title: UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern

abstract:
ImportanceThe SARS-CoV-2 non-spike structural proteins of nucleocapsid (N), membrane (M) and envelope (E) are critical in the host cell interferon response and memory T-cell immunity and have been grossly overlooked in the development of COVID vaccines.

ObjectiveTo determine the safety and immunogenicity of UB-612, a multitope vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing sequence-conserved Th and CTL epitopes on the Sarbecovirus nucleocapsid (N), membrane (M) and spike (S2) proteins.

Design, setting and participantsUB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2nd dose in 1,478 vaccinees from 3,844 healthy participants (aged 18-85 years) who completed a prior placebo (saline)-controlled, randomized, observer-blind, multi-center Phase-2 primary 2-dose series (100-g per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster.

ExposureVaccination with a booster 3rd-dose (100-g) of UB-612 vaccine.

Main outcomes and measuresSolicited local and systemic AEs were recorded for seven days in the e-diaries of study participants, while skin allergic reactions were recorded for fourteen days. The primary immunogenicity endpoints included viral-neutralizing antibodies against live SARS-CoV-2 wild-type (WT, Wuhan strain) and live Delta variant (VNT50), and against pseudovirus WT and Omicron variant (pVNT50). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining.

ResultsNo post-booster vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. The UB-612 booster prompted a striking upsurge of neutralizing antibodies against live WT Wuhan strain (VNT50, 1,711) associated with unusually high cross-neutralization against Delta variant (VNT50, 1,282); and similarly with a strong effect against pseudovirus WT (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Upon boosting, the lower VNT50 and pVNT50 titers of the elderly in the primary series were uplifted to the same levels as those of the young adults. The UB-612 also induced robust, durable VoC antigen-specific Th1-oriented (IFN-{gamma}+-) responses along with CD8+ T-cell (CD107a+-Granzyme B+) cytotoxicity.

Conclusions and relevanceWith a pronounced cross-reactive booster effect on B- and T-cell immunity, UB-612 may serve as a universal vaccine booster for comprehensive immunity enhancement against emergent VoCs.

Trial registration[ClinicalTrials.gov: NCT04773067]

KEY POINTSO_ST_ABSQuestionC_ST_ABSFacing ever-emergent SARS-CoV-2 variants and long-haul COVID, can composition-updated new vaccines be constructed capable of inducing striking, durable booster-recalled B/T-immunity to prevent infection by VoCs?

FindingsIn a Phase-2 extension study, a booster dose of UB-612 multitope protein-peptide vaccine prompted high viral-neutralizing titers against live wild-type virus (VNT50, 1,711), Delta variant (VNT50, 1,282); pseudovirus wild-type (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Robust, durable Th1-IFN{gamma}+ responses and CD8+ T cell-(CD107a+-Granzyme B+) cytotoxic activity were both observed.

MeaningUB-612 RBD-sFc vaccine armed with T cell immunity-promoting conserved N, M and S2 Th/CTL epitope peptides may serve as a universal vaccine to fend off new VoCs.

category: infectious diseases


title: Determinants of maternal morbidity during pregnancy in urban Bangladesh: Negative binomial regression approach

abstract:
AimTo investigate the prevalence of maternal morbidity during pregnancy and its determinants among the women from urban areas of Bangladesh.

MethodsThe secondary data were used and extracted from the latest Bangladesh Urban Health Survey (BUHS) 2013. Several statistical models: Poisson, negative binomial (NB) and mixed Poisson were adapted and compared to explore the best model for investigating potential determinants of maternal morbidity. Pearson chi-square statistic was used for the detection of overdispersion in the data.

ResultsOverall 13.5% of the urban women in Bangladesh suffered from at least two pregnancy complications. The study detected the overdispersion existing in the maternal morbidity count data and found the NB regression as the best choice for analyzing the data because of its smallest Akaike information criterion. Administrative division (Rangpur: p=0.003, IRR=1.34, 95% CI: 1.11 to 1.63; Sylhet: p=0.006, IRR=1.42, 95% CI: 1.11 to 1.82), wanted pregnancy (p<0.001, IRR=0.80, 95% CI: 0.71 to 0.90), place of delivery (p<0.001, IRR=0.60, 95% CI: 0.54 to 0.66) and wealth index (Rich: p<0.001, IRR=0.74, 95% CI: 0.66 to 0.84) were found to be statistically significant determinants for maternal morbidity during pregnancy among the urban women in Bangladesh.

ConclusionsThe urban women in Bangladesh with unwanted pregnancy, from poor/middle income group; and living in Rangpur and Sylhet divisional cities have higher risk of maternal morbidity during pregnancy. The women already suffering from major pregnancy related complications visit health centre to give birth. Study findings may help the government and relevant authorities to take necessary steps for reducing maternal morbidity and mortality due to pregnancy related complications.

category: health systems and quality improvement


title: Insomnia symptoms and risk of bloodstream infections: prospective data from the prospective population-based HUNT Study, Norway

abstract:
ObjectivePrevious research suggest decreased immune function and increased risk of infections in persons with insomnia. We examined the effect of insomnia symptoms on risk of bloodstream infections (BSI) and BSI-related mortality in a population-based prospective study.

MethodsA total of 53,536 participants in the Norwegian HUNT2 study (1995-97) were linked to prospective data on clinically relevant BSIs until 2011. In Cox regression, we estimated hazard ratios (HRs) with 95% confidence interval (CI) for a first-time BSI and for BSI related mortality (BSI registered [≤]30 days prior to death) associated with insomnia symptoms.

ResultsCompared with participants who reported "no symptoms of insomnia", participants reporting having "difficulty initiating sleep" often/almost every night had a HR for a first-time BSI of 1.14 (95% CI 0.96-1.34). Participants reporting "difficulties maintaining sleep" often/almost every night had a HR of 1.19 (95% CI 1.01-1.40), whereas those having a "feeling of non-restorative sleep" once a week or more had a HR of 1.23 (95% CI 1.04-1.46). Participants experiencing all three above insomnia symptoms frequently had a HR of 1.39 (1.04-1.87) and being troubled by insomnia to a degree that affected work performance was associated with a HR of 1.41 (95% CI 1.08-1.84). The HRs for BSI related mortality suggest an increased risk with increasing insomnia symptoms, but confidence intervals are wide and inconclusive.

ConclusionsWe found that frequent insomnia symptoms and insomnia symptoms that affected work performance was associated with a weak positive increased risk of BSI.


title: Multi-ancestry genome-wide analysis identifies effector genes and druggable pathways for coronary artery calcification

abstract: Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts symptomatic coronary artery disease. Identifying genetic risk factors for CAC may point to new therapeutic avenues for preventing clinical disease. Here, we conducted a multi-ancestry genome-wide association study in 26,909 individuals of European ancestry and 8,867 individuals of African American ancestry. We identified 11 independent risk loci, of which 8 are novel for CAC. Some novel loci harbor candidate causal genes supported by multiple lines of functional evidence. Together, these findings help refine the genetic architecture of CAC, extend our understanding of the biological pathways underlying CAC formation, as well as identify druggable targets for CAC.

category: cardiovascular medicine


title: Socioeconomic inequality in SARS-CoV-2 testing and COVID-19 outcomes in UK Biobank over the first year of the pandemic: can inequalities be explained byselection bias?

abstract:
BackgroundStructural barriers to testing may introduce selection bias in COVID-19 research. We explore whether changes to testing and lockdown restrictions introduce time-specific selection bias into analyses of socioeconomic position (SEP) and SARS-CoV-2 infection.

MethodsUsing UK Biobank (N = 420 231; 55 % female; mean age = 56{middle dot}3 [SD=8{middle dot}01]) we estimated the association between SEP and i) being tested for SARS-CoV-2 infection versus not being tested ii) testing positive for SARS-CoV-2 infection versus testing negative and iii) testing negative for SARS-CoV-2 infection versus not being tested, at four distinct time-periods between March 2020 and March 2021. We explored potential selection bias by examining the same associations with hypothesised positive (ABO blood type) and negative (hair colour) control exposures. Finally, we conducted a hypothesis-free phenome-wide association study to investigate how individual characteristics associated with testing changed over time.

FindingsThe association between low SEP and SARS-CoV-2 testing attenuated across time-periods. Compared to individuals with a degree, individuals who left school with GCSEs or less had an OR of 1{middle dot}05 (95% CI: 0{middle dot}95 to 1{middle dot}16) in March-May 2020 and 0{middle dot}98 (95% CI: 0{middle dot}94 to 1{middle dot}02) in January-March 2021. The magnitude of the association between low SEP and testing positive for SARS-CoV-2 infection increased over the same time-period. For the same comparisons, the OR for testing positive increased from 1{middle dot}27 (95% CI: 1{middle dot}08 to 1{middle dot}50), to 1{middle dot}73 (95% CI: 1{middle dot}59 to 1{middle dot}87). We found little evidence of an association between both control exposures and all outcomes considered. Our phenome-wide analysis highlighted a broad range of individual traits were associated with testing, which were distinct across time-periods.

InterpretationThe association between SEP (and indeed many individual traits) and SARS-CoV-2 testing changed over time, indicating time-specific selection pressures in COVID-19. However, positive, and negative control analyses suggest that changes in the magnitude of the association between SEP and SARS-CoV-2 infection over time were unlikely to be explained by selection bias and reflect true increases in socioeconomic inequalities.

FundingUniversity of Bristol; UK Medical Research Council; British Heart Foundation; European Union Horizon 2020; Wellcome Trust and The Royal Society; National Institute of Health Research; UK Economic and Social Research Council

category: epidemiology


title: Asymptomatic SARS-CoV-2 infection by age: A systematic review and meta-analysis

abstract:
ObjectivesThis systematic review and meta-analysis aimed to estimate the age-specific proportion of asymptomatic SARS-CoV-2 infected persons by year of age.

MethodsWe searched PubMed, Embase, medRxiv and Google Scholar on 10 September 2020 and 1 March 2021. We included studies conducted during January to October 2020, prior to routine vaccination against COVID-19. Since we expected the relationship between the asymptomatic proportion and age to be non-linear, multilevel mixed-effects logistic regression (QR decomposition) with a restricted cubic spline was used to model asymptomatic proportions as a function of age.

ResultsA total of 38 studies were included in the meta-analysis. In total, 6556 out of 14850 cases were reported as asymptomatic. The overall estimate of the proportion of people who became infected with SARS-CoV-2 and remained asymptomatic throughout infection was 44.1% (6556/14850, 95%CI 43.3%-45.0%). The asymptomatic proportion peaked in adolescents (36.2%, 95%CI 26.0%-46.5%) at 13.5 years, gradually decreased by age and was lowest at 90.5 years of age (8.1%, 95%CI 3.4%-12.7%).

ConclusionsGiven the high rates of asymptomatic carriage in adolescents and young adults and their active role in virus transmission in the community, heightened vigilance and public health strategies are needed among these individuals to prevent disease transmission.


title: Application of multilevel linear spline models for analysis of growth trajectories in a cohort with repeat antenatal and postnatal measures of growth: a prospective cohort study

abstract:
IntroductionAntenatal and postnatal growth are important indicators of fetal and child health and development. Studies frequently have repeat antenatal and postnatal measures of growth available and require approaches that can maximise the use of these measures to examine growth trajectories. We demonstrate the use of multilevel linear spline modelling to model growth trajectories with repeated antenatal and postnatal measures of growth from 20 weeks gestation to five years in a cohort at high risk of macrosomia.

MethodsProspective follow-up data from 720-759 mother-child pairs from the ROLO study (initially a randomized controlled trial of a low glycemic index diet in pregnancy to prevent recurrence of macrosomia [birthweight > 4K]) were analysed. Fetal measurements were obtained from ultrasound scans performed on mothers at 20-and 34-weeks gestation, including abdominal circumference (AC) and head circumference (HC). An estimated fetal weight was obtained at 20-and 34-weeks gestation, calculated using the Hadlock 4-parameter formula. At delivery, AC, HC, weight and length were recorded. Follow-up anthropometry assessments (AC, HC, weight and length/height) were also obtained in childhood at six months, two years and five years. Linear spline multilevel models were used to examine trajectories of AC, HC and weight from 20 weeks gestation to five years and length/height from birth to five years.

Results754, 756 and 759 participants were included in analyses of AC, HC and weight respectively, while 720 participants were included in analysis of length/height. Over 50% of women had 3rd level education and over 90% were of White ethnicity. Women were a mean (SD) age of 32 (4.2) at recruitment. Following exploration of a series of different models for each growth measure, the best fitting model for AC, HC and weight included a model with knots at each measurement occasion giving rise to five linear spline periods from: 20 weeks to 34 weeks gestation, 34 weeks gestation to birth, birth to six months, six months to two years and two years to five years. The best fitting models for length/height included a model with three linear spline periods from birth to six months, six months to two years and two years to five years. Comparison of observed and predicted values for each model demonstrated good model fit. For all growth measures, fetal growth rates were generally fastest in pregnancy or immediately postpartum (for length/height), with rates of growth slowing after birth and becoming slower still as infancy and childhood progressed. We found little difference in growth trajectories between the intervention and control group. There was some evidence of slightly lower HC, weight and length among females compared with males at birth which appeared to widen by age five years due to slower postnatal growth rates among females.

ConclusionWe demonstrate the application of multilevel linear spline models for examining growth trajectories when both antenatal and postnatal measures of growth are available. The approach may be useful for cohort studies or randomised controlled trials with repeat prospective assessments of growth spanning pregnancy and childhood.


title: Which innovations can improve timeliness of investigations and address the backlog in endoscopy for patients with potential symptoms of upper and lower Gastrointestinal (GI) cancers? Rapid Review

abstract:
TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal, and evidence synthesis to answer a specific question and identify key research gaps. They take 1-2 months, depending on the breadth and complexity of the research topic/ question(s), extent of the evidence base, and type of analysis required for synthesis.

Background / Aim of Rapid ReviewMany patients were not able to access routine diagnostic care through 2020/21 because of extraordinary pressures on the NHS due to COVID-19 and the UK national lockdowns. For some patients this can have serious short and long-term consequences to their health and life expectancy. The NHS has limited resources and is looking for new ways to meet many demands and patient needs.

This Rapid Review Report aims to answer the question "Which innovations can be used to accelerate the patients journey through the endoscopic cancer diagnosis pathway?" The report highlights evidence of innovations and new ways to improve the timeliness of access to endoscopy and to address the backlog of unmet need for patients who have waited a long time for such tests and investigations by selecting those at highest for prioritisation. It does not evaluate in terms of effectiveness on clinical outcomes.

Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABS{blacksquare} Nine papers were included in the rapid review in total.
{blacksquare}Two reviews were identified. One review examined the novel colon capsule endoscopy (CCE) procedure and the second review summarised the effects of COVID-19 on colorectal cancer (CRC) screening, the potential long-term? outcomes, and ways to adapt CRC screening during the COVID-19 pandemic.
{blacksquare}Seven primary studies assessed innovations for the diagnosis of Gastrointestinal (GI) cancers. Five of these studies examined faecal immunochemical testing (FIT) for prioritising patients for further testing.
{blacksquare}Two studies reported pathways/innovations to triage patients e.g. from primary care. These methods of triage used interventions such as Cytosponge for oesophageal symptoms.

Recency of the evidence base{blacksquare} Of the primary studies, one was published in 2020 and six were published in 2021. Of the reviews, one was published in 2020 and one in 2021.

Evidence of effectiveness{blacksquare} The five studies investigating FIT found that it could help prioritise patients for further testing and improve targeting of high-risk patients.
{blacksquare}One review proposed CCE may offer a useful solution for investigating colorectal patients to reduce the need for some endoscopies following the pandemic.
{blacksquare}One review found a shift from current CRC screening and surveillance practices towards an individualized approach based on risk factors, could result in the allocation of resources to people with higher risks and prevent inappropriate use of healthcare resources for those with lower risks.

Best quality evidence{blacksquare} All studies were quality appraised using the relevant JBI checklist. Five studies were of low to moderate quality.

Policy Implications{blacksquare} Increased use of faecal immunochemical testing (FIT) could reduce the endoscopy backlog and save NHS resources if those with low FIT scores can be excluded from further testing.
{blacksquare}Policy in Wales supports prioritisation of potential gastrointestinal cancer patients for endoscopy using FIT test scores (NHS Wales 2021) although local implementation currently varies, so it is not yet fully utilised. The FIT test gives results which could be utilised by healthcare professionals to prioritise those who are most in need of urgent diagnosis. The viability of this method to prioritise those in greatest need of being referred for diagnosis through endoscopy is proven (though safety-netting is still required), and the FIT test is part of the diagnostic pathway already in Wales. It will be important to ensure all areas of Wales have equal access to the use of FIT testing for this purpose, and that clinical guidelines are harmonised and adhered to throughout Wales.
{blacksquare}Innovations to reduce backlog and speed up time to diagnosis should be explored including:
{circ}Triage in primary care settings such as GP surgeries using innovations such as the cytosponge for oesophageal symptoms (e.g. reflux).
{circ}Direct referral from primary care settings to specialist investigation, without the need for prior additional referrals in secondary care.

Strength of Evidence{blacksquare} The evidence presented in this review is recent, however with small samples (di Pietro et al., 2020), short-term follow up periods (Sagar et al., 2020) and assumptions required for modelling studies (Loveday et al., 2021). This reduces the generalisability and confidence of conclusions. The confidence in the strength of evidence about FIT testing is rated as  low-moderate confidence. Cytosponge evidence is rated  low confidence.

Review team and stakeholder involvementThis Rapid Review is being conducted as part of the Wales COVID-19 Evidence Centre Work Programme. The above question was developed in consultation with Cancer Research UKs identified research gaps and with Professor Tom Crosby OBE. Professor Crosby is a Consultant Oncologist, National Cancer Clinical Director for Wales and Clinical Lead for Transforming Cancer Services and acted as the expert stakeholder for this review.

The search questions were identified as a priority during the Cancer/COVID-19 Research Summit hosted by Cancer Research UK (CRUK), Public Health England (PHE) and the National Cancer Research Institute (NCRI). The stakeholder group supporting the review work here is Cancer Research Wales.

category: gastroenterology


title: Assessment of Alzheimer-related Pathologies of Dementia Using Machine Learning Feature Selection

abstract: Although a variety of brain lesions may contribute to the pathological diagnosis of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remain uncertain. Systematically assessing neuropathological measures in relation to the cognitive and functional definitions of dementia may enable the development of better diagnostic systems and treatment targets. The objective of this study is to apply machine learning approaches for feature selection to identify key features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification as an unbiased comparison of neuropathological features and assessment of their diagnostic performance using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Braak neurofibrillary tangle stage, Beta-amyloid and cerebral amyloid angiopathy features were the most highly ranked, although were highly correlated with each other. The best performing dementia classifier using the top eight ranked neuropathology features achieved 79% sensitivity, 69% specificity, and 75% precision. A substantial proportion (40.4%) of dementia cases was consistently misclassified by all seven algorithms and any combination of the 22 ranked features. These results highlight the potential of using machine learning to identify key indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for the classification of dementia.

category: pathology


title: Correlation of Suspected COVID-19 Symptoms with COVID-19 Positivity in Children

abstract:
BackgroundEarly in the pandemic, COVID-19 was found to infect adults at higher rates than children, leaving limited data on disease presentation in children. Further understanding of the epidemiology of COVID-19 symptoms among children is needed. Our aim was to explore how symptoms vary between children testing positive for COVID-19 infection versus children testing negative.

MethodsData analysis of symptom prevalence among pediatric patients presenting to emergency departments (ED) in the Johns Hopkins Health System (JHHS) with concern for COVID-19 who subsequently received COVID-19 testing. Inclusion criteria included patients 0-17 years-of-age, ED evaluation between March 15th, 2020 - May 11th, 2020, and those who were ordered for COVID-19 testing. Chart review was performed to document symptoms using ED provider notes. Comparisons were made using chi-squared t-tests and Students t-tests.

ResultsFever (62.6%) and cough (47.9%) were the most prevalent symptoms among children with suspected COVID-19 infection. Compared to children with a negative COVID-19 test, children who tested positive had higher prevalence of myalgia (21.7% vs 6.0%) and loss of taste/smell (15.2% vs 0.9%). Over half of the children who tested positive for COVID-19 had public insurance (52.2%) and 58.7% of the positive tests occurred among children with Hispanic ethnicity.

ConclusionsMyalgia and loss of taste/smell were found to be significantly more prevalent among COVID-19 positive children compared to children testing negative. Additionally, children with public insurance and those with Hispanic ethnicity were more likely to test positive, emphasizing the importance of social factors in the screening and decision-making process.

category: pediatrics


title: The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study

abstract:
BackgroundTuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies.

MethodsWe developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a  no-new-vaccine counterfactual. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60, and used a 1x per-capita GDP cost-effectiveness threshold (both varied in sensitivity analyses).

FindingsVaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, vaccination was cost-effective in 65 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), vaccination was projected to be cost-effective in 75 of 105 LMICs and cost-saving in 57 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $258-447 billion in economic benefits by 2050.

InterpretationTB vaccination would be highly impactful and cost-effective in most LMICs.

FundingWorld Health Organization (2020/985800-0)

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have highlighted the economic impact of tuberculosis disease and mortality, and the potential economic impact that novel tuberculosis vaccines could have on reducing this burden in specific low- and middle-income countries (LMICs). The cost and cost-effectiveness of novel tuberculosis vaccines will depend on vaccine price and delivery strategy, which may vary by country. No modelling studies have estimated cost and cost-effectiveness with country-specific assumptions for medical and non-medical costs, indirect costs, vaccine delivery costs, and delivery strategies across a wide range of LMICs.

Added value of this studyWe estimated the costs, cost-effectiveness, and incremental net monetary benefit of tuberculosis vaccine introduction from both the health system and societal perspective in order to inform global-level decision-making for novel tuberculosis vaccine investment and introduction. Using mathematical and economic models, we assessed scenarios for the introduction of novel vaccines with a wide range of characteristics and a diverse set of health and economic outcomes. We assumed country-specific introduction years from 2028-2047, determined based on indicators for disease burden, immunization capacity, classification of the country as an "early adopter/leader," lack of regulatory barriers, and commercial prioritization. We varied vaccination coverage, vaccine delivery strategy, vaccine price, duration of protection, and future trends in tuberculosis incidence in scenario analysis.

Our analysis projected that an effective new tuberculosis vaccine could offer large potential health and economic benefits over 2028-2050. From a societal perspective, vaccination was projected to be cost-effective in 75 LMICs compared to a 1x per-capita gross domestic product threshold. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $258-447 billion in economic benefits by 2050, with greater benefits in LMICs with elevated tuberculosis incidence.

Implications of all the available evidenceIntroduction of a new tuberculosis vaccine was found to be impactful and cost-effective for a range of assumptions on vaccine price and delivery strategies, with aggregate health and economic benefits of similar scale to the most influential health interventions in LMIC settings in recent years. The results of these analyses can be used by global and country stakeholders to inform vaccine policy and introduction preparedness, as well as decision-making around future development, adoption, and implementation of novel tuberculosis vaccines.

category: public and global health


title: Childhood Stunting and Its Associated Factors in Ethiopia

abstract: Child malnutrition is the root cause of nearly half (45%) of all child deaths, especially in low-income nations. Ethiopia has the highest frequency of stunting among Sub-Saharan African countries, at 38 percent. The studys major goal was to use cluster specific models to identify risk factors for stunting in Ethiopian children under the age of five. The data was gathered from the EDHS 2016, a nationally representative survey of children aged 0 to 59 months. The research was carried out using generalized linear mixed models from the cluster specific model family. The variables childs age, mothers education level, mothers BMI, place of residence, wealth index, and prior birth interval were determined to be important drivers of child malnutrition in Ethiopia as a result of the analysis. According to the findings, children with a shorter previous birth interval (less than 24 months) were more likely to be stunted than those with a longer previous birth interval. Rural Ethiopian children were more likely than urban Ethiopian children to be stunted. It is advised that in order to reduce childhood malnutrition, parents awareness and implementation of proper young child feeding practices, as well as frequent growth monitoring and appropriate and timely interventions, should be prioritized.


title: What innovations can address inequalities experienced by women and girls due to the COVID-19 pandemic across the different areas of life/domains: work, health, living standards, personal security, participation and education? Rapid Review

abstract:
TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal and evidence synthesis to answer a specific question and identify key research gaps. They take one to two months, depending on the breadth and complexity of the research topic/question(s), the extent of the evidence base and type of analysis required for synthesis.

Background / Aim of Rapid ReviewThe COVID-19 pandemic has led to differential economic, health and social impacts illuminating prevailing gender inequalities (WEN Wales, 2020). This rapid review investigated evidence for effectiveness of interventions to address gender inequalities across the domains of work, health, living standards, personal security, participation, and education.

Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABSO_LI21 studies were identified: 7 reviews, 6 commentaries and 8 primary studies
C_LIO_LILimited evidence for the effectiveness of identified innovations in minority groups
C_LIO_LIA lack of evaluation data for educational interventions
C_LIO_LIA lack of evidence for cost-effectiveness of the identified interventions
C_LIO_LI14 additional articles were identified in the grey literature but not used to inform findings (apart from the Education domain, where there was a lack of peer-reviewed evidence).
C_LI

Recency of the evidence baseO_LIAll studies were published in 2020-2021
C_LI

Summary of findingsSome evidence supported interventions/innovations related to work: O_LIPermanent contracts, full-time hours, and national childcare programmes to increase income for women and thereby decrease the existing gender wage gap.
C_LIO_LIMore frequent use of online platforms in the presentation of professional work can reduce gender disparities due to time saved in travel away from home.
C_LI Some evidence supported interventions/innovations related to health: O_LILeadership in digital health companies could benefit from women developing gender-friendly technology that meets the health needs of women.
C_LIO_LICreate authentic partnerships with black women and female-led organisations to reduce maternal morbidity and mortality (Bray & McLemore, 2021).
C_LI Some evidence supported interventions/innovations related to living standards including: O_LIMulti-dimensional care provided to women and their children experiencing homelessness.
C_LI Limited evidence supported interventions/innovations related to personal security including: O_LISpecific training of social workers, psychologists and therapists to empower women to use coping strategies and utilise services to gain protection from abusive partners.
C_LIO_LIHelplines, virtual safe spaces smart phone applications and online counselling to address issues of violence and abuse for women and girls.
C_LI Very limited evidence supported interventions/innovations related to participation including: O_LIUse of online platforms to reduce gender disparities in the presentation of academic/professional work.
C_LIO_LIEnsuring equal representation, including women and marginalised persons, in pandemic response and recovery planning and decision-making.
C_LI Limited evidence from the grey literature described interventions/innovations related to education including: O_LITeacher training curricula development to empower teachers to understand and challenge gender stereotypes in learning environments.
C_LIO_LIEducation for girls to enable participation in STEM.
C_LI

Policy ImplicationsThis evidence can be used to map against existing policies to identify which are supported by the evidence, which are not in current policy and could be implemented and where further research/evaluation is needed.

Further research is needed to evaluate the effectiveness of educational innovations, the effectiveness of the innovations in minority groups and the social value gained from interventions to address gender inequalities.

Strength of EvidenceOne systematic review on mobile interventions targeting common mental disorders among pregnant and postpartum women was rated as high quality (Saad et al., 2021). The overall confidence in the strength of evidence was rated as  low due to study designs. Searches did not include COVID specific resources or pre-prints. There may be additional interventions/innovations that have been implemented to reduce inequalities experienced by women and girls due to the COVID-19 pandemic but have not been evaluated or published in the literature and are therefore not included here.


title: WHO TARGETS FOR CERVICAL CANCER CONTROL BY 2030: A BASELINE ASSESSMENT IN SIX AFRICAN COUNTRIES

abstract:
AimWe present and analyze the findings of a survey of the readiness of the healthcare systems in Eswatini, Guinea, Malawi, Rwanda, Uganda and Zambia, to implement the necessary measures for attaining the targets for cervical cancer control, set by WHO, by the year 2030.

MethodsA questionnaire with 129 questions with preset answer options was completed in 2020, by ministries of health program coordinators for non-communicable diseases, cancer control and/or reproductive health, and by WHO country offices, in the six countries selected.

ResultsThe findings on demographics, burden of disease, governance and management, laboratory services, equipment, supplies and medicines, as well as on personnel and training will be presented here.

The burden of cervical cancer in the countries studied is considerable, based on the IARC estimations. The incidence of the disease is augmented by the high prevalence of HIV infection, in most of the countries surveyed. Most of the population live in rural areas, where access to the health services is far from ideal. Facilities for screening with HPV tests and for histopathology are limited. One pathologist covers the diagnostic needs of between 0.5 million and 4 million inhabitants. Most other categories of health professionals are under-represented, and the capacity to train them is inadequate.

ConclusionsStrong country commitment and leadership, innovative solutions and extensive international cooperation would be needed to attain the targets of cervical cancer control set by WHO, in these countries.


title: A Framework for Advancing Sustainable MRI Access in Africa

abstract:
MRI technology has profoundly transformed current healthcare and research systems globally. The rapidly growing burden of non-communicable diseases in Africa has underscored the importance of improving access to MRI equipment as well as training and research opportunities on the continent. The Consortium for Advancement of MRI Education & Research in Africa (CAMERA) is a network of African experts, global partners, and ISMRM/ESMRMB members implementing novel strategies to advance MRI access and research in Africa. To identify challenges to MRI usage and provide a framework for addressing MRI needs in the region, CAMERA conducted a Needs Assessment Survey (NAS) and a series of symposia at international MRI society meetings over a 2-year period. The 68-question NAS was distributed to MRI users in Africa and completed by 157 clinicians and scientists from across Sub-Saharan Africa (SSA). On average, the number of MRI scanners per million people remained at <1, of which, 39% were obsolete low-field systems yet still in use to meet clinical needs. The feasibility of coupling stable energy supplies from various sources has contributed to the growing number of higher-field (1.5T) MRI scanners in the region. However, these systems are underutilized with only 8% of facilities reporting clinical scans of 15 or more patients daily per scanner. The most frequently reported MRI scans were neurological and musculoskeletal. Our NAS combined with the World Health Organization and International Atomic Energy Agency data provides the most up-to-date data on MRI density in Africa and offers unique insight into Africas MRI needs. Reported gaps in training, maintenance, and research capacity indicate ongoing challenges in providing sustainable high-value MRI access in SSA. Findings from the NAS and focused discussions at ISMRM and ESMRMB provided the basis for the framework presented here for advancing MRI capacity in SSA.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/22274588v1_ufig1.gif" ALT="Figure 1">
View larger version (15K):
org.highwire.dtl.DTLVardef@1014baaorg.highwire.dtl.DTLVardef@ec4fdorg.highwire.dtl.DTLVardef@1a6c74eorg.highwire.dtl.DTLVardef@66d5ce_HPS_FORMAT_FIGEXP  M_FIG C_FIG Africa has a massive population with few infrastructural resources and an untapped potential to effect transformative change in healthcare. To advance MRI access across all African countries and meet the sustainable development goals of improving health and wellbeing in low-resource settings over the next decade, the MRI community is called to partner with CAMERA to create enabling clinical and research MRI environments that will utilize the rich intellectual resources in Africa to realize lasting and equitable MRI for all Africans and the world at large.

category: radiology and imaging


title: Change in stroke presentations during COVID-19 pandemic in South-Western Sydney.

abstract:
BackgroundAustralia managed relatively well during the global COVID-19 pandemic owing to our swift mandated public health response. During the NSW lockdown restrictions, we noted a decrease in acute stroke presentations at our institution, similar to what was subsequently reported worldwide.

AimsWe aimed to test our hypothesis that (i) the true numbers of ischaemic strokes did not change, however patients were presenting later and (ii) the proportion of TIAs decreased.

MethodsWe conducted a retrospective audit of all stroke and TIA presentations in 2020 and compared these with data from 2019. We collected information about stroke subtype, severity, time from stroke/TIA onset to presentation and acute reperfusion therapies.

ResultsBetween January-February and April-March 2020, there was a 15% drop in acute stroke presentations (128 vs. 109). In the same period "stroke mimic" presentations dropped by 22%. The proportion of patients attending the emergency department within 4.5hrs was only 36% compared with 48% over the similar period in 2019.

ConclusionsAlthough the raw numbers of ischemic stroke presentations remained stable during NSW Covid lockdown, the proportion of patients presenting within time window for acute reperfusion therapies fell. The number of TIAs similarly fell suggesting COVID-19 discouraged patients from presenting to hospital which placed them at higher risk of disabling stroke. The opportunity cost of lockdown restrictions on stroke outcome should be considered in future policy directives.

category: neurology


title: Presence of Major Depressive Disorder influences both neuropsychiatric symptoms and the cognitive profile in Mild Cognitive impairment and Alzheimers disease

abstract:
ObjectivesThe impact of depression, as quantified with specific tests, and neuropsychiatric symptoms (NPS) on mnesic and executive performance has been documented previously. However, the depression can be also diagnosed as Major Depressive Disorder (MDD) based on the DSM-V. We aimed to determine how MDD influences NPS and cognitive performance in Alzheimers disease (AD), Mild Cognitive Impairment (MCI) and Healthy Controls (CH).

Participants647 HC, 291 patients with MCI and 208 patients with AD were extracted from the National Alzheimers Coordinating Center database.

MeasurementsDuring their inclusion in the cohort, each patient was assessed by a physician to distinguish those with a diagnosis of MDD from those without MDD. Patients were assessed with the NeuroPsychiatric Inventory and a comprehensive cognitive assessment. We performed logistic regression and a MANCOVA models respectively with NPS and cognitive performance as variables of interest and MDD as fixed factors within each group. The MANCOVA was controlled for the effects of age, sex, and education.

ResultsOur results exhibited that: MDD was associated with and predicted psychotic, affective and behavioral NPS in MCI, and affective/behavioral NPS in CH and AD; MCI with MDD had lower performance of selective attention and mental flexibility whereas AD with MDD had better working memory performance, than those without MDD.

ConclusionsMDD was mainly associated with higher prevalence of NPS in CH and both level of cognitive decline. This suggest that early treatment of MDD could reduce essentially neuropsychiatric symptomatology and caregiver mental burden.


title: Effect of a 12-mo milk-based micronutrient-fortified drink intervention on children: a systemic analysis of placebo-controlled study dataset

abstract:
BackgroundNutritional deficiencies have many immediate and long-term effects on physical and cognitive development outcomes, with the children not achieving their full potential. A milk-based health drink fortified with micronutrients as a part of a daily balanced diet can promote physical and cognitive growth in children by increasing macronutrients and micronutrients availability in the body. The systematic analysis aims to quantify the effect of a formulated health drink on childrens physical, clinical, and cognitive development outcomes.

MethodsThe dataset used in the analysis was obtained from literature and consisted of 900 children between 7 to 12 years of age. These children were distributed equally into the Control group (no micronutrient-fortified health drink is given), Group I (micronutrient-fortified health drink in water), and Group II (micronutrient-fortified health drink in the toned milk).

ResultsThe analysis shows that micronutrient-fortified health drinks in water (by 2.1-fold) and toned milk (by 2.5-fold) improve the height gain velocities and anthropometric and body composition parameters. It helped children achieve healthy IAP growth percentiles compared to the control group. The analysis also shows a 1.6- and 2-fold change in the cognitive tests grades in groups I & II, respectively, compared to the control group.

ConclusionsThe analysis indicates that two servings of 33g micronutrient-fortified health drink in water and toned milk for a year significantly improved the gain velocities of anthropometric and body composition parameters, reduced time taken to complete the physical activity task, reduced the number of anaemia and morbidity cases among groups, and improved the scoring grades in cognitive assessment test in studied children population. The IAP data benchmarking clearly indicated that a micronutrient fortified milk-protein-based powder significantly improved childrens overall growth with better health.

category: nutrition


title: Genetic effects on the timing of parturition and links to fetal birth weight

abstract: The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of the timing of parturition, identifying 22 loci associated with gestational duration (n = 195,555) and 6 with preterm delivery (cases = 18,797, controls = 260,246). We observed modest differences in the genetic effects between gestational duration and preterm delivery, with most loci shared between the two. Analysis of the transmitted and non-transmitted parental alleles (n = 136,833) shows that 15 of the identified variants act through the maternal genome, while nine have fetal or both maternal and fetal effects. We observe a sex-specific genetic link between testosterone (negative) and sex hormone-binding globulin (positive) on the timing of parturition, likely due to pleiotropic effects. Finally, we provide evidence of maternal-fetal antagonistic effects on gestational duration and birth weight: maternal alleles that increase gestational duration have negative effects on birth weight when present in the fetus.

category: genetic and genomic medicine


title: Have infection control and prevention measures resulted in any adverse outcomes for care home and domiciliary care residents and staff?

abstract:
TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal and evidence synthesis to answer a specific question and identify key research gaps. They take 1-2 months, depending on the breadth and complexity of the research topic/question(s), the extent of the evidence base and type of analysis required for synthesis.

Background / Aim of Rapid ReviewCare for older and vulnerable people must sustain core infection prevention and control (IPC) practices and remain vigilant for COVID-19 transmission to prevent virus spread and protect residents and healthcare professionals from severe infections, hospitalisations and death.

However, these measures could potentially lead to adverse outcomes such as decreased mental wellbeing in patients and staff. A recent publication by Public Health England examines the effectiveness of IPC practices for reducing COVID-19 transmission in care homes (Duval et al., 2021). We explore evidence relating to adverse outcomes from IPC practices to help inform policy recommendations and identify gaps within the literature where further research can be prioritised.

Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABSO_LI15 studies were identified: 14 primary studies and one rapid review
C_LI

Recency of the evidence baseO_LIOf the primary studies, six were published in 2020 and eight were published in 2021
C_LIO_LIThe rapid review was published in 2021.
C_LI

Summary of findingsThis rapid review focuses on adverse outcomes resulting from increased IPC measures put in place during the COVID-19 pandemic. Whilst there is some evidence to show that there may be a link between IPC measures and adverse outcomes, causation cannot be assumed.

O_LIDuring the COVID-19 restrictions, the cognition, mental wellbeing and behaviour of residents in care homes were negatively affected
C_LIO_LIIncreased IPC procedures during the COVID-19 pandemic increased stress and burden among care staff because of increased workload and dilemmas between adhering well to IPC procedures and providing the best care for the care recipients
C_LIO_LICOVID-19 IPC procedures were not well developed at the beginning of the COVID-19 pandemic, but evidence from 2021 suggests that good adherence to IPC measures can enable visitations by family members and medical professionals into care homes
C_LIO_LIOnly one study investigating domiciliary care was found. Therefore, it is difficult to make conclusions related specifically to this care setting
C_LIO_LINo published studies have reported on the costs or cost-effectiveness of IPC measures or have explored the cost implications of adverse outcomes associated with IPC measures
C_LI

Best quality evidenceOnly one study was deemed as high quality based on the quality appraisal checklist ranking. This was a mixed methods study design (Tulloch et al., 2021).

Policy ImplicationsSince March 2020, there have been many changes to government guidelines relating to procedures to keep the population safe from COVID-19 harm. Policies vary according to country, even within the UK. Important issues such as care home visitation policies have changed in such a way that care home staff have felt it difficult to keep up with the changes, which in itself increased the burden on those staff. The following implications were identified from this work:

O_LIIPC policies should be clear, concise and tailored to care homes and domiciliary care settings
C_LIO_LIIncreased attention to workforce planning is needed to ensure adequate staffing and to reduce individual burden
C_LIO_LIRestrictions (e.g. visitation) for care home residents needs to be balanced by additional psychological support
C_LIO_LIFurther research with robust methods in this area is urgently needed especially in the domiciliary care setting
C_LI

Strength of EvidenceOne limitation is the lack of high-quality evidence from the included studies. Confidence in the strength of evidence about adverse outcomes of COVID-19 IPC procedures was rated as  low overall. Whilst the majority of studies achieved a  moderate score based on the quality appraisal tools used, due to the nature of the methods used, the overall quality of evidence is low.


title: Durability of the immune response to a third BNT162b2 dose; five months follow-up

abstract:
BackgroundTwo doses of the BNT162b2 vaccine yielded high effectiveness that wanes within several months. The third dose was effective in mounting a significant humoral and cellular immune response..

MethodsWe followed BNT162b2-vaccinated health-care workers monthly for IgG and neutralizing antibody (NeutAb) titers. Avidity, T-cell activation and microneutralization of sera against different variants of concern (VOC) were assessed for a sub-cohort. Linear mixed models were used to compare the durability of the second and third doses, and to assess if Omicron breakthrough infections were associated with waning dynamics.

ResultsOverall 3972 participants with a third dose were followed, the rate of waning of IgG and NeutAb was slower after the third (1.32%/day and 1.32%/day, respectively) compared to the second (2.26%/per day and 3.34%/day) dose. Live-neutralization of Omicron VOC was lower compared to previous strains and demonstrated similar waning from 111 (95%CI:75-166) to 26 (95%CI:16-42) within 4 months. Mean T cell activity decreased from 98{+/-}5.4 T cells/106 PBMC to 59{+/-}9.3, within 3-5 months. Omicron breakthrough infections were associated with lower IgG peak (ratio of means 0.86 95%CI 0.80-0.91), and among participants over 65y with faster waning of both IgG and NeutAb (ratio of mean rates 1.40 95% CI 1.13-1.68 and 3.58 95% CI 1.92-6.67). No waining in IgG avidity was obsereved during 112 days after the 3rd dose.

ConclusionThe third dose is more durable than the second dose, yet Omicron is relatively resistant to direct neutralization. The level of humoral response may predict breakthrough infections.


title: Antibody responses to AZD1222 vaccination in West Africa

abstract:
BackgroundThere are no real world data on vaccine elicited neutralising antibody responses for the worlds most widely used vaccine, AZD1222, in African populations following scale up. Here, we measured i) baseline SARS-CoV-2 seroprevalence and levels of protective neutralizing antibodies prior to vaccination rollout using both flow cytometric based analysis of binding antibodies to nucleocapsid (N), coupled with virus neutralisation approaches and ii) neutralizing antibody responses to VOC prior to vaccination (January 2021) and after two-doses of AZD1222 vaccine administered between June and July 2021 in Lagos, Nigeria - a period when the Delta variant was circulating.

MethodsHealth workers at multiple sites in Lagos were recruited to the study. For binding antibody measurement, IgG antibodies against SARS-COV-2 Wuhan-1 receptor-binding domain (RBD), trimeric spike protein (S), nucleocapsid protein (N) and Omicron S1 were measured using the Luminex-based SARS-CoV-2-IgG assay by flow cytometry. For plasma neutralising antibody measurement, SARS-CoV-2 lentiviral pseudovirus (PV) were prepared by transfecting 293T cells with Wuhan-614G wild type (WT), B.1.617.2 (Delta) and BA.1 (Omicron) plasmids in conjunction with HIV-1 expression vectors and luciferase encoding genome flanked by LTRs. We performed serial plasma dilutions from each time point and mixed plasma with PV before infecting HeLa-ACE2 cell lines, reading out luminescence and calculating ID50 (reciprocal dilution of sera required to inhibit 50% of PV infection).

ResultsOur study population receiving at least one dose of vaccine comprised 140 participants with a median age of 40 (interquartile range: 33, 48). 62/140 (44%) participants were anti-N IgG positive prior to administration of first vaccine dose. 49 had plasma samples available at baseline prior to vaccination and at two follow-up timepoints post vaccination for neutralization assays. Half of the participants, 25/49 (51%) were IgG anti-N positive at baseline. Of the 24 individuals anti-N Ab negative at baseline, 12/24 had ID50 above the cut-off of 20. In these individuals, binding antibodies to S were also detectable, and neutralisation correlated with IgG anti-S, suggesting waning of N antibody after infection. Overall, neutralizing Ab titres to WT 1 month after second dose were 2579 and at 3 months post second-dose were 1695. As expected, lower levels of neutralization were observed against the Delta GMT 549 and Omicron variants 269 at 1 month. Positive anti-N IgG Ab status at baseline was associated with significantly higher titres of neutralizing antibodies following vaccination across all tested VOC. Those with anti-N Abs present at baseline did not experience waning of responses between months 1 and 3 post second dose. When data were analysed for negative anti-N IgG status at any timepoint, there was a significant decline in neutralization and binding antibodies between 1 month and 3 months post second-dose. The GMT in these individuals for Delta and Omicron was approximately 100, nearly a log lower in comparison to WT. We tested anti-N IgG in subjects who were anti-N IgG negative at baseline (n=78) and became positive between 1- and 3-months post second dose and found 7/49 (14%) with de-novo infection, with one additional participant demonstrating both reinfection and breakthrough infection to yield a total breakthrough rate of 8/49 (16%). Neutralising and binding Ab titres 1 month post vaccine, prior to breakthrough, were not associated with breakthrough infection. Neutralizing titres were higher at the last time point in individuals who had experienced vaccine breakthrough infection (with no evidence of infection prior to vaccine), indicating a boosting effect of infection in addition to vaccine. The increase in titres against Delta PV observed in breakthrough was significantly greater than the increase for WT and Omicron PVs, coincident with in the Delta wave of infection during the sampling period.

ConclusionsAZD1222 is immunogenic in this real world west African cohort with significant background seroprevalence and incidence of breakthrough infection over a short time period. Prior infection and breakthrough infection induced higher anti-SARS-CoV-2 Ab responses at 3 months post vaccine against all widely circulating VOC. However, responses to Omicron BA.1 were low at three months regardless of prior exposure or breakthrough infection. Booster doses after AZD1222 should be considered for those at high risk in the African setting, even after natural infection, as future variants may be more pathogenic as well as immune evasive in the context of waning immunity.


title: SARS-CoV-2 neutralizing antibodies in Chile after a vaccination campaign with five different schemes

abstract: Using levels of neutralizing antibodies (nAbs), we evaluate the successful Chilean SARS-CoV-2 vaccine campaign, which combines technologies and heterologous boosters. In 120 randomly selected seropositive individuals from a population-based study, we conclude that the booster dose, regardless of vaccine technology or natural infection, and mRNA vaccines significantly improve nAbs response.


title: Development and evaluation of low-volume tests to detect and characterise antibodies to SARS-CoV-2

abstract: Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilised pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID- 19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in- house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterised samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries.


title: IDENTIFICATION OF GENOTYPE III OF HEPATITIS DELTA VIRUS IN ANDEAN AND AMAZONIAN COMMUNITIES OF PERU

abstract:
Objectivesto identify the genotypes of Hepatitis Delta Virus (HDV) circulating in populations of the inter-Andean valley of Huanta and three indigenous peoples of the Peruvian Amazon.

Materials and MethodsObservational and cross-sectional study, from 582 reactive samples for anti-HBc-HBV antibodies in inhabitants of the andean province of Huanta (Ayacucho) and the Amazonian towns of Matses, Kandozi and Chapra (Loreto). Analysis was performed for HDV infection markers: anti-HDV IgM and anti-HDV IgG by ELISA using Wantai brand kits. Anti-HDV positive samples by ELISA were processed with the nRT-PCR method for the detection of HDV RNA. HDV genotype was determined by direct Sanger-type sequencing and phylogenetic analysis of the R0 fragment. 111 reference sequences from GenBank were used. The 42 sequences of the study were edited, assembled and cut with the programs Chromas 2.6.5, Bioedit v7.2, ClustalW v.1.6 of Mega v.7.0 and the Gblocks server. Phylogenetic and evolutionary analysis was performed with the following software: Beast V2.5.2, Jmodeltest v2.1.10, Tracer v1.7.1, Tree Annotator and Figtree v1.4.4. The Bayesian Yule and Birth Death skyline serial models were used, the MCMC at 30 and 80 million respectively, with the relaxed uncorrelated Exponential molecular clock. Summary and central tendency measures were calculated using the program in STATA 14.0.

ResultsThe mean age was 38 years (0 to 86 years), 52.75% (N=307) were women. 582 blood samples positive for anti-HBc were analyzed for anti-HVD antibodies using the ELISA method, with 101 positive samples being found. HDV RNA was detected in 49.50% of the anti-HDV ELISA reactive samples. Phylogenetic analysis determined the presence of genotype 3.

ConclusionsThe presence of HDV genotype 3 in Andean and Amazonian communities of Peru is evidenced.


title: Statin intolerance - Prevalence and practical management in a specialized lipid clinic

abstract:
AimsStatins are recommended as first-line treatment to prevent cardiovascular disease, but high rates of adverse events and subsequent discontinuation can prevent effective treatment in some patients. We aimed to describe the intensity, nature and frequency of adverse effects caused by statins and other lipid-lowering drugs, and to assess their association with clinical predictors and treatment strategies.

MethodsThis is a retrospective study of 121 consecutive unselected patients followed at a specialized lipid referral clinic in Lausanne University Hospital, Switzerland, in 2018 whose clinical data spanned 2016 until 2019.

ResultsAdverse effects were reported by 58% of patients, causing musculoskeletal (72%), neurologic (40%), gastrointestinal (25%) and other (25%) symptoms. Gastrointestinal symptoms affected 35% of women, but only 12% of men (p=0.06). Statins caused more adverse effects than other drugs, with atorvastatin (63%) and simvastatin (64%) achieving the lowest rates, pravastatin (87%) and fluvastatin (100%) the highest. Fenofibrate was associated with significantly less frequent adverse effects than statins (22% vs. 57%, p=0.006). Adaptation and termination of the treatment led to 86% and 88% lower intensity of symptoms, respectively.

ConclusionWhile the predominance of musculoskeletal symptoms caused by lipid-lowering drugs is known, symptoms affecting other organ systems should not be ignored. Statins were the lipid-lowering drug class with the highest rates of adverse effects. To maintain compliance and cardiovascular prevention, treatment strategies such as a change of dosage, frequency of administration, daily timing, or switching active substance can contribute to better tolerance of statin treatment. Further investigation is needed to establish specific treatment strategies for individual patient profiles.


title: Optimal thromboprophylaxis strategies in non-critically ill patients with COVID-19 pneumonia. The PROTHROMCOVID Randomized Controlled Trial.

abstract:
BackgroundHospitalized patients with COVID-19 are at increased risk for thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown.

ObjectiveTo evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia.

Design, setting, and participantsRandomized controlled, multicenter trial (PROTHROMCOVID) enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia.

InterventionsPatients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) doses of tinzaparin during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge.

MeasurementsThe primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days.

ResultsOf the 311 subjects randomized, 300 were included in the analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]. The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (P= 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences.

ConclusionsIn non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to increase benefit regarding the likelihood of thrombotic event, non-invasive ventilation or high-flow oxygen, or death.

Trial RegistrationClinicalTrials.gov Identifier (NCT04730856).

FundingThis independent research initiative was supported by Leo-Pharma; Tinzaparin was provided by Leo Pharma.


title: Cutaneous surgical wounds have distinct microbiomes from intact skin

abstract:
BackgroundInfections are relatively rare following cutaneous surgical procedures, despite the potential for wound exposure to pathogens both during surgery and throughout the healing process. Although gut commensals are believed to reduce the risk of intestinal infections, an analogous role for skin commensals has not been described. In fact, the microbiome of normally healing surgical skin wounds has not yet been profiled using culture-independent techniques.

ResultsWe characterized the wound microbiome in 52 patients who underwent skin cancer surgery and healed without signs or symptoms of infection. A week after surgery, several bacterial species displayed significant differences in relative abundance when compared to control, non-operated skin from the same patient. The most common bacteria found on intact skin, Cutibacterium acnes, was depleted in wounds 5-fold. Surprisingly, Staphylococcus aureus, a frequent cause of postoperative skin infections, was enriched 6.4-fold in clinically non-infected wounds, suggesting active suppression of this pathogen. Finally, members of the Corynebacterium genus were the dominant organism is postoperative wounds, making up 37% of the average wound microbiome.

ConclusionsWe observed distinct bacterial communities in acute wounds a week after surgery and anatomically-matched normal skin from the same patient. Future studies focused on the biological and clinical significance of the wound microbiome may shed light on normal wound healing and potential therapeutic opportunities to mitigate infection risk.

category: dermatology


title: Assessment of Standard HIV Testing Services Delivery to Injured Persons Seeking Emergency Care in Nairobi, Kenya: A Prospective Observational Study

abstract:
Emergency departments (EDs) in Africa are contact points for key groups for HIV testing services (HTS) but understanding of ED-testing delivery is limited which may impeded program impacts. This study evaluated the offering and uptake of standard HTS among injured persons seeking ED care at Kenyatta National Hospital (KNH) in Nairobi, Kenya.

An ED population of adult injured persons was prospectively enrolled (1 March - 25 May 2021) and followed through ED disposition. Participants requiring admission were followed through hospital discharge and willing participants were contacted at 28-days for follow up. Data on population characteristics and HTS were collected by personnel distinct from clinicians responsible for standard HTS. Descriptive analyses were performed and prevalence values with 95% confidence intervals (CI) were calculated for HIV parameters.

The study enrolled 646 participants. The median age was 29 years with the majority male (87.8%). Most ED patients were discharged (58.9%). A prior HIV diagnosis was reported by 2.3% of participants and 52.7% reported their last testing as >6 months prior. Standard ED-HTS were offered to 49 or 8.6% of participants (95% CI: 5.8-9.9%), among which 89.8% accepted. For ED-tested participants 11.4% were newly diagnosed with HIV (95% CI: 5.0-24.0%). Among 243 participants admitted, testing was offered to 6.2% (95% CI: 3.9-9.9%), with 93.8% accepting. For admitted participants tested 13.3% (95% CI: 4.0-35.1%) were newly diagnosed (all distinct from ED cases). At 28-day follow up an additional 22 participants reported completing testing since ED visitation, with three newly diagnosed. During the full follow-up period the HIV prevalence in the population tested was 10.3% (95% CI: 5.3-19.0%); all being previously undiagnosed.

Offering of standard HTS was infrequent, however, when offered, uptake and identification of new HIV diagnoses were high. These data suggest that opportunities exist to improve ED-HTS which could enhance identification of undiagnosed HIV.

category: emergency medicine


title: The spread and burden of the COVID-19 pandemic in sub-Saharan Africa: comparison between predictions and actual data and lessons learned.

abstract:
IntroductionSub-Saharan Africa (SSA) was predicted to be severely affected by the coronavirus disease 2019 (COVID-19) pandemic, but the actual data seem to have contradicted these forecasts. This study attempted to verify this observation by comparing predictions against actual data on the spread and burden of the COVID-19 pandemic in SSA.

MethodsFocused on the period from March 1st to September 30th, 2020, we compared (1) the predicted interval dates when each SSA country would report 1 000 and 10 000 COVID-19 cases, to the actual dates when these numbers were attained, as well as (2) the daily number of predicted versus actual COVID-19 cases.

Further, we calculated the case fatality ratio of the COVID-19 infection in SSA, and the correlation coefficient between the weekly average number of confirmed COVID-19 cases reported by each country and the weekly average stringency index of its anti-COVID-19 policy measures.

Results84.61% (33) and 100% (39) of the 39 SSA countries for which predictions were made did not reach a total of 1 000 and 10 000 confirmed COVID-19 cases at the predicted interval dates. The daily number of confirmed COVID-19 cases was lower than the one projected for all SSA countries. The case fatality ratio of the COVID-19 infection in SSA was 3.42%. Among the 44 SSA countries for which the correlation could be estimated, it was negative for 17 (38.6 %) of them.

ConclusionsThe natural characteristics of SSA and the public health measures implemented might partly explain that the actual data were lower than the predictions on the COVID-19 pandemic in SSA, but the low case ascertainment and the numerous asymptomatic cases did significantly influence this observation.


title: Predicting Oncogene Mutations of Lung Cancer Using Deep Learning and Histopathologic Features on Whole-Slide Images

abstract: Lung cancer is a leading cause of death in both men and women globally. The recent development of tumor molecular profiling has opened opportunities for targeted therapies for lung adenocarcinoma (LUAD) patients. However, the lack of access to molecular profiling or cost and turnaround time associated with it could hinder oncologists willingness to order frequent molecular tests, limiting potential benefits from precision medicine. In this study, we developed a weakly supervised deep learning model for predicting somatic mutations of LUAD patients based on formalin-fixed paraffin-embedded (FFPE) whole-slide images (WSIs) using LUAD subtypes-related histological features and recent advances in computer vision. Our study was performed on a total of 747 hematoxylin and eosin (H&E) stained FFPE LUAD WSIs and the genetic mutation data of 232 patients who were treated at Dartmouth-Hitchcock Medical Center (DHMC). We developed our convolutional neural network-based models on 172 training cases and tested on 60 independent cases to analyze whole slides and predict five major genetic mutations, i.e., BRAF, EGFR, KRAS, STK11, and TP53. We additionally used 111 cases from the LUAD dataset of the CPTAC-3 study for external validation. Our model achieved an AUROC of 0.799 (95% CI: 0.686-0.904) and 0.686 (95% CI: 0.620-0.752) for predicting EGFR genetic mutations on the DHMC and CPTAC-3 test sets, respectively. Predicting TP53 genetic mutations also showed promising outcomes. Our results demonstrated that H&E stained FFPE LUAD whole slides could be utilized to predict oncogene mutations, such as EGFR, indicating that somatic mutations could present subtle morphological characteristics in histology slides, where deep learning-based feature extractors can learn such latent information.


title: Protection against omicron severe disease 0-7 months after BNT162b2 booster

abstract: Following a rise in cases due to the delta variant and evidence of waning immunity after 2 doses of the BNT162b2 vaccine, Israel began administering a third BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the omicron variant compared to the delta variant and that this protection wanes quickly. In this study, we used data from Israel to estimate the protection of the 3rd dose against severe disease up to 7 months from receiving the booster dose. The analysis shows that protection conferred by the 3rd dose against omicron did not wane over a 7-month period and that a 4th dose further increased protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts.


title: Pregnant women's knowledge of obstetrical danger signs: A cross-sectional survey in Kigali, Rwanda

abstract:
BACKGROUNDMaternal mortality remains critically high worldwide, particularly in sub-Saharan Africa. The leading causes of maternal death in Rwanda include postpartum hemorrhage and obstructed labor. Maternal recognition of obstetrical danger signs is critical for timely access to emergency care, in order to reduce maternal mortality.

OBJECTIVETo assess the knowledge of obstetrical danger signs among pregnant women attending antenatal care in Kigali, Rwanda.

METHODSA cross-sectional study was conducted between September and December 2018 at five health centers and one district hospital in Kigali, Rwanda. Pregnant women attending antenatal care (ANC) services completed a structured questionnaire. Data were analyzed using descriptive statistics.

RESULTSA total of 382 pregnant women were included in the study. The majority of women (67.8%) were aged 23-35 years, and 44.5% had completed secondary education. Almost half (43.2%) reported traveling more than 30 minutes to reach the health facility; only 23.3% were within 15 minutes of the health facility. Over half (57%) reported attending three or more ANC visits during pregnancy. The majority (85.6%) knew at least one obstetrical danger sign, with nearly half (46.1%) obtaining knowledge of danger signs from midwives and nurses.

CONCLUSIONKnowledgeability was significantly associated with the parity and number of ANC visits, though CHW was also a good source of information for pregnant women. We encourage a systematically designed curriculum to teach mothers during their follow-up visits for ANC.

category: sexual and reproductive health


title: Development and Validation of Audio-based Guided Imagery and Progressive Muscle Relaxation Tools for Functional Bloating

abstract: Mind-body techniques, including Guided Imagery (GI) or Progressive Muscle Relaxation (PMR), may effectively manage bloating. The current study aimed to develop and validate (psychometric and psychological responses) audio-based GI and PMR techniques for bloating. Audio scripts were first developed from literature reviews and in-depth interviews of participants with bloating diagnosed based on the Rome IV criteria. Scripts were validated using psychometric (content & face validity index) and physiological approaches (brain event-related potentials & heart rate variability). 45/63 participants completed the in-depth interview, and  balloon emerged as the synonymous imagery description for bloating, of which inflation correlated with a painful sensation. The final tools consisted of narrated audio scripts in the background of a validated choice of music. Overall, content and face validity index for PMR and GI ranged from 0.92 - 1.00. For ERP and HRV, 17/20 participants were analysed. For ERP, there was significant difference between GI and PMR for alpha waves (p=0.029), delta waves (p=0.029) and between PMR and control for delta waves (p=0.014). For HRV, both GI and PMR exhibited similar autonomic responses over controls (overall p<0.05). The newly developed GI and PMR audio-based tools have been validated using psychometric and physiological approaches.


title: Decreased cerebral blood flow in non-hospitalized adults who self-isolated due to COVID-19

abstract: The long-term consequences of coronavirus disease 2019 (COVID-19) on brain physiology and function are not yet well understood. From the recently described NeuroCOVID-19 study, we examined cerebral blood flow (CBF) in 50 participants recruited to one of two groups: 1) adults who previously self-isolated at home due to COVID-19 (n = 39; 116.5 {+/-} 62.2 days since positive diagnosis), or 2) adults who experienced flu-like symptoms but had a negative COVID-19 diagnosis (n = 11). Participants underwent arterial spin labeling magnetic resonance imaging at 3 Tesla to yield measures of CBF. Voxel-wise analyses of CBF were performed to assess for between-group differences, after controlling for age and sex. Relative to controls, the COVID-19 group exhibited decreased CBF in the thalamus, orbitofrontal cortex, and regions of the basal ganglia. Within the COVID-19 group, CBF differences in occipital and parietal regions were observed between those with (n = 11) and without (n = 28) self-reported on-going fatigue. These results suggest long-term changes in brain physiology in adults across the post-COVID-19 timeframe. Moreover, CBF may aid in understanding the heterogeneous symptoms of the post-COVID-19 condition. Future longitudinal studies are needed to further characterize the consequences of COVID-19 on the brain.


title: Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa

abstract:
The Uganda Genome Resource (UGR) is a well characterised genomic database, with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC) - a population-based open cohort study established in 1989 by the Medical Research Council (MRC) UK in collaboration with the Uganda Virus Research Institute (UVRI).

In 2011, UGR was launched with genotype data on [~]5000 and whole genome sequence data on [~]2000 Ugandan individuals from 9 ethno-linguistic groups. Leveraging other available platforms at the MRC Uganda such as Biorepository centre for sample storage, Clinical Diagnostic Laboratory Service (CDLS) for sample diagnostic testing, sequencing platform for DNA extraction, Uganda Medical informatics Unit (UMIC) for large-scale data analysis, GPC for additional sample collection, UGR is strategically poised to expand and generate scientific discoveries.

Here, we describe UGR and highlight the important genetic findings thus far including how UGR is providing opportunities to: (1) discover novel disease susceptibility genetic loci; (2) refine association signals at new and existing loci; (3) develop and test Polygenic Risk Score (PRS) to determine individuals disease risk; 4) assess how some risk factors including infectious diseases are causally related to non-communicable diseases (NCDs) in Africa; (5) develop research capacity for genomics in Africa; and (6) enhance African participation in the global genomics research arena. Leveraging established research infrastructure, expertise, local genomic leadership, global collaboration and strategic funding, we anticipate that UGR can develop further to a comparable level of European and Asian large-scale genomic initiatives.


title: PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

abstract:
RationaleIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. Novel therapies and prognostic biomarkers are needed.

ObjectiveTo identify and validate molecular determinants of IPF survival.

MethodsA staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance.

Main ResultsAfter quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma and negatively correlated with survival. Peripheral blood PCSK6 gene expression and plasma concentration were associated with reduced transplant-free survival.

ConclusionsWe identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target.


title: Supporting the revision of the health benefits package in Uganda: a constrained optimisation approach

abstract: This study demonstrates how the linear constrained optimization approach can be used to design a health benefits package (HBP) which maximises the net disability adjusted life years (DALYs) averted given the health system constraints faced by a country, and how the approach can help assess the marginal value of relaxing health system constraints. In the analysis performed for Uganda, 58 interventions were included in the HBP in the base scenario, resulting in a total of 49.9 million net DALYs averted. When task shifting of pharmacists and nutrition officers tasks to nurses is allowed, 68 interventions were included in the HBP resulting in a total of 53.8 million net DALYs averted (a 7.8% increase). Further, investing only $39 towards hiring additional nutrition officers time could avert one net DALY; this increased to $55, $56, and $123 for nurses, pharmacists and doctors respectively, and $971 for expanding the consumable budget.

category: health economics


title: STIMULATE-ICP-CAREINEQUAL - Defining usual care and examining inequalities in Long Covid support: protocol for a mixed-methods study (part of STIMULATE-ICP: Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways).

abstract:
IntroductionIndividuals with Long Covid represent a new and growing patient population. In England, fewer than 90 Long Covid clinics deliver assessment and treatment informed by NICE guidelines. However, a paucity of clinical trials or longitudinal cohort studies means that the epidemiology, clinical trajectory, healthcare utilisation and effectiveness of current Long Covid care are poorly documented, and that neither evidence-based treatments nor rehabilitation strategies exist. In addition, and in part due to pre-pandemic health inequalities, access to referral and care varies, and patient experience of the Long Covid care pathways can be poor.

In a mixed methods study, we therefore aim to: (1) describe the usual healthcare, outcomes and resource utilisation of individuals with Long Covid; (2) assess the extent of inequalities in access to Long Covid care, and specifically to understand Long Covid patients experiences of stigma and discrimination.

Methods and analysisA mixed methods study will address our aims. Qualitative data collection from patients and health professionals will be achieved through surveys, interviews and focus group discussions, to understand their experience and document the function of clinics. A patient cohort study will provide an understanding of outcomes and costs of care. Accessible data will be further analysed to understand the nature of Long Covid, and the care received.

Ethics and disseminationEthical approval was obtained from South Central - Berkshire Research Ethics Committee (reference 303958). The dissemination plan will be decided by the patient and public involvement and engagement (PPIE) group members and study Co-Is, but will target 1) policy makers, and those responsible for commissioning and delivering Long Covid services, 2) patients and the public, and 3) academics.


title: Asymptomatic carriage of Plasmodium falciparum in children living a hyperendemic area occurs independently of IgG responses but is associated with induction of IL-10

abstract:
BackgroundMalaria immuno-epidemiological data suggest that two key immunological processes, including anti-parasite and anti-disease immunity, may be implicated in the maintenance of asymptomatic infections. However, in highly exposed persons where the duration of chronic malaria infection could range from a few weeks to several years, the host immunological factors that determine the persistence of asymptomatic parasitemia remain poorly understood. This study therefore aimed to define the association between antibody or cytokine responses with asymptomatic malarial parasitemia amongst highly exposed individuals in Cameroon.

MethodsAn initial cross-sectional study was carried out (week 1) and individuals were classified as having asymptomatic Plasmodium parasitemia with no fever (AS), symptomatic Plasmodium parasitemia with an axillary temperature [≥]37.5{degrees}C (SY) and non-infected (NI) (no Plasmodium parasitemhia and a normal body temperature). Asymptomatic individuals were followed for 10 weeks before being treated with artemisinin-based combination treatment (ACT) and a final sample taken at week 16, 5 weeks after treatment. Those who continued to carry Plasmodium parasites with no measureable fever were defined as having chronic asymptomatic malaria. Antibody levels to P. falciparum schizont extract (SE), merozoite extract (ME), erythrocyte binding antigen-175 (EBA-175) and merozoite surface protein-1 (MSP-1) were quantified by ELISA. The growth inhibitory activities of circulating anti-parasite antibodies were quantified using the 3D7 laboratory strain of P. falciparum and a Sybr Green-I based parasite growth inhibition assay. Plasma levels of 38 cytokines were measured by Luminex technology.

ResultsAmongst infected individuals, parasitemia significantly decreased with increased age although this decrease in parasitemia with age was only observed until age 20. Individuals older than 20 years of age had low parasitemia and this remained constant between the ages of 20 and 80. Although there was no difference in the magnitude of the antibody response between AS, SY and NI groups to any of the antigens tested, median levels of antibody against P. falciparum crude extracts and recombinant proteins EBA-175 and MSP-1 were significantly higher in those older than 20 years of age compared with the younger age group as might be expected from lower parasite levels. Parasite densities and P. falciparum clones fluctuated widely over the 10-week follow-up period in individuals with persistent asymptomatic parasitemia but collectively there was no change in the antibody levels over time within this group. Similar to antibody levels, many levels of the cytokines measured were stable over time. However, IL-10 levels decreased after treatment indicating that this cytokine was associated with parasite carriage in asymptomatic individuals. The ratio of IL-10 to pro-inflammatory cytokines, tumor necrosis factor- (TNF-) and lymphotoxin- (LT-) ratios were higher in the symptomatic group compared to the asymptomatic individuals but only in the younger (<20 years old) age group.

ConclusionTaken together, the above findings indicate that asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of antibody responses, but is associated with induction of IL-10.


title: Repurposing EEG monitoring of general anaesthesia for building biomarkers of brain ageing: An exploratory study

abstract:
BackgroundEEG is a common tool for monitoring anaesthetic depth but is rarely reused at large for biomedical research. This study sets out to explore repurposing of EEG during anaesthesia to learn biomarkers of brain ageing.

MethodsWe focused on brain age estimation as an example. Using machine learning, we reanalysed 4-electrodes EEG of 323 patients under propofol and sevoflurane. We included spatio-spectral features from stable anaesthesia for EEG-based age prediction applying recently published reference methods. Anaesthesia was considered stable when 95% of the total power was below a frequency between 8Hz and 13Hz.

ResultsWe considered moderate-risk patients (ASA <= 2) with propofol anaesthesia to explore predictive EEG signatures. Average alpha-band power (8-13Hz) was informative about age. Yet, state-of-the-art prediction performance was achieved by analysing the entire power spectrum from all electrodes (MAE = 8.2y, R2 = 0.65). Clinical exploration revealed that brain age was systematically linked with intra-operative burst suppression - commonly associated with age-related postoperative cognitive issues. Surprisingly, the brain age was negatively correlated with burst suppression in high-risk patients (ASA = 3), pointing at unknown confounding effects. Secondary analyses revealed that brain-age EEG signatures were specific to propofol anaesthesia, reflected by limited prediction performance under sevoflurane and poor cross-drug generalisation.

ConclusionsEEG from general anaesthesia may enable state-of-the-art brain age prediction. Yet, differences between anaesthetic drugs can impact the effectiveness of repurposing EEG from anaesthesia. To unleash the dormant potential of repurposing EEG-monitoring for clinical and health research, collecting larger datasets with precisely documented drug dosage will be key enabling factors.

category: anesthesia


title: Trends in Diabetes Biomarkers and Treatment Statuses of Non-Institutionalized Canadians: Canadian Health Measures Survey 2007 to 2015

abstract:
BackgroundDiabetes has been a major source of disease burden in Canada. Moreover, untreated diabetes can lead to complications and severe conditions. A few studies exist on the prevalence of diabetes and the adequacy of diabetes management for the Canadian population, and so this study aims to estimate the diabetes prevalence rates using biomarkers and the treatment statuses of non-institutionalized Canadian patients.

MethodsThe Canadian Health Measures Survey (CHMS) cycles 1 to 4 were conducted between 2007 and 2015 as interviews with non-institutionalized Canadians. Four blood diabetic markers were measured: insulin, glycosylated hemoglobin percentages, random-spot glucose, and fasting glucose. Subjects with levels higher than normal ranges were considered to have pre-diabetes or diabetes. Treatment statuses were categorized into treated (using anti-diabetic agents or diagnosed with diabetes), probably treated (taking prescriptions or diagnosed with chronic conditions), potentially treated (taking any medications or diagnosed with chronic conditions), and untreated (not taking any medications and not diagnosed with chronic conditions). Weights were applied to generate nationally representative statistics.

ResultsThe blood insulin levels in cycle 4 were significantly higher than those in cycle 1 (ratio = 1.42, 95% CI = 1.04 to 1.79). The proportions of patients with pre-diabetes and diabetes were estimated differently at 0.75% using random-spot glucose and 42.17% using glycosylated hemoglobin percentages, respectively. The proportions of Canadians with uncontrolled pre-diabetes or diabetes varied from 0.59% using random-spot glucose levels to 4.63% using fasting glucose levels, respectively. Through cycles 1 to 4, the proportions of untreated Canadians with pre-diabetes or diabetes ranged from 3.86% to 3.73%. More than 93% of those with high fasting glucose levels were taking prescription medications or had been diagnosed with chronic conditions (probably treated). Less than 33% of those with high fasting glucose levels were diagnosed or actively being treated with anti-diabetic agents (treated).

ConclusionDiabetes biomarkers might be useful for screening untreated and undertreated patients with pre-diabetes or diabetes. The treatment categories we used indicated different intensities of intervention that might be useful for determining levels of patient outreach and for planning targeted screening in Canada.

category: endocrinology


title: Post-acute health care burden after SARS-CoV-2 infection: A retrospective cohort study among 530,892 adults

abstract: Importance: The SARS-CoV-2 pandemic portends a significant increase in health care use related to post-acute COVID sequelae, but the magnitude is not known. Objective: To assess the burden of post-acute health care use after a positive versus negative polymerase chain reaction (PCR) test for SARS-CoV-2. Design, Setting, and Participants: Retrospective cohort study of community-dwelling adults January 1, 2020 to March 31, 2021 in Ontario, Canada, using linked population-based health data. Follow-up began 56 days after PCR testing. Exposures: Individuals with a positive SARS-CoV-2 PCR test were matched 1:1 to individuals who tested negative based on hospitalization, test date, public health unit, sex, and a propensity score of socio-demographic and clinical characteristics. Main Outcomes and Measures: The health care utilization rate was the number of outpatient clinical encounters, homecare encounters, emergency department visits, days hospitalized, and days in long-term care per person-year. Mean health care utilization for test-positive versus negative individuals was compared using negative binomial regression, and rates at 95th and 99th percentiles were compared. Outcomes were also stratified by sex. Results: Among 530,232 unique, matched individuals, mean age was 44 years (sd 17), 51% were female, and 0.6% had received [≥]1 COVID-19 vaccine dose. The mean rate of health care utilization was 11% higher in test-positive individuals (RR 1.11, 95% confidence interval [CI] 1.10-1.13). At the 95th percentile, test-positive individuals had 2.1 (95% CI 1.5-2.6) more health care encounters per person-year, and at the 99th percentile 71.9 (95% CI 57.6-83.2) more health care encounters per person-year. At the 95th percentile, test-positive women had 3.8 (95% CI 2.8-4.8) more health care encounters per person-year while there was no difference for men. At the 99th percentile, test-positive women had 76.7 (95% CI 56.3-89.6) more encounters per person-year, compared to 37.6 (95% CI 16.7-64.3) per person-year for men. Conclusions and Relevance: Post-acute health care utilization after a positive SARS-CoV-2 PCR test is significantly higher compared to matched test-negative individuals. Given the number of infections worldwide, this translates to a tremendous increase in use of health care resources. Stakeholders can use these findings to prepare for health care demand associated with long COVID.