title: Feasibility and Sensitivity of Saliva GeneXpert MTB/RIF Ultra for Tuberculosis Diagnosis in Adults in Uganda

abstract: The objective of this prospective, observational study carried out at China-Uganda Friendship Hospital-Naguru in Kampala, Uganda, was to determine the performance of GeneXpert MTB/RIF Ultra (Xpert) testing on saliva for active tuberculosis (TB) disease among consecutive adults undergoing diagnostic evaluation. We calculated sensitivity to determine the diagnostic performance in comparison to that of the composite reference standard of Mycobacterium tuberculosis liquid and solid cultures on two spot sputum specimens. GeneXpert Ultra on saliva had a sensitivity of 90% (95% confidence interval [CI], 81-96%); this was similar to that of sputum fluorescence smear microscopy (FM) of 87% (95% CI, 77-94%). Sensitivity was 24% lower (95% CI for difference 2-48%, p=0.003) among persons living with HIV (71%, 95%CI 44-90%) than among persons living without HIV (95%, 95%CI 86-99%) and 46% lower (95% CI for difference 14-77%, p<0.0001) among sputum microscopy positive (96%, 95% CI 87-99%) than among sputum microscopy negative patients (50%, 95% CI 19-81%). Semi-quantitative Xpert grade was higher in sputum than in paired saliva samples from the same patient. In conclusion, saliva specimens appear to be feasible and similarly sensitive to sputum for active TB diagnosis using molecular testing, suggesting promise as a non-sputum diagnostic test for active TB in high-burden settings.


title: Deep Learning-Derived Myocardial Strain

abstract:
BackgroundEchocardiographic strain measurements require extensive operator experience and have significant inter-vendor variability. This study sought to develop an automated deep learning strain (DLS) analysis pipeline and validate its performance both externally and prospectively.

MethodsThe DLS pipeline takes blood pool semantic segmentation results from the EchoNet-Dynamic network and derives longitudinal strain from the frame-by-frame change in the length of the left ventricular endocardial contour. The pipeline was developed using 7,465 echocardiographic videos, with preprocessing steps optimized to determine the change in endocardial length from systole to diastole. It was evaluated on a large external retrospective dataset and was prospectively compared with manual within-patient acquisition of repeated measures by two experienced sonographers and two separate vendor speckle-tracking methods on different machines.

ResultsIn the external validation set, the DLS method maintained moderate agreement (intraclass correlation coefficient (ICC) 0.58, p<0.001) with a bias of -2.33% (limits of agreement -10.61 to 5.93%). The absolute difference in measurements was independent of subjective image quality ({beta}: 0.12, SE: 0.10, p=0.21). Compared to readers on repeated measures, our method has reduced variability (standard deviation: 1.35 vs. 2.55%) and better inter-vendor agreement (ICC: 0.45 vs. 0.29).

ConclusionsThe DLS measurement provides lower variance than human measurements and similar quantitative results. The method is rapid, consistent, vendor-agnostic, publicly released, and robust across a wide range of imaging qualities.

category: cardiovascular medicine


title: Prevalence of intraventricular haemorrhage and determinants of its early outcomes among preterm neonates at the newborn unit of a teaching hospital in Western Kenya

abstract: Intraventricular haemorrhage (IVH) screened using cranial ultrasounds (cUS) is a major cause of morbidity and mortality among preterm neonates. Despite the adverse neonatal outcomes attributed to IVH, there are limited studies conducted in sub-Saharan Africa on IVH occurrence and determinants of early outcomes. This study assessed the proportion of neonates with IVH, its determinants and the early outcomes of preterm neonates with the condition. A prospective descriptive study conducted at the newborn unit of Moi Teaching and Referral Hospital in Western Kenya between March 2020 to March 2021. The neonates sampled systematically had their clinical characteristics and that of their mothers collected from medical records. A cUS screening was conducted on the third and fourteenth day of life while hydrocephalus was screened using serial weekly measurements of head circumference and mortality assessed within the first 28 days of life. Bivariate analysis was used to test for an association between patient characteristics, occurrence of IVH and early outcomes. Confounders were controlled using a multivariate logistic regression model. We enrolled 201 pre-term neonates of whom 105 (52.2%) were male and 68 (33.8%) had IVH. Among neonates with IVH, 46 (67.6%) had mild while 22 (32.4%) had severe IVH. Antenatal steroids significantly reduced the risk of IVH while extreme/very low gestational age and extremely low birthweight significantly increased the risk of IVH two and three-fold respectively. Neonates with thrombocytopenia and on mechanical ventilation were significantly more likely to be diagnosed with IVH. Early outcomes of IVH were hydrocephalus (4.0%) and mortality (19.1%). Intraventricular haemorrhage was seen in one-third of neonates enrolled with majority of them presenting with the lower IVH grades. The IVH risk significantly increased among neonates with very low gestational age and extremely low birthweight but was lowered by antenatal steroid use. Mortality rates were significantly higher among neonates with thrombocytopenia.

category: pediatrics


title: The Influence of Contextual Factors on Maternal Healthcare Utilization in sub-Saharan Africa: A Scoping Review of Multilevel Models

abstract:
IntroductionSub-Saharan Africa still bears the heaviest burden of maternal mortality among the regions of the world, with an estimated 201,000 (66%) women dying annually due to pregnancy and childbirth related complications. Utilisation of maternal healthcare services including antenatal care, skilled delivery and postnatal care contribute to a reduction of maternal and child mortality and morbidity. Factors influencing use of maternal healthcare occur at both the individual and contextual levels. The objective of this study was to systematically examine the evidence regarding the influence of contextual factors on uptake of maternal health care in sub-Saharan Africa.

Materials and MethodsThe process of scoping review involved searching several electronic databases, identifying articles corresponding to the inclusion criteria and selecting them for extraction and analysis. Peer reviewed multilevel studies on maternal healthcare utilisation in sub-Saharan Africa published between 2007 and 2019 were selected. Two reviewers independently evaluated each study for inclusion and conflicts were resolved by consensus.

ResultsWe synthesised 34 studies that met the criteria of inclusion out of a total of 1,654 initial records. Most of the studies were single-country, cross-sectional in nature and involved two-level multilevel logistic regression models. The findings confirm the important role played by contextual factors in determining use of available maternal health care services in sub-Saharan Africa. The level of educational status, poverty, media exposure, autonomy, empowerment and access to health facilities within communities are some of the major drivers of use of maternal health services.

ConclusionsThis review highlights the potential of addressing high-level factors in bolstering maternal health care utilisation in sub-Saharan Africa. Societies that prioritise the betterment of social conditions in communities and deal with the problematic gender norms will have a good chance of improving maternal health care utilisation and reducing maternal and child mortality. Better multilevel explanatory mechanisms that incorporates social theories are recommended in understanding use of maternal health care services in sub-Saharan Africa.

category: sexual and reproductive health


title: Assessment of prescribing in under-five pediatric outpatients in Nigeria: an application of the POPI (Pediatrics: Omission of Prescription and Inappropriate Prescription ) tool

abstract:
BackgroundEnsuring the right drug for the right clinical condition in children under five years of age will dramatically reduce morbidity and mortality rates in developing countries where these values are alarmingly high. This study evaluated prescribing in children under the age of five attending pediatric outpatient clinics at three Central hospitals in Delta State, Nigeria, using the Pediatics: Omission of Prescriptions and Inappropriate Prescription (POPI) tool.

MethodsThis was a prospective descriptive study of prescriptions made to children from 0 to 59 months who attended the clinics between August and November 2018.Prescriptions were evaluated using the POPI tool, occurrence of potentially inappropriate prescriptions and prescribing omissions were reported as percentages and inappropriate prescription types and prescription omissions were also reported as frequencies. Relationship between inappropriate prescriptions, omissions of prescriptions, and categorical variables of age group and sex, p <.05 were considered significant.

ResultsA total of 1,327 prescriptions from the three centers were analyzed. There was a preponderance of infants (> 1 month-12 months of age) in the study (43.0%) and a somewhat even gender distribution. Exactly 29.8% of all the prescriptions studied had at least one occurrence of inappropriate prescription. The use of H1 antagonists with sedative or atropine-like effects accounted for the majority of inappropriate prescriptions (49.5%), while the prescription of drinkable amoxicillin or other antibiotics in doses other than mg was the most frequent omission of prescription (97.2%). There was a significant relationship between the occurrence of inappropriate prescription and age group (p> 0.001).

ConclusionThe occurrence of inappropriate prescriptions and omissions of prescriptions was high and effectively detected by the POPI tool. Measures should be taken to improve prescribing in order to reduce morbidity and mortality in children below five years.


title: Toxoplasma gondii  infection and insomnia: a case control seroprevalence study

abstract:
AimTo determine the association between Toxoplasma gondii (T. gondii) infection and insomnia.

Materials and methodsThrough an age-and gender-matched case-control study, 577 people with insomnia (cases) and 577 people without insomnia (controls) were tested for anti-T. gondii IgG and IgM antibodies using commercially available enzyme-immunoassays.

ResultsAnti-T. gondii IgG antibodies were found in 71 (12.3%) of 577 individuals with insomnia and in 46 (8.0%) of 577 controls (OR=1.62; 95% CI: 1.09-2.39; P=0.01). Men with insomnia had a higher (16/73: 21.9%) seroprevalence of T. gondii infection than men without insomnia (5/73: 6.8%) (OR: 3.81; 95% CI: 1.31-11.06; P=0.009). The rate of high (>150 IU/ml) anti-T. gondii IgG antibody levels in cases was higher than the one in controls (OR=2.21; 95% CI: 1.13-4.31; P=0.01). Men with insomnia had a higher (8/73: 11.0%) rate of high anti-T. gondii IgG antibody levels than men without insomnia (0/73: 0.0%) (P=0.006). The rate of high anti-T. gondii IgG antibody levels in cases >50 years old (11/180: 6.1%) was higher than that (3/180: 1.7%) in controls of the same age group (OR: 3.84; 95% CI: 1.05-14.00; P=0.05). No difference in the rate of IgM seropositivity between cases and controls was found (OR=1.33; 95% CI: 0.57-3.11; P=0.50).

ConclusionsResults of this seroepidemiology study suggest that infection with T. gondii is associated with insomnia. Men older than 50 years with T. gondii exposure might be prone to insomnia. Further research to confirm the association between seropositivity and serointensity to T. gondii and insomnia are needed.

category: epidemiology


title: Comparison of the 2021 COVID-19 'Roadmap' Projections against Public Health Data

abstract: Control and mitigation of the COVID-19 pandemic in England has relied on a combination of vaccination and non-pharmaceutical interventions (NPIs) such as closure of non-essential shops and leisure activities, closure of schools, social distancing, mask wearing, testing followed by isolation and general public health awareness. Some of these measures are extremely costly (both economically and socially), so it is important that they are relaxed promptly but without overwhelming already burdened health services. The eventual policy was a Roadmap of four relaxation steps throughout 2021, taking England from lock-down to the cessation of all restrictions on social interaction; with a minimum of five weeks between each step to allow the data to reflect the changes in restrictions and the results to analysed. Here we present a retrospective analysis of our six Roadmap documents generated in 2021 to assess the likely impacts of future relaxation steps in England. In each case we directly compare results generated at the time with more recent public health data (primarily hospital admissions, but also hospital occupancy and death) to understand discrepancies and potential improvements. We conclude that, in general, the model projections generated a reliable estimation of medium-term hospital admission trends, with the data points up to September 2021 generally lying within our 95% projection intervals. The greatest uncertainties in the modelled scenarios came from estimates of vaccine efficacy, hampered by the lack of data in the early stages of the Alpha and Delta variant waves, and from assumptions about human behaviour in the face of changing restrictions and changing risk. These are clearly avenues for future study.


title: Relative effectiveness of booster vs. 2-dose mRNA Covid-19 vaccination in the Veterans Health Administration: Self-controlled risk interval analysis

abstract:
ImportancePrevious studies have analyzed effectiveness of booster mRNA Covid-19 vaccination and compared it with 2-dose primary series for both Delta and Omicron variants. Observational studies that estimate effectiveness by comparing outcomes among vaccinated and unvaccinated individuals may suffer from residual confounding and exposure misclassification.

ObjectiveTo estimate relative effectiveness of booster vaccination versus the 2-dose primary series with self-controlled study design

Design, Setting and ParticipantsWe used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans enrolled in care [≥]2 years who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster following expanded recommendation for booster vaccination, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021-11/30/2021) or Omicron (1/1/22-3/1/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval.

Exposurescontrol interval (days 4-6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14-16 post-booster vaccination, presumably following gain of booster immunity)

Outcomes and MeasuresPositive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders.

ResultsWe found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during Delta period, and 137 and 66, respectively, in Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95%CI: 42%, 84%) lower during the Delta period and 56% (95%CI: 38%, 67%) lower during Omicron. Results were similar for ages <65 and [≥]65 years in the Omicron period. In sensitivity analyses among those with prior Covid-19 history, and age stratification, ORs were similar to the main analysis.

ConclusionsBooster vaccination was more effective relative to a 2-dose primary series, the relative effectiveness was consistent across age groups and was higher during the Delta predominant period than during the Omicron period.


title: Effects of Transcranial Direct Current Stimulation in Children and Young People with Psychiatric Disorders: A Systematic Review

abstract:
BackgroundTranscranial Direct Current Stimulation (tDCS) has demonstrated benefits in adults with various psychiatric disorders, but its clinical utility in children and young people (CYP) remains unclear.

ObjectiveThis PRISMA systematic review used published and ongoing studies to examine the effects of tDCS on disorder-specific symptoms, mood and neurocognition in CYP with psychiatric disorders.

MethodsWe searched Medline via PubMed, Embase, PsychINFO via OVID, and Clinicaltrials.gov up to January 2022. Eligible studies involved multiple session (i.e. treatment) tDCS in CYP ([≤] 25 years-old) with psychiatric disorders. Two independent raters assessed the eligibility of studies and extracted data using a custom-built form.

ResultsOf 28 eligible studies (participant N= 379), the majority (n = 23) reported an improvement in at least one outcome measure of disorder-specific symptoms. Few studies (n = 9) examined tDCS effects on mood and/or neurocognition, but findings were mainly positive. Overall, tDCS was well-tolerated with minimal side-effects. Of 11 eligible ongoing studies, many are sham-controlled RCTs (n = 9) with better blinding techniques and a larger estimated participant enrolment (M = 74.7; range: 11-172) than published studies.

ConclusionsFindings provide encouraging evidence of tDCS-related improvement in disorder-specific symptoms, but evidence remains limited, especially in terms of mood and neurocognitive outcomes. Ongoing studies appear to be of improved methodological quality; however, future studies should broaden outcome measures to more comprehensively assess the effects of tDCS and develop dosage guidance (i.e. treatment regimens).

category: pharmacology and therapeutics


title: Updated population-level estimates of child restraint practices among children aged 0-12 years in Australia, ten years after introduction of age-appropriate restraint use legislation.

abstract:
Children must correctly use an appropriate restraint type to receive optimal crash protection. To this end, legislation was introduced in Australia in 2009/2010 requiring correct use of age-appropriate restraints among all children up to age 7 years. Prior to this legislation population-referenced estimates of restraint practices in NSW, Australia in 2008 showed suboptimal restraint practices to be widespread. There have been no updated estimates since that time. In this study, we aim to update these estimates using data collected approximately 10 years after the introduction of the legislation.

A stratified cluster sample was constructed to collect population referenced observational data from children aged 0-12 years across the Greater Sydney region of NSW. Data collection methods mimicked those used in the 2008 data. Randomly selected children were observed in their own restraints in their own vehicles by trained researchers. Appropriate use was assessed based on compliance with current NSW legislation. Correct use was defined as use exactly as the manufacturer intended. Errors were categorised as minor or serious on their likely impact of crash protection, and whether they related to installing the restraint in the vehicle or securing the child in the restraint.

Almost all children were appropriately restrained (99.3%, 95%CI 98.4-100). However, less than half were correctly restrained (Any error = 40.4%, 95%CI 32.6-48.3; Any serious error= 43.8%, 95%CI 35.0-52.7). Both securing and installation related errors remain common. There were variations in the extent of errors in use in different restraint types with the least errors among seat belt and the most among booster seat users. While, overall, the odds of incorrect use decreased with increasing age (OR), the relationship between age and incorrect use was different among booster seats user, with decreasing odds with ever year older.

While there was no attempt to test the impact of the legislation on restraint use, it was clear there had been substantial increases in the proportion of children using appropriate forms of restraint over the last 10 years. However there appears to have been no real change in rates of correct use.

category: public and global health


title: Distinct genome-wide DNA methylation and gene expression signatures in classical monocytes from African American patients with systemic sclerosis

abstract:
BackgroundSystemic sclerosis (SSc) is a multisystem autoimmune disorder that has an unclear etiology and disproportionately affects women and African Americans. Despite this, African Americans are dramatically underrepresented in SSc research. Additionally, monocytes show heightened activation in SSc and in African Americans relative to European Americans. In this study, we sought to investigate DNA methylation and gene expression patterns in classical monocytes in a health disparity population.

MethodsClassical monocytes (CD14++CD16-) were FACS-isolated from 34 self-reported African American women. Samples from 12 SSc patients and 12 healthy controls were hybridized on MethylationEPIC BeadChip array, while RNA-seq was performed on 16 SSc patients and 18 healthy controls. Analyses were computed to identify differentially methylated CpGs (DMCs), differentially expressed genes (DEGs), and CpGs associated with changes in gene expression (eQTM analysis).

ResultsWe observed modest DNA methylation and gene expression differences between cases and controls. The genes harboring the top DMCs, the top DEGs, as well as the top eQTM loci were enriched for metabolic processes. Genes involved in immune processes and pathways showed a weak upregulation in the transcriptomic analysis. While many genes were newly identified, several other have been previously reported as differentially methylated or expressed in different blood cells from patients with SSc, supporting for their potential dysregulation in SSc.

ConclusionsWhile contrasting with results found in several blood cell types in largely European-descent groups, the results of this study reflect the variation in DNA methylation and gene expression that exists among individuals of different genetic, clinical, social, and environmental backgrounds. This finding supports the importance of including diverse, well-characterized patients to understand the different roles of DNA methylation and gene expression variability in the dysregulation of classical monocytes in diverse populations, which might help explaining the health disparities.

category: rheumatology


title: Severe Acute Respiratory Coronavirus-2 Antibody and T cell response after a third vaccine dose in hemodialysis patients compared with healthy controls

abstract:
1.Hemodialysis patients (HD patients) have a high health risk from Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection. In this study, we assess the impact of a third vaccine dose (3D) on antibody levels and T cell response in HD patients and compare the results to those of a healthy control group.

We conducted a prospective cohort study consisting of 60 HD patients and 65 healthy controls. All of them received two doses of the Comirnaty mRNA vaccine and a third mRNA vaccine dose (Spikevax or Comirnaty). The SARS-CoV-2 S antibody response in all participants was measured 6 months after the second vaccine dose and 6 to 8 weeks after administration of the 3D. We also assessed INF-{gamma} secretion 6-8 weeks after the 3D in 24 healthy controls, 17 HD patients with a normal and 20 HD patients with a low or no antibody response after the second dose. The groups were compared using univariate quantile regressions and multiple analyses. The adverse effects of vaccines were assessed via a questionnaire.

After the 3D, the SARS-CoV-2-specific antibody and INF-{gamma} titers of most HD patients were comparable to those of healthy controls. A subgroup of HD patients who had shown a diminished antibody response after the first two vaccine doses developed a significantly lower antibody and INF-{gamma} response compared to responder HD patients and controls, even after the 3D. A new strategy is needed to protect this patient group from severe COVID-19 infection.

category: nephrology


title: A multiplexed Cas13-based assay with point-of-care attributes for simultaneous COVID-19 diagnosis and variant surveillance

abstract: Point-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection--such as multiplexed detection for viral variant surveillance--may limit their widespread adoption. Herein, we developed a robust multiplexed CRISPR-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose SARS-CoV-2 infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-- including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)--all while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool--CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance which can be locally manufactured--may enable sustainable use of CRISPR diagnostics technologies for COVID- 19 and other diseases in POC settings.

category: infectious diseases


title: From Delta to Omicron SARS-CoV-2 variant: switch to saliva sampling for higher detection rate

abstract:
BackgroundReal-time polymerase chain reaction (RT-PCR) testing on a nasopharyngeal swab is the current standard for SARS-CoV-2 virus detection. Since collection of this sample type is experienced uncomfortable by patients, saliva- and oropharyngeal swab collections should be considered as alternative specimens.

ObjectivesEvaluation of the relative performance of oropharyngeal swab, nasopharyngeal swab and saliva for the RT-PCR based SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant detection.

Study designNasopharyngeal swab, oropharyngeal swab and saliva were collected from 246 adult patients who presented for SARS-CoV-2 testing at the screening centre in Ypres (Belgium). RT-PCR SARS-CoV-2 detection was performed on all three sample types separately. Variant type was determined for each positive patient using whole genome sequencing or Allplex SARS-CoV-2 variants I and II Assay.

Results and conclusionsSaliva is superior compared to nasopharyngeal swab for the detection of the Omicron variant. For the detection of the Delta variant, nasopharyngeal swab and saliva can be considered equivalent specimens. Oropharyngeal swab is the least sensitive sample type and shows little added value when collected in addition to a single nasopharyngeal swab.

HighlightsO_LISaliva is the preferred sample type for Omicron variant (B.1.1.529) detection
C_LIO_LINasopharyngeal swab and saliva are equivalent for Delta variant (B.1.617.2) detection
C_LIO_LIOropharyngeal swab is the least preferred sample type for SARS-CoV-2 detection
C_LI


title: Molecular and spatial epidemiology of HCV among people who inject drugs in Boston, Massachusetts

abstract: Integration of genetic, social network, and spatial data has the potential to improve understanding of transmission dynamics in established HCV epidemics. Sequence data were analyzed from 63 viremic people who inject drugs recruited in the Boston area through chain referral or time-location sampling. HCV subtype 1a was most prevalent (57.1%), followed by subtype 3a (33.9%). The phylogenetic distances between sequences were no shorter comparing individuals within versus across networks, nor by location or time of first injection. Social and spatial networks, while interesting, may be too ephemeral to inform transmission dynamics when the date and location of infection are indeterminate.


title: Detection of Bourbon virus specific serum neutralizing antibodies in human serum in Missouri, USA

abstract:
Bourbon virus (BRBV) was first discovered in 2014 in a fatal human case. Since then it has been detected in the Amblyomma americanum tick in the states of Missouri and Kansas in the United States. Despite the high prevalence of BRBV in ticks in these states, very few human cases have been reported, and the true infection burden of BRBV in the community is unknown. Here, we developed two virus neutralization assays, a VSV-BRBV pseudotyped rapid assay, and a BRBV focus reduction neutralization assay, to assess the seroprevalence of BRBV neutralizing antibodies in human sera collected in 2020 in St. Louis, Missouri. Out of 440 human serum samples tested, three (0.7%) were able to potently neutralize both VSV-BRBV and wild type BRBV. These findings suggest that human infections with BRBV are more common than previously recognized.

ImportanceSince the discovery of the Bourbon virus (BRBV) in 2014, a total of five human cases have been identified, including two fatal cases. BRBV is thought to be transmitted by the Lone Star tick, which is prevalent in the East, Southeast, and Midwest of the United States (US). BRBV has been detected in ticks in Missouri and Kansas and serological evidence suggests that it is also present in North Carolina. However, the true infection burden of BRBV in humans is not known. In the present study, we developed two virus neutralization assays to assess the seroprevalence of BRBV specific antibodies in human sera collected in 2020 in St. Louis, Missouri. We found that a small subset of individuals is seropositive for neutralizing antibodies against BRBV. Our data suggest that BRBV infection in humans is more common than previously thought.


title: Pattern and risk factors of menstrual regulation service use among ever-married women in Bangladesh: evidence from a nationally representative cross-sectional survey

abstract:
BackgroundAround 47% of the total conceptions in Bangladesh are unintended which leads to several adverse consequences, including maternal and child mortality. Availability of menstrual regulation (MR) service and its use can help women to end conception at an earlier stage, as such, reducing adverse consequences related to the unintended pregnancy. We explored the prevalence and determinants of MR service knowledge and its use among ever-married women in Bangladesh.

MethodsA total of 20 127 ever-married women data from the 2017 Bangladesh Demographic and Health Survey were analyzed. Knowledge about menstrual regulation (MR) and its use were our outcomes of interest. Several individual, household and community-level factors were considered as explanatory variables. The multilevel mixed-effects Poisson regression model was used to determine the factors associated with MR service knowledge and its use in Bangladesh.

ResultsAround 71% of the total analyzed women reported they know about MR service while only 7% of them reported they used this service within three years of the survey date. MR service knowledge was found to be higher among women with increased age and education and engaged in income-generating employment. Knowledge about MR service was also found to be higher among women whose husbands were higher educated and engaged in physical work or business. Rural women and women who resided in the community with lower poverty and higher illiteracy were reported lower knowledge of MR service. MR service use was found higher among higher-aged women, women whose husbands were either physical workers or businessmen, women who have an increased number of children and inherent in the community with lower poverty. Lower use of MR service was found among women who resided in the Chattogram, Khulna, and Mymensingh divisions and women who resided in the community with increased illiteracy.

ConclusionUse of MR service is very low in Bangladesh. This could be responsible for higher adverse consequences related to unintended pregnancy including higher maternal and child mortality. Policies and programs are important to aware women of MR.


title: SARS-CoV-2 virus dynamics in recently infected people - data from a household transmission study

abstract: We used daily real-time reverse-transcription polymerase chain reaction (rRT-PCR) results from 67 cases of SARS-CoV-2 infection in a household transmission study to examine the trajectory of cycle threshold (Ct) values, an inverse correlate of viral RNA concentration, from nasal specimens collected between April 2020 and May 2021. Ct values varied over the course of infection, across RT-PCR platforms, and by participant age. Specimens collected from children and adolescents showed higher Ct values and adults aged [≥]50 years showed lower Ct values than adults aged 18-49 years. Ct values were lower on days when participants reported experiencing symptoms.


title: COVID-19 Disease Model with Reservoir of Infection : Cleaning Surfaces and Wearing Masks Strategies

abstract: At the end of 2019 a new coronavirus (called SARS-COV-2) epidemic appears in china and spreads from China to the rest of the world at beginning of 2020 and caused a new disease called COVID -19. Its well known that, COVID -19 disease spreads between humans through the air by coughing and sneezing or by contact. In this paper, we develop a mathematical SIR model which takes into account the effect of disease transmission by coughing and sneezing and the period of latency which is represented by time delays. We prove that, there is non effect of latency period on the dynamics of the propagation and transmission of the coronavirus, and for some critical value of the basic reproduction number a transcritical bifurcation may occur and the disease disappears for values smaller than this critical value and persist otherwise. In the end, we carry out some numerical simulations in order to illustrate our theoretical results. Our study confirm that, cleaning surfaces and wearing masks is a controlling strategy for limiting the propagation of COVID - 19.


title: Assessing performance and clinical usefulness in prediction models with survival outcomes: practical guidance for Cox proportional hazards models

abstract:
Risk prediction models need thorough validation to assess their performance. Validation of models for survival outcomes poses challenges due to the censoring of observations and the varying time horizon at which predictions can be made. We aim to give a description of measures to evaluate predictions and the potential improvement in decision making from survival models based on Cox proportional hazards regression.

As a motivating case study, we consider the prediction of the composite outcome of recurrence and death (the  event) in breast cancer patients following surgery. We develop a Cox regression model with three predictors as in the Nottingham Prognostic Index in 2982 women (1275 events within 5 years of follow-up) and externally validate this model in 686 women (285 events within 5 years). The improvement in performance was assessed following the addition of circulating progesterone as a prognostic biomarker.

The model predictions can be evaluated across the full range of observed follow up times or for the event occurring by a fixed time horizon of interest. We first discuss recommended statistical measures that evaluate model performance in terms of discrimination, calibration, or overall performance. Further, we evaluate the potential clinical utility of the model to support clinical decision making. SAS and R code is provided to illustrate apparent, internal, and external validation, both for the three predictor model and when adding progesterone.

We recommend the proposed set of performance measures for transparent reporting of the validity of predictions from survival models.


title: Diagnostic performance of non-invasive fibrosis markers for chronic hepatitis B in sub-Saharan Africa: a Bayesian individual patient data meta-analysis

abstract:
ObjectiveIn sub-Saharan Africa, hepatitis B is the principal cause of liver disease. Non-invasive biomarkers of liver fibrosis are needed to identify patients requiring antiviral treatment. We assessed aspartate aminotransferase-to-platelet ratio index (APRI), gamma-glutamyl transferase-to-platelet ratio (GPR) and FIB-4 to diagnose significant fibrosis and cirrhosis in an individual patient data (IPD) meta-analysis.

DesignIn total, 3,549 patients from 12 cohorts of HBsAg positive individuals in 8 sub-Saharan African countries were included. Transient elastography was used as a reference test for cirrhosis (>12.2 kPa), excluding patients who were pregnant, had hepatitis C, D, or HIV co-infection, were on hepatitis B therapy, or had acute hepatitis. A bivariate Bayesian IPD model was fitted with patient-level covariates and study-level random effects.

ResultsAPRI and GPR had the best discriminant performance (area under receiver operating curve 0.81 and 0.82) relative to FIB-4 (0.77) for cirrhosis. The World Health Organization (WHO) recommended APRI threshold of [≥]2.0 was associated with a sensitivity and specificity (95% credible interval) of 16.5% (12.5-20.5) and 99.5% (99.2-99.7) for cirrhosis. For APRI, we identified an optimised rule-in threshold for cirrhosis (cut-off 0.65) with a sensitivity and specificity of 56.2% (50.5-62.2) and 90.0% (89.0-91.0), and an optimised rule-out threshold (cut-off 0.36) with a sensitivity and specificity of 80.6% (76.1-85.1) and 64.3% (62.8-65.8).

ConclusionsThe WHO recommended APRI threshold of 2.0 is too high to diagnose cirrhosis in sub-Saharan Africa. We identified new and optimised rule-in and rule-out thresholds for cirrhosis, with direct consequences for treatment guidelines in this setting.

category: gastroenterology


title: Effectiveness of whole virus COVID-19 vaccine at protecting health care personnel against SARS-CoV-2 infections in Lima, Peru

abstract:
In February 2021, Peru launched a vaccination campaign among healthcare personnel using BBIBP-CorV inactivated whole virus (BBIBP-CorV) COVID-19 vaccine. Two doses of BBIBP-CorV vaccine are recommended, 21 days apart. Data on BBIBP-CorV vaccine effectiveness will inform the use and acceptance of vaccination with BBIBP-CorV vaccine.

We evaluated BBIBP-CorV vaccine effectiveness among an existing multi-year influenza cohort at two hospitals in Lima. We analyzed data on 290 participants followed between February and May 2021. Participants completed a baseline questionnaire and provided weekly self-collected anterior nasal swabs tested for SARS-CoV-2 by rRT-PCR for sixteen weeks. We performed multivariable logistic regression models adjusting for pre-selected characteristics (age, sex, exposure to COVID-19 patients, work in intensive care unit or emergency department, BMI, and exposure time in days). BBIBP-CorV vaccine effectiveness was calculated after the two-week post-vaccination period as (1-Odds Ratio for testing SARS-CoV-2 positive)x100%.

SARS-CoV-2 was detected by rRT-PCR among 25 (9%) participants during follow-up (February-May 2021). Follow-up period ranged 1-11 weeks (median: 2 weeks). Among cohort participants who were fully vaccinated the adjusted vaccine effectiveness against SARS-CoV-2 infection was estimated as 95% (95% CI: 70%, 99%) and 100% (95% CI: 88%, 100%) for those partially vaccinated.

During the study period, vaccination of healthcare personnel with BBIBP-CorV vaccine was effective at reducing SARS-CoV-2 infections in the weeks immediately following vaccination. This information can be used to support vaccination efforts in the region, especially among those who could be concerned about their effectiveness.


title: Characteristics of mental health stability during COVID-19: An online survey with people residing in the Liverpool City Region

abstract:
Background and aimDespite the significant mental health challenges the COVID-19 pandemic and its associated government measures have presented, research have shown that the majority of people have adapted and coped well. The aim of this study was i) to determine the proportion of people with mental stability and volatility during the pandemic in a North West urban environment sample and ii) to establish group differences in psychosocial variables. Mental stability and volatility refer to the extent to which individuals reported change in levels of common mental health symptoms over the course of 12 weeks.

Methoda two-wave-online survey (N = 163) was used to explore the psychological and social impact of the pandemic on relatively disadvantaged neighbourhoods within the Liverpool City Region over 12 weeks. Kruskal-Wallis with post-hoc tests were used to determine how people with mental stability and volatility differed on factors categorised within an ecological framework of resilience (individual, community, societal, and COVID-19 specific).

ResultsIndividuals categorised as  stable in terms of mental health symptoms (63.6%) had better mental and physical health; were more tolerant of uncertainty; reported higher levels of resilience and wellbeing compared to  very volatile people (19.8%). These individuals also reported feeling less socially isolated, experienced a greater sense of belonging to their community which was more likely to fulfil their needs, and were more likely to have access to green space nearby for their recommended daily exercise.  Stable individuals did not report worrying any more during the pandemic than usual and tolerated uncertainty better compared to those in the  volatile group.

ImplicationsThe majority of participants in this sample were mentally stable and coping well with the challenges presented by the pandemic. The resilience of these individuals was related to key place-based factors such as a strong sense of community and useable local assets. The data showcase the role of place-based social determinants in supporting resilience and thereby highlight key preventative measures for public mental health during times of international crisis.


title: Patient-reported respiratory outcome measures in the recovery of adults hospitalised with COVID-19: A systematic review and meta-analysis

abstract:
BackgroundAcute COVID-19 clinical symptoms have been clearly documented, but long-term functional and symptomatic recovery from COVID -19 is less well described.

MethodsA systematic review and meta-analysis were conducted to describe patient-reported outcome measures (PROMs) in adults at least 8 weeks post hospital discharge for COVID-19. Comprehensive database searches in accordance with the PRISMA statement were carried out up till 31/05/2021. Data were narratively synthesized, and a series of meta-analyses were performed using the random-effects inverse variance method.

ResultsFrom 49 studies, across 14 countries with between 2-12 months follow up, the most common persisting symptom reported was fatigue with meta-analysis finding 36.6% (95 % CI 27.6 to 46.6, n=14) reporting it at 2-4 months, decreasing slightly to 32.5% still reporting it at >4 months (95% CI 22.6 to 44.2, n=15). This was followed by dyspnoea. Modified MRC score (mMRC) [≥]1 was reported in 48% (95% CI 30 to 37, n=5) at 2-4months reducing to 32% (95% CI 22 to 43, n=7) at 4 months. Quality of life (QOL) as assessed by the EQ-5D-5L VAS remained reduced at >4 months (73.6 95% CI 68.1 to 79.1, n=6). Hospitalisation with COVID-19 also resulted in persisting sick leave, change in scope of work, and continued use of primary and secondary healthcare.

ConclusionThe symptomatic and functional impact of COVID-19 continues to be felt by patients months after discharge from hospital. This widespread morbidity points towards a multi-disciplinary approach to aid functional recovery.

category: respiratory medicine


title: Selection of appropriate reference genes for normalization of qRT-PCR based gene expression analysis in SARS-CoV-2, and Covid-associated Mucormycosis infection

abstract: Selection of reference genes in quantitative PCR is critical to determine accurate and reliable mRNA expression. Despite this knowledge, not a single study has investigated the expression stability of housekeeping genes to determine their suitability to act as reference gene in SARS-CoV-2 or Covid19 associated mucormycosis (CAM) infections. Herein, we address these gaps by investigating the expression stability of nine most commonly used housekeeping genes including TBP, CypA, B2M, 18S, PGC-1, GUSB, HPRT-1, {beta}-ACTIN and GAPDH in the patients of varying severity (asymptomatic, mild, moderate and severe). We observed significant differences in the expression of candidate genes across the disease spectrum. Next, using various statistical algorithms (delta Ct, Normfinder, Bestkeeper, RefFinder and GeNorm), we observed that CypA demonstrated the most consistent expression across the patients of varying severity and emerged as the most suitable gene in Covid19, and CAM infections. Incidentally, the most commonly used reference gene GAPDH showed maximum variations and found to be the least suitable. Lastly, comparative evaluation of expression of NRF2 is performed following normalization with GAPDH and CypA to highlight the relevance of an appropriate reference gene. Our results reinforce the idea of a selection of housekeeping genes only after validation especially during infections.


title: Suppression of de novo antibody responses against SARS-CoV2 and the Omicron variant after mRNA vaccination and booster in patients with B cell malignancies undergoing active treatment, but maintenance of pre-existing antibody levels against endemic viruses.

abstract: The impact of SARS-CoV2 vaccination in cancer patients remains incompletely understood given the heterogeneity of cancer and cancer therapies. We assessed vaccine-induced antibody response to the SARS-CoV2 Omicron (B.1.1.529) variant in 57 patients with B cell malignancies with and without active B cell-targeted therapy. Ancestral- and Omicron-reactive antibody levels were determined by ELISA and neutralization assays. In over one third of vaccinated patients at the pre-booster timepoint, there were no ELISA-detectable antibodies against either the ancestral strain or Omicron variant. The lack of vaccine-induced antibodies was predominantly in patients receiving active therapy such as anti-CD20 monoclonal antibody (mAb) or Brutons tyrosine kinase inhibitors (BTKi). While booster immunization was able to induce detectable antibodies in a small fraction of seronegative patients, the benefit was disproportionately evident in patients not on active therapy. Importantly, in patients with post-booster ELISA-detectable antibodies, there was a positive correlation of antibody levels against the ancestral strain and Omicron variant. Booster immunization increased overall antibody levels, including neutralizing antibody titers against the ancestral strain and Omicron variant; however, predominantly in patients without active therapy. Furthermore, ancestral strain neutralizing antibody titers were about 5-fold higher in comparison with those to Omicron, suggesting that even with booster administration, there may be reduced protection against the Omicron variant. Interestingly, in almost all patients regardless of active therapy, including those unable to generate detectable antibodies against SARS-CoV2 spike, we observed comparable levels of EBV, influenza, and common cold coronavirus reactive antibodies demonstrating that B cell-targeting therapies primarily impair de novo but not pre-existing antibody levels. These findings suggest that patients with B cell malignancies on active therapy may be at disproportionately higher risk to new versus endemic viral infection and suggest utility for vaccination prior to B cell-targeted therapy.


title: Founder effect contributes to the unique pattern of SARS-CoV-2 variant B.1.1.519 emergence in Alaska

abstract: Alaska is the largest geographic state in the United States with the lowest population density and a mix of urban centers and isolated rural communities. The differences in population dynamics in Alaska from the contiguous United States may have contributed to a unique pattern of emergence and spread of SARS-CoV-2 variants observed in early 2021. Here we examined 2,323 virus genomes from Alaska and 278,635 virus genomes from the contiguous United States collected between the first week of December 2020 through the last week of June 2021. We focused on this timeframe because of the notable emergence and spread of the SARS-CoV-2 lineage B.1.1.519 observed in Alaska. We found that this variant was consistently detected in Alaska from the end of January through June of 2021 with a peak prevalence in April of 77.9% unlike the rest of the United States with a peak prevalence of 4.6%. In Alaska, the earlier emergence of B.1.1.519 coincided with a later peak of Alpha (B.1.1.7) when compared to the rest of the United States. We also observed differences in the composition of lineages and variants over time between the two most populated regions of Alaska. Although there was a modest increase in COVID-19 cases during the peak incidence of B.1.1.519, it is difficult to disentangle how social dynamics conflated changes in COVID-19 during this time. We suggest that the viral characteristics, such as amino acid substitutions in the spike protein, and a founder effect likely contributed to the unique spread of B.1.1.519 in Alaska.


title: An immune dysfunction score for stratification of patients with acute infection based on whole blood gene expression

abstract: Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of deaths globally each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole blood transcriptomics for stratification of patients with severe infection by integrating data from 3,149 samples of sepsis patients and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 19-gene signature. Finally, we built a machine learning framework, SepstratifieR, to deploy SRSq in sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, thus bringing us closer to precision medicine in infection.

category: intensive care and critical care medicine


title: A log-odds system for waning and boosting of COVID-19 vaccine effectiveness

abstract: Immunity to SARS-CoV-2 following vaccination wanes over time in a non-linear fashion, making modelling of likely population impacts of COVID-19 policy options challenging. We observed that it was possible to mathematize non-linear waning of vaccine effectiveness (VE) on the percentage scale as linear waning on the log-odds scale, and developed a random effects logistic regression equation based on UK Health Security Agency data to model VE against Omicron following two and three doses of a COVID-19 vaccine. VE on the odds scale reduced by 47% per month for symptomatic infection after two vaccine doses, lessening to 35% per month for hospitalisation. Waning on the odds scale after triple dose vaccines was 35% per month for symptomatic disease and 19% for hospitalisation. This log-odds system for estimating waning and boosting of COVID-19 VE provides a simple solution that may be used to parametrize SARS-CoV-2 immunity over time parsimoniously in epidemiological models.


title: Protection of prior natural infection compared to mRNA vaccination against SARS-CoV-2 infection and severe COVID-19 in Qatar

abstract:
BACKGROUNDProtection conferred by natural SARS-CoV-2 infection versus COVID-19 vaccination has not been investigated in rigorously controlled studies. We compared head-to-head protection conferred by natural infection to that from the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines in Qatar, between February 28, 2020 and March 6, 2022.

METHODSTwo national matched retrospective target-trial cohort studies were conducted to compare incidence of SARS-CoV-2 infection and COVID-19 hospitalization and death among those with a documented primary infection to incidence among those with a two-dose primary-series vaccination. Associations were estimated using Cox proportional-hazards regression models.

RESULTSThe overall adjusted hazard ratio (AHR) for infection was 0.46 (95% CI: 0.45-0.48) comparing those with a prior infection to those vaccinated with BNT162b2, and 0.51 (95% CI: 0.48-0.53) comparing those with a prior infection to those vaccinated with mRNA-1273. For BNT162b2, the AHR decreased gradually from 0.55 (95% CI: 0.46-0.65) in the fourth month after primary infection/vaccination to 0.31 (95% CI: 0.27-0.37) in the eighth month, while for mRNA-1273, it decreased from 0.80 (95% CI: 0.59-1.07) to 0.35 (95% CI: 0.29-0.41) over the same time period. During the Omicron wave, the AHR was [~]0.50 for BNT162b2 and [~]0.60 for mRNA-1273. The overall AHR for any severe, critical, or fatal COVID-19 (against all variants) was 0.32 (95% CI: 0.10-1.00) for BNT162b2, and 0.58 (95% CI: 0.14-2.43) for mRNA-1273.

CONCLUSIONSNatural infection was associated with stronger and more durable protection against infection, regardless of the variant, than mRNA primary-series vaccination. Nonetheless, vaccination remains the safest and optimal tool of protection against infection and COVID-19 hospitalization and death.


title: Risk of diabetes and cardiovascular diseases in women with pregnancies complicated by vaginal bleeding: Danish population-based cohort study

abstract:
ObjectiveTo investigate an association between childbirths affected by vaginal bleeding within 20 gestational weeks and womens subsequent risks of diabetes and cardiovascular diseases.

DesignCohort study in Denmark, 1979-2018.

SettingDanish nationwide registries.

ParticipantsBetween 1979 and 2017, we identified 3,085,955 pregnancies among 1,329,331 women. Of these pregnancies, 69,230 ended in a childbirth affected by vaginal bleeding (VB) within 20 gestational weeks; 2,180,855 ended in a VB-unaffected childbirth; 578,355 ended in a termination, and 258,430 ended in a miscarriage.

Main outcome measuresThe outcomes were diabetes types 1 and 2, hypertension, ischaemic heart disease, including myocardial infarction, atrial fibrillation or flutter, heart failure, ischaemic and haemorrhagic stroke, coronary artery bypass grafting, and percutaneous coronary intervention. We computed the incidence rates per 10,000 person-years and cumulative incidences of cardiovascular outcomes at up to 40 years of follow-up. Hazard ratios (HRs) with 95% confidence intervals adjusted for age, calendar year, reproductive history, baseline comorbidities, and socioeconomic factors were computed using conventionally and inverse probability of treatment weighted Cox proportional hazards regression.

ResultsAt the end of the follow-up, among women with VB-affected vs VB-unaffected childbirths, the cumulative risks of the outcome events were 4.5% vs 3.5% for diabetes type 1; 13.8% vs 11.1% for diabetes type 2; 25.1% vs 21.4% for hypertension; 10.6% vs 8.2% for ischaemic heart disease, including 2.9% vs 2.6% for myocardial infarction; 5.3% vs 4.4% for atrial fibrillation or flutter; 2.3% vs 2.0% for heart failure; 5.1% vs 4.0% for ischaemic stroke; 1.8% vs 1.4% for haemorrhagic stroke; 0.5% vs 0.4% for coronary artery bypass graft; and 2.4% vs 1.9% for percutaneous coronary intervention. Adjusted HRs were 1.2 to 1.3-fold increased for diabetes types 1 and 2, hypertension, ischaemic heart disease, atrial fibrillation or flutter, heart failure, ischaemic and haemorrhagic stroke as well as a coronary artery bypass grafting. Following womens first pregnancies and in sensitivity analyses, the HRs remained increased. For comparisons of VB-affected childbirths with terminations, HRs were up to 1.3-fold increased for diabetes and 1.1-fold increased for hypertension, ischaemic heart disease, atrial fibrillation or flutter, and haemorrhagic stroke. HRs were unity when we compared having a VB-affected childbirth with having a miscarriage.

ConclusionsWomens risks of diabetes types 1 and 2 and multiple cardiovascular outcomes were increased on the relative scale following childbirths affected by VB within 20 gestational weeks when compared with VB-unaffected childbirths and terminations, but not when compared with miscarriages.

O_TEXTBOXWHAT IS ALREADY KNOWN ON THIS TOPICO_LIVaginal bleeding is a common complication affecting up to 30% of clinically detected pregnancies.
C_LIO_LIAlthough an association between miscarriages and greater risk of cardiovascular events is known, the risk of cardiovascular outcomes following a childbirth complicated by vaginal bleeding not ending in a miscarriage is not well investigated.
C_LI

WHAT THIS STUDY ADDSO_LIThis nationwide registry-based cohort study with up to 40 years of follow-up showed that compared with having a childbirth without vaginal bleeding, having a childbirth with vaginal bleeding within 20 gestational weeks was associated with womans increased risk of diabetes types 1 and 2, hypertension, ischaemic heart disease, including myocardial infarction, atrial fibrillation or flutter, heart failure, coronary artery bypass grafting, ischaemic and haemorrhagic stroke.
C_LIO_LIThe cardiovascular risks were increased following womens first pregnancies and when additionally adjusted for smoking and body-mass index.
C_LIO_LIThe long-term cardiovascular risk profile of women with vaginal bleeding-affected childbirths was similar to that of women with miscarriages.
C_LI

C_TEXTBOX


title: Mobility was a Significant Determinant of Reported COVID-19 Incidence During the Omicron Surge in the Most Populous U.S. Counties

abstract:
BackgroundSignificant immune escape by the Omicron variant, along with the emergence of widespread worry fatigue, have called into question the robustness of the previously observed relation between population mobility and COVID-19 incidence.

MethodsWe employed principal component analysis to construct a one-dimensional summary indicator of six Google mobility categories. We related this mobility indicator to case incidence among 111 of the most populous U.S. counties during the Omicron surge from December 2021 through February 2022.

ResultsReported COVID-19 incidence peaked earlier and declined more rapidly among those counties exhibiting more extensive decline in mobility between December 20 and January 3. Based upon a fixed-effects, longitudinal cohort model, we estimated that every 1-percent decline in mobility between December 20 and January 3 was associated with a 0.63 percent decline in peak incidence during the week ending January 17 (95% confidence interval, 0.40-0.86 percent). Based upon a cross-sectional analysis including mean household size and vaccination participation as covariates, we estimated that the same 1-percent decline in mobility was associated with a 0.36 percent decline in cumulative reported COVID-19 incidence from January 10 through February 28 (95% CI, 0.18-0.54 percent).

ConclusionOmicron did not simply sweep through the U.S. population until it ran out of susceptible individuals to infect. To the contrary, a significant fraction managed to avoid infection by engaging in risk-mitigating behaviors. More broadly, the behavioral response to perceived risk should be viewed as an intrinsic component of the natural course of epidemics in humans.


title: Bone morphogenetic protein 2 is a new molecular target linked to nonalcoholic fatty liver disease with potential value as non-invasive screening tool.

abstract: Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being nonalcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about its involvement in NAFLD onset and progression. This study aimed to elucidate the impact of BMP2 in NAFLD pathophysiology. Hepatic and circulating levels of BMP2 were quantified in serum and liver specimens from 115 biopsy-proven NAFLD patients and 75 subjects with histologically normal liver (NL). In addition, BMP2 content and release was determined in cultured human hepatocytes upon palmitic acid (PA) overload. We found that BMP2 expression was abnormally increased in livers from NAFLD patients than in subjects with NL and this was reflected in higher serum BMP2 levels. Notably, we observed that PA upregulated BMP2 expression and secretion by human hepatocytes. An algorithm based on serum BMP2 levels and clinically relevant variables to NAFLD showed an AUROC of 0.886 (95%CI, 0.83-0.94) to discriminate NASH. We used this algorithm to develop SAN (Screening Algorithm for NASH): a SAN < 0.2 implied a low risk and a SAN [≥] 0.6 indicated high risk of NASH diagnosis. This proof-of-concept study shows BMP2 as a new molecular target linked to NAFLD and introduces SAN as a simple and efficient algorithm to screen individuals at risk for NASH.


title: How can instructions and feedback with external focus be shaped to enhance motor learning in children? A systematic review

abstract:
AimThis systematic review investigates the effectiveness of instructions and feedback with external focus applied with reduced frequency, self-controlled timing and/or in visual or auditory form, on the performance of functional gross motor tasks in children aged 2 to 18 with typical or atypical development.

MethodsFour databases (PubMed, Web of Science, Scopus, Embase) were systematically searched (last updated May 31st 2021). Inclusion criteria were: 1. children aged 2 to 18 years old; 2. Instructions/feedback with external focus applied with reduced frequency, self-controlled timing, and/or visual or auditory form as intervention, to learn functional gross motor tasks; 3. Instructions/feedback with external focus applied with continuous frequency, instructor-controlled timing, and/or verbal form as control; 4. performance measure as outcome; 5. (randomized) controlled studies. Article selection and risk of bias assessment (with the Cochrane risk of bias tools) was conducted by two reviewers independently. Due to heterogeneity in study characteristics and incompleteness of the reported data, a best-evidence synthesis was performed.

ResultsThirteen studies of low methodological quality were included, investigating effectiveness of reduced frequencies (n = 8), self-controlled timing (n = 5) and visual form (n = 1) on motor performance of inexperienced typically (n = 348) and atypically (n = 195) developing children, for acquisition, retention and/or transfer. For accuracy, conflicting or no evidence was found for most comparisons, at most time points. However, there was moderate evidence that self-controlled feedback was most effective for retention, and limited evidence that visual analogy was most effective for retention and transfer. To improve quality of movement, there was limited evidence that continuous frequency was most effective for retention and transfer.

ConclusionMore methodologically sound studies are needed to draw conclusions about the preferred frequency, timing or form. However, we cautiously advise considering self-controlled feedback, visual instructions, and continuous frequency.

RegistrationProspero CRD42021225723


title: TARGET-HF: Developing a model for detecting incident heart failure among symptomatic patients in general practice using routine health care data

abstract:
BackgroundTimely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data.

MethodsOur study involved a dynamic cohort of patients ([≥]35 years) who consulted their GP with either dyspnea and/or peripheral edema within the Amsterdam metropolitan area in 2011-2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor.

ResultsData from 31,905 patients were included (40% male, median age 60) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n=25,524) and validation (n=6,381) set. TARGET-HF attained a C-statistic of 0.853 (95%-CI:0.834-0.872) on the validation set, which proved to provide a better discrimination than C=0.822 for age alone (95% CI:0.801-0.842, p<0.001) and C=0.824 for the hospital-based model (95% CI:0.802-0.843, p<0.001).

ConclusionThe TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at time of GP consultation.

category: primary care research


title: Survey of nationwide public perceptions regarding acceptance of wastewater used for community health monitoring in the United States

abstract: During the coronavirus disease 2019 (COVID-19) pandemic researchers looked for evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in feces dissolved in wastewater samples to assess levels of infection across communities. This activity is known colloquially as sewer monitoring and called wastewater-based epidemiology in academic settings. When used for public health surveillance in the United States, wastewater monitoring is not regulated, although general ethical principles have been described. Prior to this study, no nationwide data existed regarding the publics perceptions of wastewater being used for community health monitoring. Using an online survey distributed to a representative sample of adults in the Unites States (N=3,083), we investigated the publics perceptions regarding what is monitored, where monitoring occurs, and privacy concerns related to wastewater monitoring as a public health surveillance tool. Further, the Privacy Attitudes Questionnaire assessed respondents general privacy boundaries. The results suggest that respondents supported using wastewater for health monitoring, but within some bounds. Participants were most likely to support or strongly support monitoring for disease (95%), environmental toxins (94%), and terroristic threats (90%, e.g., anthrax). Two-thirds of respondents endorsed no prohibition to locations being monitored while the most common category of location respondents wanted to be prohibited from monitoring was personal residencies. Additionally, the findings suggest that those younger in age and living in an urban area were more supportive of wastewater monitoring, compared to older, suburban dwellers.


title: Direct estimates of absolute ventilation in primary health care clinics in South Africa

abstract:
BackgroundHealthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis (Mtb). Natural ventilation can play an important role in reducing this transmission. In primary health care (PHC) clinics in low and middle-income settings, susceptible people, including healthcare workers, are exposed to individuals with infectious pulmonary tuberculosis. We measured rates of natural ventilation in PHC clinics in KwaZulu-Natal and Western Cape provinces, South Africa.

Methods and FindingsWe measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels, under reasonable assumptions about occupants metabolic rates. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. We used these ventilation rates to estimate the risk of Mtb transmission using the Wells-Riley Equation. We obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338-4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0-1451 m3/hr). Ventilation was better in permanent than in temporary structures. When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Our Wells-Riley estimates show that, following sustained exposure, or contact with highly infectious index cases, some risk of Mtb infection may persist in the best ventilated clinical spaces unless other components of transmission risk are also addressed.

ConclusionsAmong the clinical spaces studied, we observed substantial variation in natural ventilation. Ventilation interventions may have considerable impact on Mtb transmission in this setting. We recommend these form part of a package of infection prevention and control interventions.

category: occupational and environmental health


title: Immunogenomic profiling of lung adenocarcinoma reveals high-grade growth patterns are associated with an immunogenic tumor microenvironment

abstract: Lung cancer is the leading cause of cancer-related mortality in the United States. Lung adenocarcinoma (LUAD) is the most common subtype and the most epidemiologically and genetically heterogeneous. Pathologists have routinely observed phenotypic heterogeneity among LUAD primary tumors as reflected by distinct patterns of tumor growth. However, despite prior implications on the association of immune-genomic environment and prognosis, this information is not utilized clinically. Herein, applying multiplatform immune-genomic analysis, we investigate two distinct classification systems and demonstrate that high-grade patterns of growth are associated with a distinct immunogenic tumor microenvironment that is predicted with a favorable response to immunotherapy, a finding with growing importance in the era of adjuvant and neoadjuvant immunotherapy.

category: oncology


title: Monoclonal antibody and antiviral therapy for treatment of mild-to-moderate COVID-19 in pediatric patients

abstract: The recent surge of SARS-CoV-2 Omicron variant (B.1.1.529) coincided with new treatment options for mild-to-moderate Covid-19 in high-risk adolescents and adults. In this report we describe patient characteristics, treatment-related process measures and outcomes associated with early Covid-19 therapy in high-risk pediatric patients.


title: Modelling the impact of non-pharmaceutical interventions on workplace transmission of SARS-CoV-2 in the home-delivery sector

abstract:
ObjectiveWe aimed to use mathematical models of SARS-COV-2 to assess the potential efficacy of non-pharmaceutical interventions on transmission in the parcel delivery and logistics sector.

MethodsWe developed a network-based model of workplace contacts based on data and consultations from companies in the parcel delivery and logistics sectors. We used these in stochastic simulations of disease transmission to predict the probability of workplace outbreaks in this settings. Individuals in the model have different viral load trajectories based on SARS-CoV-2 in-host dynamics, which couple to their infectiousness and test positive probability over time, in order to determine the impact of testing and isolation measures.

ResultsThe baseline model (without any interventions) showed different workplace infection rates for staff in different job roles. Based on our assumptions of contact patterns in the parcel delivery work setting we found that when a delivery driver was the index case, on average they infect only 0.18 other employees, while for warehouse and office workers this went up to 0.93 and 2.58 respectively. In the large-item delivery setting this was predicted to be 0.83, 0.94, and 1.61 respectively. Nonetheless, the vast majority of simulations resulted in 0 secondary cases among customers (even without contact-free delivery). Our results showed that a combination of social distancing, office staff working from home, and fixed driver pairings (all interventions carried out by the companies we consulted) reduce the risk of workplace outbreaks by 3-4 times.

ConclusionThis work suggests that, without interventions, significant transmission could occur in these workplaces, but that these pose minimal risk to customers. We found that identifying and isolating regular close-contacts of infectious individuals (i.e. house-share, carpools, or delivery pairs) is an efficient measure for stopping workplace outbreaks. Regular testing can make these isolation measures even more effective but also increases the number of staff isolating at one time. It is therefore more efficient to combine these measures with social distancing and contact reduction interventions, as these reduce both transmission and the number of people needing to isolate.

IMPORTANCEDuring the COVID-19 pandemic the home-delivery sector has been vital to maintaining peoples access to certain goods, and sustaining levels of economic activity for a variety of businesses. However, this important work necessarily involves contact with a large number of customers as well as colleagues. This means that questions have often been raised about whether enough is being done to keep customers and staff safe. Estimating the potential risk to customers and staff is complex, but here we tackle this problem by building a model of workplace and customer contacts, from which we simulate SARS-CoV-2 transmission. By involving industry representatives in the development of this model, we have simulated interventions that have either been applied or considered, and so the findings of this study are extremely relevant to decisions made in that sector moving forward. Furthermore, we can learn generic lessons from this specific case study which apply to many types of shared workplace as well as highlighting implications of the highly stochastic nature of disease transmission in small populations.


title: Spatially constrained ICA enables robust detection of schizophrenia from very short resting-state fMRI data

abstract: Resting-state functional network connectivity (rsFNC) has shown utility for identifying characteristic functional brain patterns in individuals with psychiatric and mood disorders, providing a promising avenue for biomarker development. However, several factors have precluded widespread clinical adoption of rsFNC diagnostics, namely a lack of standardized approaches for capturing comparable and reproducible imaging markers across individuals, as well as the disagreement on the amount of data required to robustly detect intrinsic connectivity networks (ICNs) and diagnostically relevant patterns of rsFNC at the individual subject level. Recently, spatially constrained independent component analysis (scICA) has been proposed as an automated method for extracting ICNs standardized to a chosen network template while still preserving individual variation. Leveraging the novel scICA methodology, which solves the former challenge of standardized neuroimaging markers, we investigate the latter challenge of identifying a minimally sufficient data length for clinical applications of resting-state fMRI (rsfMRI). Using a dataset containing individuals with schizophrenia and controls (M = 310) as well as simulated rsfMRI, we evaluate the robustness of ICN and rsFNC estimates at both the subject- and group-level, as well as the performance of diagnostic classification, with respect to the length of the rsfMRI time course. We found individual estimates of ICNs and rsFNC from the full-length (5 minute) reference time course were sufficiently approximated with just 3-3.5 minutes of data (r = 0.85, 0.88, respectively), and significant differences in group-average rsFNC could be sufficiently approximated with even less data, just 2 minutes (r = 0.86). The results from the shorter clinical data were consistent with the results from the longer simulated data, reliably estimating both individual- and group-level metrics from the full-length (30 minute) reference with just 3-4 minutes of data (r = 0.85 - 0.88). Furthermore, we found a model trained on 2 minutes of data retained 97-98% classification accuracy relative to that of the full-length reference model. Our results suggest that clinical rsfMRI scans, when decomposed with scICA, could potentially be shortened to just 2-4 minutes without significant loss of individual rsFNC information or classification performance of longer scan lengths.

category: psychiatry and clinical psychology


title: Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project

abstract: Genomic sequencing of healthy newborns to screen for medically important genetic information has long been anticipated but data around downstream medical consequences are lacking. Among 159 infants randomized to the sequencing arm in the BabySeq Project, an unanticipated monogenic disease risk (uMDR) was discovered in 18 (11.3%). We assessed uMDR actionability by visualizing scores from a modified ClinGen Actionability SemiQuantitative Metric and tracked medical outcomes in these infants for 3-5 years. All uMDRs scored as highly actionable (mean 9, range: 7-11 on a 0-12 scale) and had readily available clinical interventions. In 4 cases, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 cases provided risk stratification for future surveillance. In 8 cases, uMDRs prompted screening for multiple at-risk family members. These results suggest that actionable uMDRs are more common than previously thought and support ongoing efforts to evaluate population-based newborn genomic screening.

category: genetic and genomic medicine


title: Phenotypic variability and Gastrointestinal Manifestations/Interventions for growth in Ogden syndrome (also known as NAA10-related Syndrome)

abstract: Our study of 61 children with Ogden Syndrome, an X-linked disorder due to NAA10 gene mutations, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure-to-thrive diagnostic range; although dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with OS includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in OS probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G-tube or GJ-tube fed probands demonstrates that G/GJ-tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if OS children are not tracking above the FTT range past 1 year of age despite such efforts, they should promptly undergo G-tube placement to avoid prolonged growth failure. If G-tubes are not immediately inducing weight gain after insertion, recommendations include altering formula, increasing caloric input, or exchanging a G-tube for a GJ-tube by means of a minimally invasive procedure. Future directions could include a prospective natural history study investigating whether G/GJ tube insertion affects the cognitive trajectory, rate of reaching developmental milestones, and GI symptomatology of OS children in a positive or negative manner.


title: Ticagrelor responsive platelet genes are associated with platelet function and bleeding

abstract:
Structured AbstractO_ST_ABSImportanceC_ST_ABSTicagrelor inhibits platelet function, prevents myocardial infarction, and causes bleeding. A comprehensive analysis of the on- and off-target platelet effects of ticagrelor that underlie its clinical effects is lacking.

ObjectiveTo test the hypothesis that platelet transcripts that change in response to ticagrelor exposure are associated with platelet function or bleeding.

DesignA discovery cohort of healthy volunteers were sequentially exposed to aspirin, aspirin washout, and ticagrelor. Messenger RNA sequencing (mRNAseq) of purified platelets was performed pre/post each exposure. We defined the ticagrelor exposure signature (TES) as the ratio of mean expression of up-vs. down-regulated genes by ticagrelor that were prioritized based on lasso regression, weighted gene co-expression networks, and isoform level analyses. A separate healthy cohort was recruited to validate ticagrelors effects on TES genes measured using Nanostring. Platelet function was measured at baseline and in response to ticagrelor exposure in all participants. Self-reported bleeding was systematically queried during periods of ticagrelor exposure.

SettingAn early phase, academic, clinical research unit.

ParticipantsSelf-reported, healthy volunteers age > 30 and < 75, non-smoking, taking no daily prescribed medications.

ExposuresTicagrelor (90 mg twice daily) and aspirin (81 mg/day and 325 mg/day) each for 4 weeks.

Main outcomes and measuresExpression levels of platelet messenger RNA, platelet count, mean platelet volume, and 9 different measures of ex vivo platelet function (aggregated into a previously described platelet function score), and self-reported bleeding at baseline and after each exposure.

ResultsIn the discovery cohort (n = 58, mean age 43, 39 female) platelet mRNAseq identified (FDR < 5%) 1820 up- and 1589 down-regulated genes associated with ticagrelor exposure. We prioritized 84 of these transcripts to calculate a TES score, which was increased by ticagrelor and unaffected by either dose of aspirin. In an independent cohort (n = 49, mean age 44, 24 female) we validated that ticagrelor exposure (beta = 0.48, SE = 0.08, p < 0.0001) increases TES scores. In combined analyses of discovery and validation cohorts, when TES levels were calculated using baseline platelet RNA, higher TES levels were associated with lower levels of baseline platelet function (meta-analysis beta = -0.60, standard error [SE] 0.29, P = 0.04) and self-reported bleeding during ticagrelor exposure (meta-analysis beta = 0.28, standard error [SE] = 0.14, P = 0.04). In contrast, we found no associations between bleeding with baseline platelet count, platelet volume, or platelet function.

Conclusions and RelevanceTicagrelor exposure reproducibly and specifically changes a set of platelet transcripts, the baseline levels of which are a biomarker for platelet function and bleeding tendency on ticagrelor.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the global effects of ticagrelor exposure on platelets beyond platelet inhibition?

FindingsIn an experimental human study of different antiplatelet therapies, we comprehensively characterized the effects of ticagrelor on platelet messenger RNA (mRNA). We found that 4 weeks of 90mg twice daily ticagrelor therapy specifically and reproducibly changes the levels of selected platelet mRNA. At baseline, volunteers with levels of platelet gene expression that mimic ticagrelor exposure had lower levels of platelet function and when exposed to ticagrelor a greater tendency for minor bleeding.

MeaningBy using ticagrelor exposure as a molecular probe, we identified a platelet RNA biomarker that may identify patients at higher risk for ticagrelor-associated bleeding.

category: cardiovascular medicine


title: AI-Augmented Clinical Decision Support in a Patient-Centric Precision Oncology Registry

abstract:
PurposexDECIDE is a clinical decision support system, accessed through a web portal and powered by a "Human-AI Team", that offers oncology healthcare providers a set of treatment options personalized for their cancer patients, and provides outcomes tracking through an observational research protocol. This article describes the xDECIDE process and the AI-assisted technologies that ingest semi-structured electronic medical records to identify and then standardize clinico-genomic features, generate a structured personal health record (PHR), and produce ranked treatment options based on clinical evidence, expert insights, and the real world evidence generated within the system itself.

MethodPatients may directly enroll in the IRB-approved pan-cancer XCELSIOR registry (NCT03793088). Patient consent permits data aggregation, continuous learning from clinical outcomes, and sharing of limited datasets within the research team. Assisted by numerous AI-based technologies, the xDECIDE team aggregates and processes patients electronic medical records, and applies multiple levels of natural language processing (NLP) and machine learning to generate a structured case summary and a standardized list of patient features. Next a ranked list of treatment options is created by an ensemble of AI-based models, called xCORE. The output of xCORE is reviewed by molecular pharmacologists and expert oncologists in a virtual tumor board (VTB). Finally a report is produced that includes a ranked list of treatment options and supporting scientific and medical rationales. Treating physicians can use an interactive portal to view all aspects of these data and associated reports, and to continuously monitor their patients information. The xDECIDE system, including xCORE, is self-improving; feedback improves aspects of the process through machine learning, knowledge ingestion, and outcomes-directed process improvement.

ResultsAt the time of writing, over 2,000 patients have enrolled in XCELSIOR, including over 650 with CNS cancers, over 300 with pancreatic cancer, and over 100 each with ovarian, colorectal, and breast cancers. Over 150 VTBs of CNS cancer patients and [~]100 VTBs of pancreatic cancer patients have been performed. In the course of these discussions, [~]450 therapeutic options have been discussed and over 2,000 consensus rationales have been delivered. Further, over 500 treatment rationale statements ("rules") have been encoded to improve algorithm decision making between similar therapeutics or regimens in the context of individual patient features. We have recently deployed the xCORE AI-based treatment ranking algorithm for validation in real-world patient populations.

ConclusionClinical decision support through xDECIDE is available for oncologists to utilize in their standard practice of medicine by enrolling a patient in the XCELSIOR trial and accessing xDECIDE through its web portal. This system can help to identify potentially effective treatment options individualized for each patient, based on sophisticated integration of real world evidence, human expert knowledge and opinion, and scientific and clinical publications and databases.

category: health informatics


title: Hospital length of stay in a mixed Omicron and Delta epidemic in New South Wales, Australia

abstract:
AimTo estimate the length of stay distributions of hospitalised COVID-19 cases during a mixed Omicron-Delta epidemic in New South Wales, Australia (16 Dec 2021 - 7 Feb 2022), and compare these to estimates produced over a Delta-only epidemic in the same population (1 Jul 2021 - 15 Dec 2022).

BackgroundThe distribution of the duration that clinical cases of COVID-19 occupy hospital beds (the  length of stay) is a key factor in determining how incident caseloads translate into health system burden as measured through ward and ICU occupancy.

ResultsUsing data on the hospital stays of 19,574 individuals, we performed a competing-risk survival analysis of COVID-19 clinical progression. During the mixed Omicron-Delta epidemic, we found that the mean length of stay for individuals who were discharged directly from ward without an ICU stay was, for age groups 0-39, 40-69 and 70+ respectively, 2.16 (95% CI: 2.12-2.21), 3.93 (95% CI: 3.78-4.07) and 7.61 days (95% CI: 7.31-8.01), compared to 3.60 (95% CI: 3.48-3.81), 5.78 (95% CI: 5.59-5.99) and 12.31 days (95% CI: 11.75-12.95) across the preceding Delta epidemic (15 Jul 2021 - 15 Dec 2021). We also considered data on the stays of individuals within the Hunter New England Local Health District, where it was reported that Omicron was the only circulating variant, and found mean ward-to-discharge length of stays of 2.05 (95% CI: 1.80-2.30), 2.92 (95% CI: 2.50-3.67) and 6.02 days (95% CI: 4.91-7.01) for the same age groups.

ConclusionsHospital length of stay was substantially reduced across all clinical pathways during a mixed Omicron-Delta epidemic compared to a prior Delta epidemic. These changes in length of stay have contributed to lessened health system burden despite greatly increased infection burden and should be considered in future planning of response to the COVID-19 pandemic in Australia and internationally.


title: Good recovery of immunization stress-related responses presenting as cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations

abstract:
BackgroundImmunization stress-related responses presenting as stroke-like symptoms may develop following COVID-19 vaccination. This study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination.

MethodsWe conducted a retrospective study of the secondary data of reported adverse events following COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score (i.e., defining the degree of severity/dependence, with higher scores indicating greater disability). The affected side was evaluated for associations with the injection site.

ResultsIn total, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (53.8%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 90% of those receiving ChAdOx1 recovered well (modified Rankin scores [≤]2, indicating slight or no disability).

ConclusionsImmunization stress-related responses presenting as stroke-like symptoms can develop following COVID-19 vaccination. Symptoms that are more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs.

category: neurology


title: Breakthrough Covid-19 cases despite tixagevimab and cilgavimab (Evusheld™) prophylaxis in kidney transplant recipients

abstract:
While the combination of casirivimab-imdevimab (Ronapreve Roche Regeneron) has been shown to confer satisfactory protection against the delta variant kidney transplant recipients (KTRs) with COVID-19, it has limited neutralizing activity against the current variants of concern (Omicron BA.1, BA.1.1 and BA.2). In contrast, cilgavimab-tixagevimab combination (Evusheld, Astra Zeneca) retains a partial neutralizing activity against omicron in vitro. We examined whether preexposure prophylaxis with Evusheld can effectively protect kidney transplant recipients (KTRs) against the Omicron variant.

Of the 416 KTRs who received intramuscular prophylactic injections of Evusheld (150 mg tixagevimab and 150 mg cilgavimab), 39 (9.4%) developed COVID-19. With the exception of one patient, all KTRs were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients, respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n=1). Viral neutralizing activity of the serum against BA.1 variant was negative in the 12 tested patients, suggesting that this prophylaxis strategy provides insufficient protection against this variant of concern.

Preexposure prophylaxis with Evusheld does not adequately protect KTRs against Omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.


title: Omicron Spread in Vaccinated Jurisdictions: a Statistical Study

abstract: A correlation hypothesis between the level of vaccination and the rate of spread of the new Covid-19 variant is investigated based on the case and vaccination data from European and North American jurisdictions available in the public domain at the time point of past the crest of the Omicron wave in most jurisdictions. Statistical variables describing the rate of the spread based on observed new case statistics defined and discussed. An unexpected moderate positive correlation between the rate of the variant spread measured by two related parameters and vaccination level based on the dataset in the study is reported. While negative correlation was not statistically excluded, the analysis of the data in the study statistically excluded moderate to strong negative correlation. The results of this work, if confirmed by further independent studies can have implications for development of policies aimed at controlling future course of the Covid-19 pandemic.

category: epidemiology


title: An investigation into the wellbeing of optometry students.

abstract:
IntroductionWellbeing is synonymous with positive mental health and impacts the efficacy of student learning. The wellbeing of optometry students is an understudied topic. The wellbeing of optometry students studying in a blended undergraduate course during the COVID-19 pandemic was also unknown. The aim of this study was to determine the status of optometry students wellbeing during COVID-19, by identifying their experiences of symptoms of anxiety and depression. Moreover, to determine to what extent students experience these symptoms and what specific factors influenced their wellbeing.

MethodologyParticipants from four year groups completed online questionnaires. The response rate was 78.38% (n=87). Zung self-rating depression and anxiety scale questionnaires were used to determine whether students identified with a given list of symptoms commonly linked to anxiety or depression. Through open ended questions students wellbeing was further investigated.

ResultsParticipants experienced normal levels of anxiety symptoms and most participants experienced mild to moderate depression symptoms. Of concern is the severe depression symptoms identified in the third and fourth year student cohorts. Mental health, Academics, Lifestyle, Relationships and Sleep were main themes identified that had an influence on the students general wellbeing. Uncertainty and Physical Health themes were additional influences of wellbeing specifically related to COVID-19.

ContributionThis preliminary study into wellbeing of optometry students was undertaken in a unique timeframe, due to the COVID-19 pandemic. The results provide a platform to determine baseline wellbeing in the future student cohorts and the exploratory identification of factors causing stress and anxiety. The impact of COVID-19 on the wellbeing of students is evident.

ConclusionOptometry students do experience symptoms of depression. COVID-19 has had considerable impact on their academic experience and their wellbeing.

category: medical education