title: Effectiveness of BBIBP-CorV, BNT162b2 and mRNA-1273 vaccines against hospitalisations among children and adolescents during the Omicron outbreak in Argentina

abstract:
BackgroundAlthough paediatric clinical presentations of COVID-19 are usually less severe than in adults, serious illness and death have occurred. Many countries started the vaccination rollout of children in 2021; still, information about effectiveness in the real-world setting is scarce. The aim of our study was to evaluate vaccine effectiveness (VE) against COVID-19-associated-hospitalisations in the 3-17-year population during the Omicron outbreak.

MethodsWe conducted a retrospective cohort study including individuals aged 3-17 registered in the online vaccination system of the Buenos Aires Province, Argentina. mRNA-1273 and BNT162b2 were administered to 12-17-year subjects; and BBIBP-CorV to 3-11- year subjects. Vaccinated group had received a two-dose scheme by 12/1/2021. Unvaccinated group did not receive any COVID-19 vaccine between 12/14/2021-3/9/2022, which was the entire monitoring period. Vaccine effectiveness (VE) against COVID-19-associated hospitalisations was calculated as (1-OR) x100.

FindingsBy 12/1/2021, 1,536,435 individuals aged 3-17 who had received zero or two doses of SARS-CoV-2 vaccines were included in this study. Of the latter, 1,440,389 were vaccinated and 96,046 not vaccinated. VE were 78{middle dot}0% [68{middle dot}7-84{middle dot}2], 76{middle dot}4%[62{middle dot}9-84{middle dot}5] and 80{middle dot}0%[64{middle dot}3-88{middle dot}0] for the entire cohort, 3-11 subgroup and 12-17 subgroup, respectively. VE for the entire population was 82{middle dot}7% during the period of Delta and Omicron overlapping circulation and decreased to 67{middle dot}7% when Omicron was the only variant present.

InterpretationThis report provides evidence of high vaccine protection against associated-hospitalisations in the paediatric population during the Omicron outbreak but suggests a decrease of protection when Omicron became predominant. Application of a booster dose in children aged 3-11 warrants further consideration.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is limited evidence on the effectiveness of vaccines in the pediatric population, particularly in children aged 3-11 years after the SARS-CoV-2 B.1.1.529 (Omicron) variants emergence.

We searched preprint and peer-reviewed published articles in PubMed, medRxiv, and SSRN for observational studies, with no language restrictions, using the term "COVID-19 OR SARS-CoV-2" AND "vaccine effectiveness" OR "vaccine impact" AND "children" OR "pediatric" AND "Omicron" published between December 1, 2021, and April 1, 2022. We found 4 studies that included subjects in the 3-17-year population who received a two-dose-scheme of any of the available vaccines-according to each countrys authorisation. Three studies were from the US; two were test-negative-case-control studies and one was a retrospective non-peer-reviewed cohort study. The reported vaccine effectiveness (VE) for 2-doses of BNT162b2-mRNA (Pfizer-BioNTech) in preventing hospitalisations during Omicron predominance was 48-78%; and it was 40-92% for 5-11 and 12-17-year subgroups, respectively. The fourth was a cohort study still in preprint form conducted in Chile and utilized an inactivated vaccine, CoronaVac (SinoVac), widely used in Latin-America. VE for two doses of CoronaVac in the 3-5-year subgroup against hospitalisations was 64% and 69% against ICU admissions.

Added value of this studyUp to date, there are no published studies about the effectiveness of the BBIBP-CorV vaccine against hospitalisation in the pediatric population. Additionally, there are no real-world studies from low and middle-income countries about VE in the 12-17 aged population during the Omicron outbreak.

This study shows that VE after 14 days or more from two-dose-scheme was 78{middle dot}0% [68{middle dot}7-84{middle dot}2], 76{middle dot}4% [62{middle dot}9-84{middle dot}5] and 80{middle dot}0% [64{middle dot}3-88{middle dot}0] for the 3-17-year entire group, and for 3-11-year (BBIBP-CorV) and 12-17-year (mRNA vaccines) subgroups, respectively. VE for the 3-17-year entire group was 82{middle dot}7% during the period of Delta and Omicron overlapping circulation and decreased to 67{middle dot}7% when Omicron was the only variant present. These effects were consistent across all subgroups.

Implications of all the available evidenceOur results provide evidence of high vaccine protection against COVID-19 associated-hospitalisations in the pediatric population during the Omicron outbreak, but suggest a decrease of protection when Omicron became predominant. Application of a booster dose in children aged 3-11 warrants further consideration.

category: infectious diseases


title: Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial

abstract:
ImportanceThe performance of immunoassays for determining past SARS-CoV-2 infection, which were developed in unvaccinated individuals, has not been assessed in vaccinated individuals.

ObjectiveTo evaluate anti-nucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 vaccine efficacy trial participants after SARS-CoV-2 infection during the trials blinded phase.

DesignNested analysis in a Phase 3 randomized, placebo-controlled vaccine efficacy trial. Nasopharyngeal swabs for SARS-CoV-2 PCR testing were taken from all participants on Day 1 and Day 29 (vaccination days), and during symptom-prompted illness visits. Serum samples from Days 1, 29, 57, and the Participant Decision Visit (PDV, when participants were informed of treatment assignment, median day 149) were tested for anti-N Abs.

SettingMulticenter, randomized, double-blind, placebo-controlled trial at 99 sites in the US.

ParticipantsTrial participants were [≥] 18 years old with no known history of SARS-CoV-2 infection and at appreciable risk of SARS-CoV-2 infection and/or high risk of severe Covid-19. Nested sub-study consists of participants with SARS-CoV-2 infection during the blinded phase of the trial.

InterventionTwo mRNA-1273 (Moderna) or Placebo injections, 28 days apart.

Main Outcome and MeasureDetection of serum anti-N Abs by the Elecsys (Roche) immunoassay in samples taken at the PDV from participants with SARS-CoV-2 infection during the blinded phase. The hypothesis tested was that mRNA-1273 recipients have different anti-N Ab seroconversion and/or seroreversion profiles after SARS-CoV-2 infection, compared to placebo recipients. The hypothesis was formed during data collection; all main analyses were pre-specified before being conducted.

ResultsWe analyzed data from 1,789 participants (1,298 placebo recipients and 491 vaccine recipients) with SARS-CoV-2 infection during the blinded phase (through March 2021). Among participants with PCR-confirmed Covid-19 illness, seroconversion to anti-N Abs at a median follow up of 53 days post diagnosis occurred in 21/52 (40%) of the mRNA-1273 vaccine recipients vs. 605/648 (93%) of the placebo recipients (p < 0.001). Higher SARS-CoV-2 viral copies at diagnosis was associated with a higher likelihood of anti-N Ab seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28).

Conclusions and RelevanceAs a marker of recent infection, anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected. Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing

Trial RegistrationClinicalTrials.gov NCT04470427

Key PointsO_ST_ABSQuestionC_ST_ABSDoes prior mRNA-1273 vaccination influence anti-nucleocapsid antibody seroconversion and/or seroreversion after SARS-CoV-2 infection?

FindingsAmong participants in the mRNA-1273 vaccine efficacy trial with PCR-confirmed Covid-19, anti-nucleocapsid antibody seroconversion at the time of study unblinding (median 53 days post diagnosis and 149 days post enrollment) occurred in 40% of the mRNA-1273 vaccine recipients vs. 93% of the placebo recipients, a significant difference. Higher SARS-CoV-2 viral copy number upon diagnosis was associated with a greater chance of anti-nucleocapsid antibody seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). All infections analyzed occurred prior to the circulation of delta and omicron viral variants.

MeaningConclusions about the prevalence and incidence of SARS-CoV-2 infection in vaccinated persons based on anti-nucleocapsid antibody assays need to be weighed in the context of these results.


title: Validation of Reduced S-gene Target Performance and Failure for Rapid Surveillance of SARS-CoV-2 Variants

abstract:
SARS-CoV-2, the virus that causes COVID-19, has many variants capable of rapid transmission causing serious illness. Timely surveillance of new variants is essential for an effective public health response. Ensuring availability and access to diagnostic and molecular testing is key to this type of surveillance. This study utilized reverse transcription polymerase chain reaction (RT-PCR) and whole genome sequencing results from COVID-19-positive patient samples obtained through a collaboration between Aegis Sciences Corporation and Walgreens Pharmacy that has conducted more than 8.5 million COVID-19 tests at [~]5,200 locations across the United States and Puerto Rico.

Viral evolution of SARS-CoV-2 can lead to mutations in the S-gene that cause reduced or failed S-gene amplification in diagnostic PCR tests. These anomalies, labeled reduced S-gene target performance (rSGTP) and S-gene target failure (SGTF), are characteristic of Alpha and Omicron (B.1.1.529, BA.1, and BA.1.1) lineages. This observation has been validated by whole genome sequencing and can provide presumptive lineage data following completion of diagnostic PCR testing in 24-48 hours from collection. Active surveillance of trends in PCR and sequencing results is key to the identification of changes in viral transmission and emerging variants. This study shows that rSGTP and SGTF can be utilized for near real-time tracking and surveillance of SARS-CoV-2 variants.


title: Quantifying spatial heterogeneity of malaria in the endemic Papua region of Indonesia: analysis of epidemiological surveillance data

abstract:
BackgroundAs control efforts progress towards elimination, malaria is likely to become more spatially concentrated in few local areas. The purpose of this study was to quantify and characterise spatial heterogeneity in malaria transmission-intensity across highly endemic Indonesian Papua.

MethodsWe analysed individual-level malaria surveillance data for nearly half a million cases (2019-2020) reported in the Papua and West Papua provinces and adapted the Gini index approach to quantify spatial heterogeneity at the district and health-unit levels. We showed malaria incidence trends and the spatial and temporal distribution of sociodemographic characteristics and aetiological parasites among cases.

FindingsWhile Papua province accounted for the majority of malaria cases reported in the region and had seen a rise in transmission since 2015, West Papua province had maintained a comparatively low incidence. We observed that Gini index estimates were high, particularly when the lower spatial scale of health units was evaluated. The Gini index appears to be inversely associated to annual parasite-incidence, as well as the proportions of vivax malaria, male sex, and adults.

InterpretationThis study suggests that areas with varying levels of transmission-intensities exhibited distinct characteristics. Malaria was distributed in a markedly disproportionate manner throughout the region, emphasising the need for spatially targeted interventions. Periodic quantification and characterisation of risk heterogeneity at various spatial levels using routine malaria surveillance data may aid in tracking progress towards elimination and guiding evidence-informed prioritisation of resource allocation.

FundingStrengthening Preparedness in the Asia-Pacific Region through Knowledge (SPARK) project.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to and including November 19, 2021, for relevant articles on the spatial distribution of malaria in the Papua region of Indonesia, using the terms ("malaria") AND ("distribution" OR "variation" OR "heterogeneity" OR "cluster" OR "aggregation") AND ("Papua") AND ("Indonesia"). Despite the regions mostly stable transmission areas, there has been considerable variation in transmission intensity across the region. According to community surveys conducted up to 2010, estimates of parasite prevalence of Plasmodium falciparum and Plasmodium vivax were highly variable, ranging from 0% to at least 40% and from 0% to at least 7%, respectively, across the region. Similarly, when the Papuan subset of the 2007 National Basic Health Research data was used, the degree of spatial heterogeneity in malaria risk among Papuan districts remained apparent even after sociodemographic were adjusted. Current evidence that is more representative of the current situation, including an easily interpretable and comparable measure of spatial heterogeneity across space and time, is limited.

Added value of this studyOur analysis of large-scale and routinely collected malaria surveillance data from January 2019 to December 2020 revealed significant spatial heterogeneity across the Papua region, as measured by the Gini index. Complementing conventional approaches using geospatial maps and risk tables, the Gini index can be used to provide a single, and sensitive numerical indicator summarising the degree of transmission heterogeneity at a specified spatial level of interest. Along with the previously recognised high spatial heterogeneity among districts, this study revealed a greater degree of intra-district heterogeneity at the health-unit level. That is, within the districts, there were also few health centres and hospitals with a disproportionately higher malaria burden. We observed distinct characteristics of individuals who contracted malaria in districts with varying levels of incidence. The higher transmission magnitude was associated with a lower Gini index, as well as with lower proportions of vivax malaria, male sex, and adults among the cases.

Implications of all the available evidenceThis study provides contemporary empirical evidence for the spatial heterogeneity of malaria distribution across the Papua region of Indonesia, particularly at the lower spatial resolution of health units. Evaluating spatial heterogeneity at a lower spatial scale is likely essential to refine and update local malaria control strategic planning. The combination of comprehensive, routine malaria surveillance data and the Gini index may enable policymakers to assess the magnitude and characteristics of spatial heterogeneity with increased frequency, interpretability, and comparability, allowing for the rapid identification of transmission foci and the deployment of public health measures. Effective control of parasite reservoirs associated with intense transmission may further shrink the risk of infection in adjacent areas with a lower degree of malaria exposure.


title: Similar viral loads in Omicron infections regardless of vaccination status

abstract:
BackgroundAlthough SARS-CoV-2 booster vaccinations are underway, breakthrough infections with Omicron variants are occurring. This study analyzed associations between Omicron sublineage (BA.1.1 and BA.2) viral load and vaccination history.

MethodsViral loads in nasopharyngeal swabs were evaluated by quantitative real-time PCR, and the virus strain was evaluated by whole-genome analysis or TaqMan assay.

ResultsA total of 611 patients positive for an Omicron SARS-CoV-2 variant were included; 199 were unvaccinated, 370 had received two vaccine doses, and 42 had received three doses. Similar viral loads and Ct values of BA.1.1 and BA.2 were detected regardless of vaccination history. No correlations between age and BA.1.1 and BA.2 viral load were observed.

ConclusionOmicron-infected patients who had received a third vaccine dose had viral loads similar to patients with two doses or who were unvaccinated.


title: An optimized flow cytometry protocol for simultaneous detection of T cell activation induced markers and intracellular cytokines: application to SARS-Cov-2 vaccinated individuals

abstract:
Antigen (ag)-specific T cell analysis is an important step for investigation of cellular immunity in many settings, such as infectious diseases, cancer and vaccines. Multiparameter flow cytometry has advantages in studying both the rarity and heterogeneity of these cells. In the cellular immunologists toolbox, the expression of activation-induced markers (AIM) following antigen exposure has made possible the study and sorting of ag-specific T cells without using human leukocyte antigen (HLA)-multimers. In parallel, assessing the cytokine profile of responding T cells would support a more comprehensive description of the ongoing immune response. Here, a method and flow cytometry panel were optimized to combine the detection of activated CD4+ and CD8+ T cells in a TCR-dependent manner with the evaluation of cytokine production by intracellular staining, without affecting the positivity of activation markers. In particular, the expression of CD134 (OX40) and CD69 have been tested in conjunction with intracellular (ic) CD137 (4-1BB) to detect SARS-Cov-2 Spike protein-specific activated T cells. In our setting, assessing CD134 provided minimal contribution to detect the pool of AIM+ T cells, whereas a key role was described for ic-CD69, which was co-expressed with ic-CD137 in both CD4+ and CD8+ lymphocytes. Moreover, the analysis of TCR-triggered cytokine-producing T cells (IFN{gamma}, TNF and IL-2 were assessed) further confirmed the capacity of ic-CD69 to identify functionally responsive antigen-specific T cells, which were often largely negative or poorly positive for CD134 expression. In parallel, the use of CD45RA, CCR7 and CXCR5 allowed us to describe the T cell matuarion curve and detect T helper follicular CD4+ cells, including the antigen-specific activated subsets.

In conclusion, we optimized a method and flow cytometry panel combining assessment of activation induced markers and intracellular cytokines that will be useful for measuring TCR stimulation-dependent activation of CD4+ and CD8+ T cells.

category: allergy and immunology


title: Estimating spatial disease rates from health statistics without geographic identifiers

abstract:
Effective analysis to support decision-making in public health requires adequate data that can be linked to the sociodemographic characteristics and distribution of communities that would be recipients of health programs. Although official statistics are an important source of data to support decisions on public health strategies, health statistics are of limited use if they do not include categorisations related to the spatial distribution of the population. This study introduces a method to use the frequency of disease reported by health care providers (HCP) to calculate disease rates in geographical areas in urban settings. Specifically, this study uses statistics on acute respiratory infections (ARI) to calculate the rate of these diseases at the census district level in Cucuta, a major city in Colombia. A Geographic Information System was used to establish the geographical area of influence (spatial scope) of each HCP, according to the distribution of the basic census geographical areas; the Urban Sections (USEC), in Cucuta. Three levels of increasing spatial aggregation were established considering the characteristics of the population receiving health care in primary, intermediate and tertiary public health services to establish the spatial scope of each HCP. The cases of ARI per USEC were calculated according to the proportion of the population of each USEC in each of the three levels. The spatial rate of ARI per USEC and the hotspots of higher risk of ARI were calculated using an Empirical Bayes method using a geostatistical software.

There were 97 HCP, of which, 31 provided health services in USEC in level 1; 20 provided health services in USEC in level 2; and 47 provided health services in USEC in level 3. A higher spatial rate of ARI was found in USEC in central south; central west; north and northwest; northeast; central east; and central regions, compared to the whole of Cucuta. Hotspots of higher risk were identified in two clusters of USEC in central south and west Cucuta and three isolated USEC in central and northwest Cucuta.

Health indicators at the census district geographical level could be calculated using basic statistics that do not include geographic identifiers by considering the characteristics of the HCP and the population receiving their services. The methodology of this study can be applied to other socioeconomic contexts where geographic identifiers are not attached to public health statistics to create better public health indicators and support potential health promotion and disease prevention strategies.

category: epidemiology


title: Air pollution exposure and mitochondrial DNA copy number in the UK Biobank

abstract:
BackgroundLow levels of mitochondrial DNA copy number (mtDNA-CN) are a biomarker of mitochondrial dysfunction often induced by oxidative stress. Air pollution is a pervasive source of oxidative stress, but the association between air pollution exposure and mtDNA-CN is inconclusive.

ObjectiveWe evaluated the association between long-term exposure to PM [≤] 10 {micro}m diameter (PM10) and nitrogen dioxide (NO2) with mtDNA-CN in 195,196 adults in the UK Biobank study.

MethodsAnnual average PM10 and NO2 concentrations were estimated using separate land-use regression models for years 2007 and 2010. mtDNA-CN was measured in blood samples collected between 2007 and 2010 and was calculated as the ratio of mitochondrial coverage to the nuclear genome coverage derived from whole-genome sequencing in 195,196 UK Biobank participants. We used standardized values (Z-scores) after log-transformation as the mtDNA-CN metric.

ResultsThe median (interquartile range) annual average concentrations of PM10 and NO2 were 21.8 (20.3-23.6) and 28.9 (23.7-35.1) {micro}g/m3 in 2007, and 16.2 (15.5-17.1) and 27.8 (22.7-32.4) {micro}g/m3 in 2010. An increase of 10 {micro}g/m3 in annual average PM10 and NO2 exposure was associated with an adjusted difference in mtDNA-CN of -0.089 (95% confidence interval; -0.090, -0.087) and -0.018 (-0.018, -0.017), respectively. The associations persisted for lags of up to 3 years. PM2.5-10 was also inversely associated with mtDNA-CN.

ConclusionsIn this large-scale study, long-term exposure to PM10 and NO2 were inversely associated with mtDNA-CN. These findings suggest that oxidative stress-induced mitochondrial dysfunction, reflected by reduced mtDNA-CN, may be an additional mechanism mediating the health effects of air pollution.


title: An Evaluation of Prospective COVID-19 Modeling: From Data to Science Translation

abstract:
BackgroundInfectious disease modeling can serve as a powerful tool for science-based management of outbreaks, providing situational awareness and decision support for policy makers. Predictive modeling of an emerging disease is challenging due to limited knowledge on its epidemiological characteristics. For COVID-19, the prediction difficulty was further compounded by continuously changing policies, varying behavioral responses, poor availability and quality of crucial datasets, and the variable influence of different factors as the pandemic progresses. Due to these challenges, predictive modeling for COVID-19 has earned a mixed track record.

MethodsWe provide a systematic review of prospective, data-driven modeling studies on population-level dynamics of COVID-19 in the US and conduct a quantitative assessment on crucial elements of modeling, with a focus on the aspects of modeling that are critical to make them useful for decision-makers. For each study, we documented the forecasting window, methodology, prediction target, datasets used, geographic resolution, whether they expressed quantitative uncertainty, the type of performance evaluation, and stated limitations. We present statistics for each category and discuss their distribution across the set of studies considered. We also address differences in these model features based on fields of study.

FindingsOur initial search yielded 2,420 papers, of which 119 published papers and 17 preprints were included after screening. The most common datasets relied upon for COVID-19 modeling were counts of cases (93%) and deaths (62%), followed by mobility (26%), demographics (25%), hospitalizations (12%), and policy (12%). Our set of papers contained a roughly equal number of short-term (46%) and long-term (60%) predictions (defined as a prediction horizon longer than 4 weeks) and statistical (43%) versus compartmental (47%) methodologies. The target variables used were predominantly cases (89%), deaths (52%), hospitalizations (10%), and Rt (9%). We found that half of the papers in our analysis did not express quantitative uncertainty (50%). Among short-term prediction models, which can be fairly evaluated against truth data, 25% did not conduct any performance evaluation, and most papers were not evaluated over a timespan that includes varying epidemiological dynamics. The main categories of limitations stated by authors were disregarded factors (39%), data quality (28%), unknowable factors (26%), limitations specific to the methods used (22%), data availability (16%), and limited generalizability (8%). 36% of papers did not list any limitations in their discussion or conclusion section.

InterpretationPublished COVID-19 models were found to be consistently lacking in some of the most important elements required for usability and translation, namely transparency, expressing uncertainty, performance evaluation, stating limitations, and communicating appropriate interpretations. Adopting the EPIFORGE 2020 guidelines would address these shortcomings and improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. We also discovered that most of the operational models that have been used in real-time to inform decision-making have not yet made it into the published literature, which highlights that the current publication system is not suited to the rapid information-sharing needs of outbreaks. Furthermore, data quality was identified to be one of the most important drivers of model performance, and a consistent limitation noted by the modeling community. The US public health infrastructure was not equipped to provide timely, high-quality COVID-19 data, which is required for effective modeling. Thus, a systematic infrastructure for improved data collection and sharing should be a major area of investment to support future pandemic preparedness.


title: Challenges of stakeholders' engagement for developing pragmatic, primary health care interventions for chronic respiratory diseases in low resource settings in India

abstract: Chronic respiratory diseases (CRDs) in low resource settings in India are often poorly diagnosed, leading to missed opportunities for early initiation of treatment and poor patient pathways. There is also a poor understanding in rural communities of the causes of CRDs; many symptoms are incorrectly attributed to  asthma and treatment is inconsistent and often based on inaccurate diagnoses. There is a high prevalence of CRDs in rural regions of India. It is vital that interventions are developed to improve an understanding about CRD in low resource settings in India in order to reduce exposure to common risk factors and improve access to evidence based care. We piloted a frontline health care worker delivered  educate, screen and treat intervention programme. We explored the role of stakeholders engagement towards the development of feasible community based interventions. The hypothesis was that without meaningful engagement with the key stakeholders, long term sustainability of the programme would be limited and potentially viewed as primarily for the organisations self-interest. A mixed method study combined a quantitative online survey of the sensitised health care providers and a qualitative assessment of the other stakeholders engagement activities. The methods of qualitative data collection included focus group discussions, feedback and individual interviews and data analysis used a thematic framework. We identified key stakeholders and investigated their knowledge, perceptions, beliefs, practices, educational needs and suggestions for improved care for CRD. Three main themes were 1) Community trust building 2) Mismatch between community awareness about CRD and access to evidence based care resources 3) Finding effective communication methods for low health literate and older age group population with CRD. First theme was built on two sub-themes: sensitised influential people in the community (community advisory committee); empowered, trained health workers in the community for patient screening and navigation. Second theme informed by three sub-themes: availability of sensitized health care providers and empowered health system; recognizing access to evidence based care for CRD in the region/district; recognizing the communitys change in behavior related to management of CRD with education. Third theme was informed by 2 sub-themes: communitys ability to understand the messages through different educational media and tools; challenges in engaging the low health literacy population. The findings of this study add to the literature on the numerous challenges faced by patients with CRD in low resource settings, indicating the need for identifying and educating key stakeholders, continuous support of patients, personalised education, and capacity building of health care providers. Given the significant challenges that the patients face, a feasible primary health care model needs to be developed incorporating strategies to deal with these challenges.

category: primary care research


title: Multimodal multi-center analysis of electroconvulsive therapy effects: brainwide gray matter increase without functional changes

abstract:
BackgroundElectroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC).

MethodsWe analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with treatment-resistant depression before and within two weeks after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n=27).

ResultsWide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function.

ConclusionThese results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases.

category: psychiatry and clinical psychology


title: Pathogen- and type-specific changes in invasive bacterial disease epidemiology during the first year of the COVID-19 pandemic in the Netherlands

abstract: The COVID-19 control measures have resulted in a decline in invasive bacterial disease caused by Neisseria meningitidis (IMD), Streptococcus pneumoniae (IPD), and Haemophilus influenzae (Hi-D). The species comprise different serogroups and serotypes that impact transmissibility and virulence. We evaluated type- and pathogen-specific changes in invasive bacterial disease epidemiology in the Netherlands during the first year of the SARS-CoV-2 pandemic. Cases were based on nationwide surveillance for five bacterial species with either respiratory (IMD, IPD, Hi-D) or non-respiratory (controls) transmission routes and compared between the pre-COVID period (April 2015-March 2020) and the first COVID-19 year (April 2020-March 2021). IMD, IPD, and Hi-D cases decreased by 78%, 67%, and 35%, respectively, in the first COVID-19 year compared to the pre-COVID period although effects differed per age group. Serogroup B-IMD declined by 61%, while serogroup W and Y-IMD decreased >90%. IPD caused by serotypes 7F, 15A, 12F, 33F, and 8 showed the most pronounced decline ([≥]76%). In contrast to an overall decrease in Hi-D cases, vaccine-preventable serotype b (Hib) increased by 51%. COVID-19 control measures had pathogen- and type-specific effects related to invasive infections. Continued surveillance is critical to monitor potential rebound effects once restriction measures are lifted and transmission is resumed.

category: public and global health


title: Rasch Validation of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) in Community-Dwelling Adults and in Adults with Stroke in the US

abstract:
BackgroundWith the recent ongoing global COVID-19 pandemic and political divide in the United States (US), there is an urgent need to address the soaring mental well-being problems and to promote positive well-being. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) measures the positive aspects of mental health. Previous studies confirmed its construct validity, reliability, and unidimensionality with confirmatory factor analysis. Four studies have performed a Rasch analysis on the WEMWBS, but none of them tested adults in the US. The goals of our study are to use Rasch analysis to validate the WEMWBS in the general US population and in adults with stroke.

MethodsWe recruited community-dwelling adults and adults with chronic stroke with upper limb hemiplegia or hemiparesis. We used the Rasch Unidimensional Measurement Model (RUMM) 2030 software to evaluate item and person fit, targeting, person separation reliability (PSR), and differential item functioning (DIF) for sample sizes of at least 200 persons in each subgroup.

ResultsAfter deleting two items, the WEMBS analyzed in our 553 community-dwelling adults (average age 51.22{+/-}17.18 years; 358 women) showed an excellent PSR=0.91 as well as person and item fit, but the items are too easy for this population (person mean location=2.17{+/-}2.00). There was no DIF for sex, mental health, or practicing breathing exercises. In the 37 adults with chronic stroke (average age 58{+/-}13; 11 women) the WEMWBS had a good item and person fit, and PSR=0.92, but the items were too easy for this group as well (person mean location=3.13{+/-}2.00).

ConclusionsThe WEMWBS had good item and person fit but the targeting is off when used in community-dwelling adults and adults with stroke in the US. Adding more difficult items might improve the targeting and capture a broader range of positive mental wellbeing in both populations. Our pilot data in adults with stroke needs to be confirmed in a larger sample size.

category: rehabilitation medicine and physical therapy


title: Development of a Highly Sensitive Serum Neurofilament Light Chain Assay on an Automated Immunoassay Platform

abstract:
BackgroundNeurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in cerebrospinal fluid (CSF) and blood. Numerous studies in MS have demonstrated that NfL correlates with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, widely accessible assay is needed. Our objective was to validate the analytical performance of the novel serum neurofilament light (sNfl) assay on the ADVIA Centaur(R) XP immunoassay system.

MethodsThe research assay was evaluated on the ADVIA Centaur XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), intra-assay variation, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types and transferred to Siemens CLIA laboratory, where it was analytically validated as a laboratory-developed test.

ResultsIn this study, a LLoQ of 1.85 pg/mL, intra-assay variation of <6%, and an assay range of up to 646 pg/mL were demonstrated. A cross-reactivity of <0.7% with neurofilament medium and heavy chains was observed, and the assay was not significantly affected by various interfering substances encountered in clinical specimens. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively.

ConclusionThe analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we believe the assay is acceptable for use in both research and clinical practice settings to determine elevated sNfL levels in patients.

category: neurology


title: Environmental Exposure to Respirable Particles and Estimated Risk of Sarcoidosis: A systematic Review and Meta-Analysis

abstract:
IntroductionSarcoidosis is an inflammatory disease of unknown etiology that affects multiple organs in the body. In most cases, the affected organ is the lung. Sarcoidosis risk factors include environmental exposures, genetic predisposition, and immunological factors. The main objective of this review was to assess whether exposure to respirable particles is associated with increased risk of sarcoidosis.

MethodsA comprehensive search was conducted in scientific databases. Additional search of grey literature as well as handsearching of relevant records was performed. The search was restricted to studies published between January 1998 to October 2019. Meta-analysis was performed for studies that provided quantitative data.

ResultsAfter applying inclusion/exclusion criteria, nine articles were included in the systematic review and four in the meta-analysis. Quantitative analysis suggested that people exposed to respirable particles were approximately three times more likely to develop sarcoidosis compared to people who are unexposed.

Discussion and conclusionThis study collected and aggregated available evidence that assessed exposure to respirable particles and risk of developing sarcoidosis. Evidence of increased association between exposure to respirable particles and sarcoidosis was strongly suggested based on our qualitative review. More rigorous epidemiologic exposure studies are needed to generate data that would accurately determine the risk and causal pathways through which exposure to respirable particles could lead to the development of sarcoidosis.

category: occupational and environmental health


title: EHR Foundation Models Improve Robustness in the Presence of Temporal Distribution Shift

abstract:
BackgroundTemporal distribution shift negatively impacts the performance of clinical prediction models over time. Pretraining foundation models using self-supervised learning on electronic health records (EHR) may be effective in acquiring informative global patterns that can improve the robustness of task-specific models.

ObjectiveTo evaluate the utility of EHR foundation models in improving the in-distribution (ID) and out-of-distribution (OOD) performance of clinical prediction models.

MethodsThe cohort consisted of adult inpatients admitted between 2009-2021. Gated recurrent unit (GRU)- and transformer (TRANS)-based foundation models were pretrained on EHR of patients admitted between 2009-2012 and were subsequently used to construct patient representations (CLMBR). These representations were used to learn logistic regression models (CLMBRGRU and CLMBRTRANS) to predict hospital mortality, long length of stay, 30-day readmission, and ICU admission. We compared CLMBRGRU and CLMBRTRANS with baseline logistic regression models learned on count-based representations (count-LR) and end-to-end (ETE) GRU and transformer models in ID (2009-2012) and OOD (2013-2021) year groups. Performance was measured using area-under-the-receiver-operating-characteristic curve, area- under-the-precision-recall curve, and absolute calibration error.

ResultsModels trained on CLMBR generally showed better discrimination relative to count-LR in both ID and OOD year groups. In addition, they often matched or were better than their ETE counterparts. Finally, foundation models performance in the self-supervised learning task tracked closely with the ID and OOD performance of the downstream models.

ConclusionsThese results suggest that pretraining foundation models on electronic health records is a useful approach for developing clinical prediction models that perform well in the presence of temporal distribution shift.

category: health informatics


title: Association of Socioeconomic Disparities and Predisposing Factors with Higher Prevalence of Hypertension related Left Ventricular Hypertrophy in Males: a Malaysian Community-Based Study

abstract: Left Ventricular Hypertrophy (LVH) is a risk for various cardiovascular events among those with hypertension (HT). However the prevalence of hypertension-related LVH (HT LVH+) in communities with lower socioeconomic status (SES) is not adequately reported. This study investigated the prevalence of HT LVH+ among the urban and rural males and the attributing factors. A total of 1,923 males who had echocardiographic examinations done were recruited. Their blood pressure was measured to diagnose those with or without hypertension. Left ventricular mass index was determined. Univariate analysis was performed to identify associated factors predisposing to LVH. A total of 992 males had HT, of which 264 had LVH, and were more prevalent in older age groups and Malays (p<0.001). Individuals from rural areas, with low income and low educational background were associated with higher LVH prevalence (p<0.001). Those with moderate aortic regurgitation was 3.17-fold higher in LVH. Ninety-nine normotensives had LVH, 71.7% came from rural. Total cholesterol and low density lipoprotein cholesterol levels were significantly higher in HT LVH+ from urban than the rural areas (p=0.029 and p=0.002, respectively). A quarter of the HT population in Malaysia develop LVH, majority of them were from rural, indicating that socioeconomic disparities contribute to the higher risk of HT LVH+. The rural populations may have attributed to different risk factors as opposed to those from urban, hence emphasize the need to deliver targeted strategies for prevention and management HT LVH+ by different SES.

category: cardiovascular medicine


title: The Dawn is Coming -- the Description and Prediction of Omicron SARS-CoV-2 Epidemic Outbreak in Shanghai by Mathematical Modeling

abstract: The COVID-19 Omicron outbreak in Shanghai has been going on for >1 month and 25 million population is subjected to strict lock-down quarantine. Until now, it is not clear how long this epidemic might end. Here, we present a time-delayed differentiation equation model to evaluate and forecast the spreading trend. Our model provides important parameters such as the average quarantine ratio, the detection interval from being infected to being tested positive, and the spreading coefficient to better understand the omicron progression. After data fitting, we concluded on 11 April that the maximum overall number infected in Shanghai would exceed 300,000 on 14 April and the turning point would be in the coming days around 13-15 April, 2022, which is perfectly in line with the real-life infection number. Furthermore, the quarantine ratio in Shanghai was found to be greater than 1, supportive of the effectiveness of the strict lockdown policy. Altogether, our mathematical model helps to define how COVID-19 epidemic progresses under the Shanghai lock-down unprecedented in human history and the Chinese zero tolerance policy.


title: Modelling the risk factors of malnutrition amongst children below five years of age in Uganda. A GSEM based analysis

abstract:
This study aimed at establishing the causal mechanism through which the risk factors of malnutrition act to influence the undernutrition of under-fives in Uganda. A generalized structural equation model (GSEM) was estimated based on the multifaceted nature of the risk factors according to the UNICEF 1991 conceptual framework for child malnutrition. Uganda Demographic and Health Survey (UDHS-KR) dataset was used for the analysis. An index of malnutrition which was the overall response variable in the GSEM model was derived from the three anthropometric variables of stunting, underweight, and body wasting.

The findings indicate that sex of the child, age of the child, the perceived size of the child at birth, the weight of the child at birth, duration of breastfeeding, mothers education level, working status of the mother, wealth quintile of the household and mothers weight (BMI) were the factors that had a direct and significant influence on undernutrition. Further analysis of the causal mechanism reveals about five main paths of causal mechanism and these were; (i) the mothers level of education influences the mothers weight which influences the birth weight of the child and then this combination influences under-nutrition, (ii) mothers education levels also influence the household wealth status and as observed above, household wealth significantly influences under-nutrition, (iii) residence whether rural or urban setting influences under-nutrition through its influence on the household wealth, (iv) being in urban areas is also associated with employment opportunities which in turn influences the duration of breast feeding and then influences under-nutrition, (v) size at birth which is key in influencing under-nutrition is influenced by the working status of the mother which is dependent on the place of residence.

Based on the findings, the recommendation is that a multi-faceted approach that addresses all the factors at different levels be implemented in order to get a lasting solution to the silent killer of under-fives.


title: Prognostic significance of WT1 expression level thershold in acute myeloid leukemia patients receiving hematopoietic stem cell transplantation: Meta-Analysis

abstract:
ObjectiveThe WT1 gene is considered as a poor prognostic factor for acute myeloid leukemia (AML) after Allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, the effect of the expression threshold of WT1 on the prognosisis controversial, which is evaluated in this meta-analysis.

MethodsRelevant studies about the expression threshold of WT1 on the prognosis of AML after Allo-HSCT were searched in online databases. Data were extracted from them and analyzed by Stata16.0 software.

ResultsFive studies involving 739 patients were screened out, including 433 cases experimental group and 306 cases control group. The experimental group and control group were compared for 1-year disease-free survival rate (DFS) [RR=1.19, 95%CI (1.03, 1.38), P =0.02] and 4-year DFS [RR= 1.18, 95%CI (0.98, 1.42), P =0.09]. The experimental group was lower than the control group in 1-year DFS, and there was no statistical significance in 4-year DFS. 1-year overall survival rate (OS) [RR=1.06, 95%CI (0.92, 1.23), P =0.40] and 4-year OS [RR= 1.16, 95%CI (1.03, 1.32), P =0.02], suggesting that the experimental group had a lower 4-year OS than the control group, and 1-year OS had no statistical significance.

ConclusionsHigh WT1 expression is unfavorable to the prognosis of AML patients undergoing Allo-HSCT. A threshold of 250 copies/104ABL of WT1 may be the best value for predicting the poor prognosis in these patients.

category: hematology


title: Online randomised trials with children: A scoping review protocol

abstract:
IntroductionThis scoping review will determine how online, randomised trials with children are conducted. The objectives of the review are: (a) to determine what methods and tools have been used to create and conduct online trials with children and (b) to identify the gaps in the knowledge in this field.

Over the last decade, randomised trials employing online methods have gained momentum. Decentralised methods lend themselves to certain types of trials and can offer advantages over traditional trial methods, potentially increasing participant reach and diversity and decreasing research waste. However, decentralised trials that have all aspects of the trial exclusively online are not yet common, and those involving children even less so. This scoping review will describe and evaluate the methods used in these trials to understand how they may be effectively employed.

MethodsMethods are informed by guidance from the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. The search strategy was developed in consultation with an information specialist for the following databases: MEDLINE, CENTRAL, CINAHL, and Embase. Grey literature searches will be completed with the consultation of experts in decentralised trials and digital health using internet searches and suitable trial registries. Once identified, included full-text studies references will be manually searched for any trials that may have been missed. We will include randomised and quasi-randomised trials conducted exclusively online with participants under the age of 18 published in English. We will not limit by country of conduct or date of publication. Data will be collected using a data charting tool and presented in text, graphical, and tabular formats.

Ethics and DisseminationEthical approval is not needed since all data sources used are publicly available. The review will be available as a preprint before publication in an open-access, peer-reviewed journal.


title: Confounder-adjusted MRI-based predictors of multiple sclerosis disability

abstract:
IntroductionBoth aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as accelerated aging. Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects.

MethodsStandardized brain MRI and neurological examination were acquired prospectively in 649 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n=160). MS patients were randomly split into training (n=277) and validation (n=132) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales.

ResultsConfounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperforms published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort.

ConclusionGBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.

HighlightsO_LIRegressing out physiological confounders affecting volume of CNS structures in healthy volunteers, strengthened correlations between white matter volumes and disability outcomes in MS cohorts
C_LIO_LIAggregating volumetric features into generalized boosting machine (GBM) models outperformed correlations of individual MRI biomarkers with clinical outcomes in MS
C_LIO_LIDeveloped more sensitive and reliable models that predict MS-associated disability
C_LIO_LIIndependent validation cohorts show true model performances
C_LIO_LIDeveloped GBM models should be explored in future MS clinical trials
C_LI


title: Seroclearance of HBsAg in Chronic Hepatitis B Patients after a Tolerance Breaking Therapy: GM-CSF, followed by Human HBV Vaccine

abstract:
ObjectiveSeroclearance of hepatitis B surface antigen (HBsAg) remains a challenge to the functional cure of HBV infection due to an HBV-specific immune tolerance that prevents virus eradication.

MethodsIn this clinical study, chronic hepatitis B patients treated with the standard nucleotide analog (NA) Adefovir Dipivoxil (ADV) or treated with ADV and IFN- were immunized with granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with Human HBV Vaccine.

ResultsThis THRIL-GM-Vac approach (THRee Injections of Low-dose GM-CSF followed by one dose of the HBV Vaccine) has achieved at least a 10-fold reduction of HBsAg level in 10 out of 23 (43.5%) patients tested. Moreover, two out of the ten patients eventually reached seroclearance. Thus THRIL-GM-Vac could break HBV-specific tolerance and boost HBsAg-specific cellular immunity. Consequently, the THRIL-GM-Vac approach could provide effective therapy for patients bearing medium-to-low levels of HBsAg.

ConclusionOur findings carry the clinical significance of showing a novel way to break immunotolerance that can tackle the persistent infection manifested as generated by chronic HBV burden in chronic hepatitis B (CHB) patients.

Significance of this studyO_ST_ABSWhat is already known about the subject?C_ST_ABSChronic hepatitis B virus (CHB) patients can be controlled with antiviral therapies while rarely cured or functionally cured. In addition to the standard anti-viral treatment, immunotherapeutic approaches may break the HBV established immunotolerance and, in turn, mount effective activation or reactivation of host anti-HBV immunity and can be achieved in HBV-related animal models. However, achieving such a functional cure in CHB patients has been challenging.

What are the new findings?O_LIWe demonstrated in this study that some levels of HBsAg seroclearance in CHB patients were treated with a 3-day treatment of GM-CSF followed by one HBV vaccine for six treatments within one year in addition to the standard of anti-viral treatment.
C_LIO_LINotably, dynamics of HBsAg declined in responders were correlated with dynamics of HBsAg-specific Treg cells and reciprocally associated with the dynamical changes of HBsAg-specific IFN-{gamma} +CD4+ (Th1) and IFN-{gamma} +CD8+(Tc1) T cells over the course.
C_LI

How might it impact on clinical practice in the foreseeable future?O_LIIt demonstrates in CHB patients that breaking Treg-immunotolerance can significantly be correlated with reducing the level of HBsAg in the  responders by immunotherapy.
C_LIO_LISuch correlation can be used to predict outcomes of the efficacy of an immunotherapeutic treatment prior to completing its treatments.
C_LIO_LIThe evidence of HBsAg seroclearance in CHB patients by the presented immunotherapeutic approach will also shed light on improving such approach or similar strategies and further benefit those unmet medical needs.
C_LI


title: Implementing an antibiogram profile to aid rational antimicrobial therapy and improving infection prevention in an urban hospital in The Gambia; strategies and lessons for low income and middle-income countries.

abstract:
BackgroundDiagnostic microbiological capabilities remain a challenge in low- and middle-income countries resulting in major gaps. The global antimicrobial resistance burden has necessitated use of appropriate prescribing to curb the menace. This study highlights the process used to develop an antibiogram to monitor resistance at a secondary-level health facility to aid empirical clinical decision making.

MethodsThis retrospective cross-sectional descriptive study used 3 years of cumulative data at the Medical Research Council Unit The Gambia from January 2016 to December 2018. Phenotypic data was manually imputed into WHONET and the cumulative antibiogram constructed using standardised methodologies according to CLSI M39-A4 guidelines. Pathogens were identified by standard microbiological methods and antimicrobial susceptibility testing was performed using Kirby-Bauer disc diffusion method according to CLSI M100 guidelines.

ResultsA total of 14776 non-duplicate samples (blood cultures n=4382, urines n=4914, other miscellaneous swabs and aspirates n=2821 and n=390 respectively, sputa n=334, stools n=1463, CSF 353 and other samples n= 119) were processed of which 1163 (7.9%) were positive for clinically significant pathogens. Among the 1163 pathogens, E. coli (n= 315) S. aureus (n=232), and K. pneumoniae (n=96) were the leading cause of disease Overall, the susceptibility for E. coli and K. pneumoniae from all samples were: trimethoprim-sulfamethoxazole (17% and 28%), tetracycline (26% and 33%), gentamicin (72% and 46%), chloramphenicol (76 and 60%), and ciprofloxacin (69% and 59%), amoxicillin/clavulanic (77% and 54%) respectively. Extended spectrum beta-lactamase resistance was present in 23% (71/315) vs 35% (34/96) respectively. S. aureus susceptibility for methicillin was 99%.

ConclusionThis antibiogram has confirmed susceptibility to commonly used antimicrobials was higher for E. coli than K. pneumoniae with high ESBL resistance warranting surveillance. An alternative aminoglycoside with better sensitivity such as amikacin might be relevant although this was not tested and that cloxacillin remains a drug of choice for the Staphylococci.


title: A Mixed Methods Study Evaluating Acceptability of a Daily COVID-19 Testing Regimen with a Mobile-App Connected, At-Home, Rapid Antigen Test: Implications for Current and Future Pandemics

abstract:
BackgroundWidespread use of at-home rapid COVID-19 antigen tests has been proposed as an important public health intervention to interrupt chains of transmission. Antigen tests may be preferred over PCR because they provide on-demand results for relatively low cost and can identify people when they are most likely to be infectious, particularly when used daily. Yet the extent to which a frequent antigen testing intervention will result in a positive public health impact for COVID-19 will depend on high acceptability and high adherence to such regimens.

MethodsWe conducted a mixed-methods study assessing acceptability of and adherence to a daily at-home mobile-app connected rapid antigen testing regimen among employees of a US-based media company. Acceptability was assessed across seven domains of the Theoretical Framework of Acceptability.

ResultsAmong 31 study participants, acceptability of the daily testing intervention was generally high, with participants reporting high perceived effectiveness, intervention coherence, and self-efficacy; positive affective attitude; acceptable degree of burden and opportunity cost; and assessing the intervention as ethical. 71% reported a preference to test daily using an at-home antigen test than weekly employment-based PCR. Mean adherence to the 21-day testing regimen was 88% with 43% of participants achieving 100% adherence, 48% testing at least every other day, and 10% testing less than every other day.

ConclusionsDespite overall high acceptability and adherence, we identified three implementation challenges that must be addressed for frequent serial testing for COVID-19 to be implemented at scale and have a positive public health impact. First, users need guidance on how and when to adapt testing frequencies to different epidemiological conditions. Second, users and institutions need guidelines for how to safely store and share test results. Third, implementation of serial testing strategies must prioritize health equity and protect those most vulnerable to COVID-19.


title: Potential drivers for schistosomiasis persistence: population genetic analyses from a cluster-randomized urogenital schistosomiasis elimination trial across the Zanzibar islands

abstract:
The World Health Organization revised NTD Roadmap and its newly launched Guidelines target elimination of schistosomiasis as a public health problem in all endemic areas by 2030. Key to meeting this goal is elucidating how selective pressures imposed by interventions shape parasite populations. Our aim was to identify any differential impact of a unique cluster-randomized tri-armed elimination intervention (biannual mass drug administration (MDA) applied alone or in association with either mollusciciding (snail control) or behavioural change interventions) across two Zanzibarian islands (Pemba and Unguja) on the population genetic composition of Schistosoma haematobium over space and time. Fifteen microsatellite loci were used to analyse individual miracidia collected from infected individuals across islands and intervention arms at the start (2012 baseline: 1,529 miracidia from 181 children; 303 from 43 adults; age-range 6-75, mean 12.7 years) and at year 5 (2016: 1,500 miracidia from 147 children; 214 from 25 adults; age-range 9-46, mean 12.4 years). Measures of genetic diversity included allelic richness (Ar), inbreeding coefficient (FST), parentage analysis, estimated worm burden, worm fecundity, and genetic sub-structuring. There was little evidence of differential selective pressures on population genetic diversity, outbreeding or estimated worm burdens by treatment arm, with only the MDA+snail control arm within Unguja showing a (non-significant) trend towards reduced diversity over time. The greatest differences overall, most notably in terms of parasite fecundity (mean number of eggs per adult female worm) and genetic sub-structuring, were observed between the islands, consistent with Pembas persistently higher mean infection intensities compared to neighbouring Unguja, and within islands in terms of persistent infection hotspots (across three definitions). These findings highlight the important contribution of population genetic analyses to elucidate extensive genetic diversity and biological drivers, including potential gene-environmental factors, that may override short term selective pressures imposed by differential disease control strategies.

Author SummarySchistosomiasis is a parasitic disease caused by infection with blood flukes, which leads to acute and chronic pathology in millions of infected individuals, particularly those within the poorest tropical and subtropical regions. In 2012, the World Health Organization (WHO) set the ambitious goals to achieve Elimination of Schistosomiasis as a Public Health Problem (i.e., EPHP, prevalence of heavy infection intensity less than 1% in all sentinel sites) and complete Interruption of Transmission (i.e., IoT reduction of incidence of infection to zero) in selected African regions by 2025. More recently, the revised WHO Neglected Tropical Diseases (NTD)-Roadmap and Revised Schistosomiasis Control and Elimination Guidelines aim to achieve EPHP in all regions by 2030. Here we analysed population genetic data associated with a unique 5-year cluster-randomized trial across Zanzibar (Pemba and Unguja islands) which aimed to assess the impact of contrasting interventions to achieve urogenital schistosomiasis elimination. Whilst, consistent with the main trial study, no significant differential impact of interventions was detected in terms of infection epidemilogy, our data suggested that the greatest impact on genetic diversity was within the mass drug administration plus concurrent mollusciding arm. Moreover, our analyses revealed significant differences in both the genetic sub-structuring and notably the fecundity of parasites between Pemba and Unguja islands, and within Pemba island in relation to persistent hotspots, potentially indicative of genetic and biological factors driving persistence. These findings highlight the important contribution of population genetic analyses to reveal high levels of genetic diversity, biological drivers and potential gene-environmental interactions in determining infection dynamics and persistence, all of which present additional challenges for successful control.


title: Modeling the initial phase of COVID-19 epidemic: The role of age and disease severity in the Basque Country, Spain

abstract:
Declared a pandemic by the World Health Organization (WHO), COVID-19 has spread rapidly around the globe. With eventually substantial global underestimation of infection, by the end of March 2022, more than 470 million cases were confirmed, counting more than 6.1 million deaths worldwide.

COVID-19 symptoms range from mild (or no) symptoms to severe illness, with disease severity and death occurring according to a hierarchy of risks, with age and pre-existing health conditions enhancing risks of disease severity. In order to understand the dynamics of disease severity during the initial phase of the pandemic, we propose a modeling framework stratifying the studied population into two groups, older and younger, assuming different risks for severe disease manifestation.

The deterministic and the stochastic models are parametrized using epidemiological data for the Basque Country population referring to confirmed cases, hospitalizations and deaths, from February to the end of March 2020. Using similar parameter values, both models were able to describe well the existing data. A detailed sensitivity analysis was performed to identify the key parameters influencing the transmission dynamics of COVID-19 in the population. We observed that the population younger than 60 years old of age would contribute more to the overall force of infection than the older population, as opposed to the already existing age-structured models, opening new ways to understand the effect of population age on disease severity during the COVID-19 pandemic.

With mild/asymptomatic cases significantly influencing the disease spreading and control, our findings support the vaccination strategy prioritising the most vulnerable individuals to reduce hospitalization and deaths, as well as the non-pharmaceutical intervention measures to reduce disease transmission.


title: The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

abstract:
Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks.

One-Sentence SummaryExpanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.


title: Changes of LipoxinA4 Levels Following Early Hospital Management of Patients with Non-Severe COVID-19: A Pilot Study

abstract: LipoxinA4 (LXA4) is an anti-inflammatory biomarker participating in the active process of inflammation resolution, which is suggested to be effective on infectious and inflammatory diseases like COVID-19. In this study, we hypothesized that LXA4 levels may increase following COVID-19 treatment and are even more accurate than commonly used inflammatory markers such as erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and ferritin. To test this hypothesis, a pilot study was conducted with 31 adult hospitalized patients with non-severe COVID-19. LXA4 levels were measured at the baseline and 48-72 hours later. Accordingly, ESR and CRP levels were collected on the first day of hospitalization. Moreover, the maximum serum ferritin levels were collected during the five days. LXA4 levels significantly increased at 48-72 hours compared to the baseline. ESR, CRP, and ferritin levels were positively correlated with the increased LXA4. In contrast, aging was shown to negatively correlate with the increased LXA4 levels. LXA4 may be known as a valuable marker to assess the treatment response among non-elderly patients with non-severe COVID-19. Furthermore, LXA4 could be considered as a potential treatment option under inflammatory conditions. Further studies are necessary to clarify LXA4 role in COVID-19 pathogenesis, as well as the balance between such pro-resolving mediators and inflammatory parameters.


title: High proportion of tuberculosis transmission among social contacts in rural China: a 12-year prospective population-based genomic epidemiological study

abstract:
BackgroundTuberculosis (TB) is more prevalent in rural than urban areas in China, and delineating TB transmission patterns in rural populations could improve TB control.

MethodsWe conducted a prospective population-based study of culture-positive pulmonary TB patients diagnosed between July 1, 2009 and December 31, 2020 in two rural counties in China. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms, based on whole-genome sequencing. Risk factors for clustering were identified by logistic regression. Transmission links were sought through epidemiological investigation of genomic-clustered patients.

FindingsOf 1517 and 751 culture-positive pulmonary TB patients in Wusheng and Wuchang counties, respectively, 1289 and 699 strains were sequenced. Overall, 624 (31{middle dot}4%, 624/1988) patients were grouped into 225 genomic clusters. Epidemiological links were confirmed in 41{middle dot}8% (196/469) of clustered isolates, including family (32{middle dot}7%, 64/196) and social contacts (67{middle dot}3%, 132/196). Social contacts were generally with relatives, within the community or in shared aggregated settings outside the community, but the proportion of clustered contacts in each category differed between the two sites. The time interval between diagnosis of student cases and contacts was significantly shorter than family and social contacts, probably due to enhanced student contact screening. Transmission of multidrug-resistant strains was likely responsible for 81{middle dot}4% (83/102) of MDR-TB cases, with minimal acquisition of additional resistance mutations.

InterpretationA large proportion of TB transmission in rural China occurred among social contacts, suggesting that active screening and aggressive contact tracing could benefit TB control, but contact screening should be tailored to local patterns of social interactions.

FundingNational Science and Technology Major Project of China, Natural Science Foundation of China, and Science and Technology Major Project of Shanghai

Evidence before this studyWe searched PubMed for genomic epidemiological studies of Mycobacterium tuberculosis published in English before April 2022 employing whole-genome sequencing, using the search terms "tuberculosis", "transmission", "population based", and "whole-genome sequencing". We identified only 11 studies in which whole-genome sequencing was used to investigate transmission of M tuberculosis at the population level. We also searched the China national knowledge infrastructure (CNKI) and WANFANG databases with the same search terms for papers published in Chinese, but did not identify any studies. The duration of most of the 11 studies we identified was less than 5 years. Seven studies conducted epidemiological investigations of genomic-clustered cases, but the proportion of cases with confirmed epidemiological links was very low. Therefore, no studies had sufficient evidence to identify populations and sites at high risk of TB transmission. Five studies were conducted in China but all were in urban areas and focused on MDR-TB patients and internal migrants. The pattern of TB transmission in rural China, where TB is more prevalent, had not been addressed.

Added value of this studyTo our knowledge, ours is the first population-based genomic epidemiological study to delineate TB transmission patterns in rural China. Close contacts have been shown to be a high-risk group for TB transmission in other countries. In China, however, the huge number of TB patients, limited resources for TB prevention and control and the stigma associated with tuberculosis all contribute to a failure to identify and screen many close contacts. As a consequence, close contacts have been calculated to contribute only about 2% of the total TB burden. In this study, through the investigation of genomic-clustered patients, we found at least 41{middle dot}8% of clustered patients were close contacts who comprised 9{middle dot}9% of the total TB patients in the study. Moreover, more than two-thirds of the close contacts were social contacts rather than members of the immediate family. The composition of social contacts differed between the two study sites due to differences in climate and lifestyle habits. The average time interval between the diagnosis of clustered student contacts was shorter than for family or community contacts. In addition, transmission of MDR strains was likely responsible for 81{middle dot}4% of MDR-TB cases, with minimal acquisition of additional resistance mutations. Our 12-year study identified patterns of TB transmission not identified by previous studies, demonstrating the value of long-term genomic epidemiological studies.

Implications of all the available evidenceOur study demonstrates that much of the transmission of TB in rural China was among close contacts, especially social contacts. Therefore, strengthening and improving proactive screening of close social contacts can identify more TB patients and shorten the time to patient detection. We believe that this type of vigorous active case-finding is essential for reducing TB transmission and the considerable TB burden in China. Long-term prospective genomic epidemiological studies provide a useful picture of TB transmission patterns that can help guide the design of strategies to improve TB prevention and control.


title: Implementation strategies to increase human papillomavirus vaccination uptake for adolescent girls in sub-Saharan Africa: A scoping review protocol

abstract:
IntroductionThe human papillomavirus (HPV) is sexually transmitted and infects approximately 75% of sexually active people early in their sexual life. Persistent infection with oncogenic HPVtypes can lead to malignant conditions such as cervical cancer. In 2006, the World Health Organisation approved the use of efficacious HPV vaccine for girls aged 9 to 14 years to prevent HPV related conditions. Despite the HPV vaccine having been available for about 15 years, dose completion remains at 53% in sub-Saharan Africa for countries implementing the vaccination program. A fraught of barriers to implementation exist which prevent adequate coverage. Achieving success for HPV vaccination in real-world settings requires enacted implementation strategies to overcome implementation bottlenecks. Therefore, a better understanding and mapping of the implementation strategies used in sub-Saharan Africa to increase HPV vaccination uptake is critical. This review aims to identify implementation strategies to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa and provide a basis for policy and future research including systematic reviews to evaluate effective strategies as we accelerate the elimination of cervical cancer.

Materials and MethodsThis review will consider studies that pertain to implementation strategies used to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa. Studies targeted at different stakeholders to increase adolescent vaccine uptake will be included. Studies using interventions not fitting the definition of implementation strategies as defined by the refined compilation of implementation strategies from the Expert Recommendations for Implementing Change project will be excluded. MEDLINE (via PubMed), Embase, CINAHL (via EBSCO), Scopus and Google scholar will be searched. Two independent reviewers will screen titles and abstracts for studies that meet the reviews inclusion criteria, and the full text of eligible studies will be reviewed. Data will be extracted from eligible studies using data charting table developed by this team for inclusion by two independent reviewers and presented in table and graphical form with a narrative summary.


title: The variability and performance of NHS Englands Reason to Reside criteria in predicting hospital discharge in acute hospitals in England. An observational study.

abstract:
ObjectivesNHS England (NHSE) advocates using "reason to reside" (R2R) criteria to generate a binary outcome, which supports discharge related clinical decision making. The proportion of patients without R2R and their rate of discharge are reported daily, by acute hospitals in England. R2R is however, not based upon an inter-operable standardised data model (SDM), nor has its performance been validated against its purpose. We aimed to understand the degree of inter- and intra-centre variation in R2R related metrics reported to NHSE, define a SDM implemented within a single centre Electronic Health Record to generate an eR2R, and evaluate its performance in predicting subsequent discharge.

DesignRetrospective observational cohort study using routinely collected health data.

Setting122 NHS Trusts in England for national reporting and an adult acute hospital in England for local reporting.

Participants6,602,706 patient-days were analysed using 3 months national data and 1,039,592 patient-days, using 3 years single centre data.

Main outcome measuresVariability in R2R related metrics reported to NHSE. Performance of eR2R in predicting discharge within 24 hours.

ResultsThere were high levels of intra and inter-centre variability in R2R related metrics (p<0.0001), but not in eR2R. Informedness of eR2R for discharge within 24 hours was low (J-statistic 0.09 - 0.12 across three consecutive years). In those remaining in hospital without eR2R, 61.2% met eR2R criteria on subsequent days (76% within 24 hours), most commonly due to increased NEWS2 (21.9%) or intravenous therapy administration (32.8%).

ConclusionsR2R related performance metrics are highly variable between and within acute Trusts in England. Although case-mix or community care provision may account for some variability, the absence of a SDM is a major barrier to meaningful interpretation of these metrics. The performance of eR2R based on two alternative SDMs was poor, such that they could not meaningfully contribute to clinical decision making or evaluation of performance.

SummaryO_ST_ABSWhat is knownC_ST_ABSThere is considerable pressure on hospital bed capacity and significant variation in hospital discharges with concerns raised about delays in discharge planning across National Health Service Trusts. To address this, the UK Government developed a policy and criteria to identify in-patients in whom discharge home, or to a less acute setting, should be considered. The criteria, called "reasons to reside" (R2R) have been promoted as a tool to improve discharge planning and are a mandated metric for central reporting. The performance of R2R has not been assessed.

What this study addsThis study suggests a low performance of the R2R criteria as a clinical tool to identify patients suitable for discharge, and questions its usefulness as a reported metric in its current form. There is significant intra and inter-centre variability in both the reported proportion of patients not meeting R2R criteria, and the proportion of patients not meeting R2R criteria who were later discharged. The proportion of patients not meeting R2R criteria correlates poorly with their rate of discharge over the subsequent 24 hours and the performance of the R2R criteria as dichotomous test to identify patients suitable for discharge is low. Further, the R2R criteria are not a stable phenomenon, with more than half of those who remain in hospital without R2R, subsequently acquiring a R2R during the admission.

category: health policy


title: Clinical and haematological profile of dengue among adult patients at a tertiary care hospital in Pokhara

abstract:
IntroductionDengue is an important infectious disease. This disease is prevalent in the terai belts of Nepal mainly. But in the last few years, the cases are in increasing trend in the hilly areas of Nepal also. Hence this study was done in an aim to study the clinical and haematological profile of the dengue cases.

MethodsThis was a retrospective cross-sectional quantitative study done at a tertiary teaching hospital of Pokhara, Nepal after obtaining ethical approval from the institutional ethical committee. The data of serologically confirmed dengue cases, during the period of August 2019 to December 2019, of age above 15 years, were collected and analysed using SPSS 20. Descriptive analysis in terms of mean, median, percentage as well as t-test for nominal and chi-square tests were used to compare different parameters. P-value[≤] 0.05 was considered statistically significant.

ResultsOut of 922 patients, approximately one-half (50.5%) cases were seen during the month of September. Most (82.8%) were the inhabitants of Kaski district. Median age of presentation was 29 years with slightly more cases of males (52.4%). Three hundred and forty seven patients were admitted. Fever (96.5%) and headache (40.6%) were the most common symptoms on presentation of admitted cases. Leukopenia (55.3%) was more common than thrombocytopenia (47.6%) in the admitted cases. On comparison between admitted patients with warning signs and those without signs, no significant variation was seen in terms of age, total leukocyte count and total platelet count.

ConclusionDengue is common in young population. Fever, headache and gastrointestinal symptoms are common among dengue patients. Leukopenia and thrombocytopenia are common laboratory features of dengue.


title: Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Infection Caused by the SARS-CoV-2 Omicron Variant in People with a Prior SARS-CoV-2 Infection

abstract:
BackgroundThe benefit of vaccination in people who experienced a prior SARS-CoV-2 infection remains unclear.

ObjectiveTo estimate the effectiveness of primary (two-dose) and booster (third dose) vaccination against Omicron infection among people with a prior documented infection.

DesignTest-negative case-control study.

SettingYale New Haven Health System facilities.

ParticipantsVaccine eligible people who received SARS-CoV-2 RT-PCR testing between November 1, 2021, and January 31, 2022.

MeasurementsWe conducted two analyses, each with an outcome of Omicron BA.1 infection (S-gene target failure defined) and each stratified by prior SARS-CoV-2 infection status. We estimated the effectiveness of primary and booster vaccination. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds among boosted and booster eligible people.

ResultsOverall, 10,676 cases and 119,397 controls were included (6.1% and 7.8% occurred following a prior infection, respectively). The effectiveness of primary vaccination 14-149 days after 2nd dose was 36.1% (CI, 7.1% to 56.1%) for people with and 28.5% (CI, 20.0% to 36.2%) without prior infection. The odds ratio comparing boosted and booster eligible people with prior infection was 0.83 (CI, 0.56 to 1.23), whereas the odds ratio comparing boosted and booster eligible people without prior infection was 0.51 (CI, 0.46 to 0.56).

LimitationsMisclassification, residual confounding, reliance on TaqPath assay analyzed samples.

ConclusionWhile primary vaccination provided protection against BA.1 infection among people with and without prior infection, booster vaccination was only associated with additional protection in people without prior infection. These findings support primary vaccination in people regardless of prior infection status but suggest that infection history should be considered when evaluating the need for booster vaccination.

Primary Funding SourceBeatrice Kleinberg Neuwirth and Sendas Family Funds, Merck and Co through their Merck Investigator Studies Program, and the Yale Schools of Public Health and Medicine.


title: Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Omicron Variant SARS-CoV-2 Infection in People with a Prior SARS-CoV-2 Infection | A Test Negative Case Control Study


title: High neutralizing activity against Omicron BA.2 can be induced by COVID-19 mRNA booster vaccination

abstract:
The VOC of SARS-CoV-2, Omicron (BA.1, BA.1.1, BA.2, or BA.3), is associated with an increased risk of reinfection. BA.2 has become the next dominant variant worldwide. Although BA.2 infection has been shown to be mild illness, its high transmissibility will result in high numbers of cases. In response to the surge of Omicron BA.1 cases, booster vaccination was initiated in many countries. But there is limited evidence regarding the effectiveness of a booster vaccination against BA.2. We collected blood samples from 84 physicians at Kobe University Hospital, Japan, in January 2022 [~]7 months after they had received two BNT162b2 vaccinations and [~]2 weeks after their booster vaccination. We performed a serum neutralizing assay against BA.2 using authentic virus.

Although most of the participants had no or a very low titer of neutralizing antibody against BA.2 at 7 months after two BNT162b2 vaccinations, the titer increased significantly at 2 weeks after the booster vaccination.


title: Estimated effectiveness of vaccines and extended half-life monoclonal antibodies against respiratory syncytial virus (RSV) hospitalizations in young children

abstract: Several vaccines and extended half-life monoclonal antibodies (mAbs) against RSV infection have shown promising progress in clinical trials. Aiming to project the impact of various prevention strategies against RSV hospitalizations in young children, we applied age-structured transmission models to evaluate prevention strategies including maternal immunization, live-attenuated vaccines, and long-lasting mAbs. Our results suggest that maternal immunization and long-lasting mAbs are highly effective in preventing RSV hospitalizations in infants under 6 months of age, averting more than half of RSV hospitalizations in neonates. Live-attenuated vaccines could reduce RSV hospitalizations in vaccinated age groups and are also predicted to have a modest effect in unvaccinated age groups because of disruptions to transmission. A seasonal vaccination program at the country level at most provides a minor advantage regarding efficiency. Our findings highlight the substantial public health impact that upcoming RSV prevention strategies may provide.


title: Wastewater to clinical case (WC) ratio of COVID-19 identifies insufficient clinical testing, onset of new variants of concern and population immunity in urban communities

abstract: Clinical testing has been the cornerstone of public health monitoring and infection control efforts in communities throughout the COVID-19 pandemic. With the extant and anticipated reduction of clinical testing as the disease moves into an endemic state, SARS-CoV-2 wastewater surveillance (WWS) is likely to have greater value as an important diagnostic tool to inform public health. As the widespread adoption of WWS is relatively new at the scale employed for COVID-19, interpretation of data, including the relationship to clinical cases, has yet to be standardized. An in-depth analysis of the metrics derived from WWS is required for public health units/agencies to interpret and utilize WWS-acquired data effectively and efficiently. In this study, the SARS-CoV-2 wastewater signal to clinical cases (WC) ratio was investigated across seven different cities in Canada over periods ranging from 8 to 21 months. Significant increases in the WC ratio occurred when clinical testing eligibility was modified to appointment-only testing, identifying a period of insufficient clinical testing in these communities. The WC ratio decreased significantly during the emergence of the Alpha variant of concern (VOC) in a relatively non-immunized communitys wastewater (40-60% allelic proportion), while a more muted decrease in the WC ratio signaled the emergence of the Delta VOC in a relatively well-immunized communitys wastewater (40-60% allelic proportion). Finally, a rapid and significant decrease in the WC ratio signaled the emergence of the Omicron VOC, likely because of the variants greater effectiveness at evading immunity, leading to a significant number of new reported clinical cases, even when vaccine-induced community immunity was high. The WC ratio, used as an additional monitoring metric, complements clinical case counts and wastewater signals as individual metrics in its ability to identify important epidemiological occurrences, adding value to WWS as a diagnostic technology during the COVID-19 pandemic and likely for future pandemics.


title: Early detection of acute kidney injury in critically ill children: Predictive value of renal arterial Doppler assessment

abstract:
ObjectiveRenal resistive index (RRI) and renal pulsatility index (RPI) are Doppler-based variables proposed to assess renal perfusion at the bedside in critically ill patients. This study aimed to assess the accuracy of such variables to predict acute kidney injury (AKI) in mechanically ventilated children.

DesignProspective single-center observational study

SettingPediatric intensive care unit of a quaternary care teaching hospital.

Patients84 children under controlled ventilation (median age of 5.1 months and weight of 6.6 kg).

InterventionsConsecutive children underwent renal Doppler ultrasound examination within 24 hours of invasive mechanical ventilation. Renal resistive index (RRI) and renal pulsatility index (RPI) were measured. The primary outcome was severe AKI (KDIGO stage 2 or 3) on day 3. Secondary outcomes included the persistence of severe AKI on day 5.

ResultsOn day 3, 22 patients were classified as having AKI (any stage), of which 12 were severe. RRI could effectively predict severe AKI (area under the ROC curve [AUC] 0.94; 95% CI 0.86 - 0.98; p < 0.001) as well as RPI (AUC 0.86; 95% CI 0.76 - 0.92; p < 0.001). The AUC of the IRR was significantly greater than that obtained from the RPI (p = 0.023). The optimal cutoff for RRI was 0.85 (sensitivity, 91.7%; specificity, 84.7%; positive predictive value, 50.0%; and negative predictive value 98.4%). Similar results were obtained when the accuracy to predict AKI on day 5 was assessed. Significant correlations were observed between RRI and estimated glomerular filtration rate at enrollment ({rho} = -0.495, p<0.001) and on day 3 ({rho} = -0.467, p <0.001).

ConclusionsRenal Doppler ultrasound may be a promising tool to predict AKI in critically ill children under invasive mechanical ventilation.

category: pediatrics


title: Vaccine effectiveness against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron SARS-CoV-2 variants: a nationwide Danish cohort study

abstract:
BackgroundThe continued occurrence of more contagious SARS-CoV-2 variants and waning immunity over time require ongoing re-evaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in two age groups (12-59 and 60 years or above) of two and three vaccine doses (BNT162b2 mRNA or mRNA-1273 vaccine) by time since vaccination against SARS-CoV-2 infection and COVID-19-related hospitalization in an Alpha, Delta and Omicron dominated period.

MethodsA Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron variants. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all residents in Denmark aged 12 years or above (18 years or above for the analysis of three doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021) and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models with adjustments for age, sex and geographical region. Vaccination status was included as a time-varying exposure.

FindingsIn the oldest age group, VE against infection after two doses was 91.0% (95% CI: 88.5; 92.9) for the Alpha variant, 82.2% (95% CI: 75.3; 87.1) for the Delta variant and 39.9% (95% CI: 26.4; 50.9) for the Omicron variant 14-30 days since vaccination. The VE waned over time and was 71.5% (95% CI: 54.7; 82.8), 49.8% (95% CI: 46.5; 52.8) and 4.7% (95% CI: 0.2; 8.9) >120 days since vaccination against the three variants, respectively. Higher estimates were observed after the third dose with VE estimates against infection of 86.0% (Delta, 95% CI: 83.3; 88.3) and 57.6% (Omicron, 95% CI: 55.8; 59.4) 14-30 days since vaccination. Among both age groups, VE against COVID-19-related hospitalization 14-30 days since vaccination with two or three doses was 94.8% or above for the Alpha and Delta variants, whereas among the youngest age group, VE estimates against the Omicron variant after two and three doses were 62.4% (95% CI: 46.3; 73.6) and 89.8% (95% CI: 87.9; 91.3), respectively.

ConclusionsTwo vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha and Delta variants with protection waning over time. Two vaccine doses provided only limited protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Omicron variant. The third vaccine dose substantially increased the protection against Delta and Omicron.


title: Pediatric Diarrhea Patients Living in Urban Areas Have Higher Incidence of Clostridioides difficile Infection

abstract: Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea and an unappreciated contributor to child mortality in low- and middle-income countries where diagnosis may be difficult. There is little information about the prevalence of CDI among infants, children, and adolescents in Africa. Seventy-six samples were collected from pediatric patients presenting with diarrhea, including infants ([≤] 2 years old), children (2-12 years) and adolescents (13 [≤]17 years) from three hospitals between January and December 2019. Demographic data, medical history and prior antibiotic use were recorded. Toxigenic culture and PCR were used to detect and validate the presence of C. difficile in the samples. A total of 29 (38.7%), 39 (52.0%) and 7 (9.3%) samples were from infants, children, and adolescents, respectively. Average age of the patients was 4.4 years. Of these samples, 31 (41%) were positive for C. difficile by culture and were verified by PCR amplification of C. difficile specific genes (tcdA and tcdB). Most positive cases were children (53.3%) and infants (40.0%) with the majority of them residing in the urban areas. Forty-nine (66.2%) of the patients had no known antibiotics exposure, whereas 29.0% and 29.7% reported use of over-the-counter antibiotics at 14 and 90 days, prior to the hospital visit, respectively. CDI is relatively common among children with diarrhea in Northern Nigeria. Therefore, for effective management and treatment, more attention should be given to testing for C. difficile as one of the causative agents of diarrhea.