197 breakthrough infections and found a reduced risk of infection post second dose of vaccine for individuals with anti-S levels greater than or equal to 500 U/ml compared to those with levels under 500 U/ml (HR 0.62; 95%CIs:0.44-0.87; p=0.007). Time to reach an anti-S threshold of 500 U/ml was estimated at 96 days for ChAdOx1 and 257 days for BNT162b2. We found an increased risk of a breakthrough infection for those who received the ChAdOx1 compared to those who received BNT162b2 (OR: 1.43, 95% CIs:1.18-1.73, p<0.001).

DiscussionAnti-S levels are substantially higher following the second dose of BNT162b2 compared to ChAdOx1. There is a log linear waning in levels for both vaccines following the second dose. Anti-S levels are an important correlate of protection as demonstrated by those with anti-S levels < 500U/ml following vaccination being at significantly greater risk of subsequent infection. Since anti-S levels are substantially lower in ChAdOx1 than in BNT162b2 and both decline at similar rates we would expect waning immunity to occur earlier in ChAdOx1 compared to BNT162b2. Our results showing an increased risk of breakthrough infections for those who were vaccinated with ChAdOx1 compared to BNT162b2 are in line with this hypothesis. Consistent with our data, national analyses of vaccine effectiveness also suggest that waning of immunity for infection and, to a lesser extent for severe disease, is seen earlier in ChAdOx1 than in BNT162b2. Our data demonstrate the importance of booster doses to maintain protection in the elderly and clinically vulnerable and suggest that these should be prioritised to those who received ChAdOx1 as their primary course.


title: The effect of notification window length on the epidemiological impact of COVID-19 contact tracing mobile applications

abstract: 1The reduction in SARS-CoV-2 transmission from contact tracing applications (apps) depends both on the number of contacts notified and on the probability that those contacts quarantine after notification. Referring to the number of days preceding a positive test that contacts are notified as an apps notification window, we use an epidemiological model of SARS-CoV-2 transmission that captures the profile of infection to consider the trade-off between notification window length and active app-usage. We focus on 5-day and 2-day windows, the lengths used by the NHS COVID-19 app in England and Wales before and after 2nd August 2021, respectively. Short windows can be more effective at reducing transmission if they are associated with higher levels of active app usage and adherence to isolation upon notification, demonstrating the importance of understanding adherence to control measures when setting notification windows for COVID-19 apps.