title: Tracking white and grey matter degeneration along the spinal cord axis in degenerative cervical myelopathy

abstract:
ObjectiveTo determine tissue-specific neurodegeneration across the spinal cord in patients with mild-moderate degenerative cervical myelopathy (DCM).

MethodsTwenty-four mild-moderate DCM and 24 healthy subjects were recruited. In patients, a T2-weighted scan was acquired at the compression site, while in all participants a T2*-weighted and diffusion-weighted scan was acquired at the cervical level (C2-C3) and in the lumbar enlargement (i.e. rostral and caudal to the site of compression). We quantified intramedullary signal changes, maximal canal and cord compression, white (WM) and grey matter (GM) atrophy, and microstructural indices from diffusion-weighted scans. All patients underwent clinical (modified Japanese Orthopaedic Association (mJOA)) and electrophysiological assessments. Regression analysis assessed associations between MRI readouts and electrophysiological and clinical outcomes.

ResultsTwenty patients were classified with mild and four with moderate DCM using the mJOA scale. The most frequent site of compression was at C5-C6 level with maximum cord compression of 4.68{+/-}0.83 mm. Ten patients showed imaging evidence of cervical myelopathy. In the cervical cord, WM and GM atrophy and WM microstructural changes were evident, while in the lumbar cord only WM showed atrophy and microstructural changes. Remote cervical cord WM microstructural changes were pronounced in patients with radiological myelopathy and associated with impaired electrophysiology. Lumbar cord WM atrophy was associated with lower limb sensory impairments.

ConclusionTissue-specific neurodegeneration revealed by quantitative MRI, already apparent across the spinal cord in mild-moderate DCM prior to the onset of severe clinical impairments. WM microstructural changes are particularly sensitive to remote pathologically and clinically eloquent changes in DCM.


title: SCALP HIGH FREQUENCY OSCILLATION RATE DEPENDS ON SLEEP STAGE AND DECREASES WITH TIME SPENT IN SLEEP

abstract: High frequency oscillations (HFO) in scalp EEG are a new and promising epilepsy biomarker. HFO analysis is typically restricted to random and relatively brief sleep segments. However, considerable fluctuations of HFO rates have been observed over the recording nights, particularly in relation to sleep stages and cycles. Here, we identify the timing within the sleep period and the minimal data interval length that allow for sensitive and reproducible detection of scalp HFO. We selected 16 seizure-free whole-night scalp EEG recordings of children and adolescents with focal lesional epilepsy (median age 7.6 y, range 2.2-17.4 y). We used an automated and clinically validated HFO detector to determine HFO rates (80-250 Hz) in bipolar channels. To identify significant variability over different NREM sleep stages and over time spent in sleep, we modelled HFO rate as a Poisson process. We analysed the test-retest reliability to evaluate the reproducibility of HFO detection across recording intervals. Scalp HFO rates were higher in N3 than in N2 sleep and highest in the first sleep cycle, decreasing with time spent in sleep. In N3 sleep, the median reliability of HFO detection increased from 67% to 79% to 100% for 5-, 10-, and 15-min data intervals, improving significantly (p=0.004) from 5 to 10 min but not from 10 to 15 min. In this analysis of whole-night scalp EEG, we identified the first N3 sleep stage as the most sensitive time window for HFO rate detection. N3 data intervals of 10 min duration are required and sufficient for reliable measurements of HFO rates. Our study provides a robust and reliable framework for implementing scalp HFO as an EEG biomarker in pediatric epilepsy.

category: neurology


title: Adherence to the EAT-Lancet diet and risk of stroke and stroke subtypes: A Danish cohort study

abstract:
ObjectiveTo investigate the association between adherence to the EAT-Lancet diet, a sustainable and mostly plant-based diet, and risk of stroke and subtypes of stroke in a Danish population. For comparison, we also investigated the Alternate Healthy Eating Index-2010 (AHEI).

MethodsWe used the Danish Diet, Cancer and Health cohort (n=55,016) including adults aged 50-64 years at baseline (1993-1997). A food frequency questionnaire was used to assess dietary intake and group participants according to adherence to the diets. Stroke cases were identified using a national registry and subsequently validated by review of medical records (n=2253). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with the EAT-Lancet diet or the AHEI and risk of stroke and stroke subtypes.

ResultsAdherence to the EAT-Lancet diet was associated with a lower risk of stroke, although not statistically significant (highest vs lowest adherence: HR 0.91; 95% CI 0.76, 1.09). A lower risk was observed for the AHEI (0.75; 0.64, 0.87). For stroke subtypes we found that adherence to the EAT-Lancet diet was associated with a lower risk of subarachnoid hemorrhage (0.30; 0.12, 0.73) and the AHEI was associated with a lower risk of ischemic stroke (0.76; 0.64, 0.90) and intracerebral hemorrhage (0.58; 0.36, 0.93).

ConclusionsAdherence to the EAT-Lancet diet was associated with a lower risk of subarachnoid stroke and the AHEI was associated with a lower risk of total stroke, mainly ischemic stroke and intracerebral hemorrhage.

category: nutrition


title: Associations of genetic scores for birth weight with newborn size and later Anthropometric traits and cardiometabolic risk markers in South Asians

abstract: We recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1x10-11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P<0.01). Our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in different populations, despite phenotypic and environmental differences.

category: genetic and genomic medicine


title: Using Whole Genome Sequencing to Characterize Clinically Significant Blood Groups Among Healthy Older Australians

abstract:
There have been no comprehensive studies of a full range of blood group polymorphisms within the Australian population. The problem is compounded by the absence of any databases carrying genomic information on chronically transfused patients and low frequency blood group antigens in Australia. Here, we use RBCeq, a web server-based blood group genotyping software, to identify unique blood group variants among Australians and compare the variation detected versus global data. Whole genome sequencing data was analysed from for 2796 healthy older Australians from the Medical Genome Reference Bank and compared with data from 1000G phase 3 (1KGP3) databases comprising 661 African, 347 American, 503 European, 504 East Asian, and 489 South Asian participants. There were 688 rare variants detected in this Australian sample population, including nine variants that had clinical associations. Notably, we identified 149 variants that were computationally predicted to be novel and deleterious. No clinically significant rare or novel variants were found associated with the genetically complex ABO blood group system. For the Rh blood group system, one novel and 16 rare variants were found. Our detailed blood group profiling results provide a starting point for the creation of an Australian blood group variant database.

Key pointsO_LIWe identified unique blood group variants among the healthy older Australian population compared with global data using RBCeq software.
C_LIO_LIOur detailed blood group profiling result may be a starting point for the creation of an Australian blood group variant database.
C_LI

category: hematology


title: Single dose of BNT162b2 mRNA vaccine against SARS-CoV2 induces neutralizing antibody and polyfunctional T-cell responses in patients with CML

abstract:
Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including patients with Chronic Myeloid Leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS-CoV-2 BNT162b2 (Pfizer-BioNTech) vaccine have been raised.

We evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 CML patients. Seroconversion and cellular immune response prior and after vaccination were assessed.

By day 21 post-vaccination, anti-Spike IgG were detected in 14/16 (87.5%) of CML patients and all developed a neutralizing antibody response (ID50>50), including medium (ID50 of 200-500) or high (501-2000) neutralising antibodies titres in 9/16 (56.25%) patients. T cell response was seen in 14/15 (93.3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response 9/15, polyfunctional CD8+ T cell response 9/15).

These data demonstrate the immunogenicity of a single dose of SARS-CoV-2 BNT162b2 vaccine in most CML patients with both neutralizing antibodies and polyfunctional T-cell responses seen, in contrast to patients with solid tumour or lymphoid haematological malignancies.

FundingKings Together Rapid COVID-19 Call awards to MHM, KJD; A Huo Family Foundation Award to MHM, KJD; Chronic Disease Research Foundation award CDRF-22/2020 to KJD, MHM; Wellcome Trust Investigator Award 106223/Z/14/Z to MHM; CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1); Fondation Dormeur, Vaduz for funding equipment to KJD


title: Comparison of SARS-CoV-2 serological assays for use in epidemiological surveillance in Scotland

abstract:
BackgroundSero-surveillance of SARS-CoV-2 is crucial to monitoring levels of population exposure and informing public health responses, but may be influenced by variability in performance between available assays.

MethodsFive commercial immunoassays and a neutralising activity assay were used to detect antibodies to SARS-CoV-2 in routine primary care and paediatric samples collected during the first wave of the pandemic in NHS Lothian, Scotland as part of ongoing surveillance efforts. For each assay, sensitivity and specificity was calculated relative to consensus results and neutralising activity. Quantitative correlation was performed between serological and neutralising titres.

ResultsSeroprevalence ranged from 3.4-7.3 % in primary care patients and 3-5.9 % in paediatric patients according to different immunoassays. Neutralising activity was detectable in 2.8 % and 1.3 % respectively. Relative assay performance changed depending on comparison to immunoassay consensus versus neutralising activity and qualititative versus quantitative agreement. Cross-reactivity with endemic seasonal coronaviruses was confirmed by neutralising assay in false positives for one immunoassay. Presence of false positives for another assay was found specifically in paediatric but not adult samples.

ConclusionsFive serological assays show variable accuracy when applied to the general population, impacting seroprevalence estimates. Assay performance may also vary in detection of protective neutralising antibody levels. These aspects should be considered in assay selection and interpretation in epidemiological studies.

category: infectious diseases


title: Preexisting and new-onset diabetes in patients with COVID-19 pneumonia

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.

MethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.

ResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.

ConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.

category: endocrinology


title: Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia


title: Disaster preparedness among women with a recent live birth in Hawaii, a cross-sectional study, results from the Pregnancy Risk Assessment Monitoring System (PRAMS), 2016

abstract:
ObjectivesThis study examines emergency preparedness behaviors among women with a recent live birth in Hawaii.

MethodsUsing the 2016 Hawaii Pregnancy Risk Assessment Monitoring Survey we estimated weighted prevalence of eight preparedness behaviors.

ResultsAmong 1010 respondents (weighted response rate=56.3%), 79.3% reported at least one preparedness behavior and 11.2% performed all eight behaviors. The prevalence of women with a recent live birth in Hawaii reporting preparedness behaviors includes: 63.0% (95% CI: 58.7-67.1%) having enough supplies at home for at least seven days, 41.3% (95% CI: 37.1-45.6%) having an evacuation plan for their child(ren), 38.7% (95% CI: 34.5, 43.0) having methods to keep in touch, 37.8% (95% CI: 33.7, 42.1) having an emergency meeting place, 36.6% (95% CI: 32.6, 40.9) having an evacuation plan to leave home, 34.9% (95% CI: 30.9, 39.2) having emergencies supplies to take with if they have to leave quickly, 31.8% (95% CI: 27.9, 36.0) having copies of important documents, 31.6% (95% CI: 27.7, 35.8) having practiced what to do.

ConclusionOne in ten women practiced all eight behaviors indicating more awareness efforts are needed among this at-risk population in Hawaii. Hawaii can measure the effect of interventions to increase preparedness by tracking this question over time.

SignificanceO_ST_ABS"What is already known on this subject?"C_ST_ABSPreparedness is associated with reduced vulnerability, and postpartum women are considered an at-risk population in the post-disaster period with special clinical needs. One prior study has assessed disaster preparedness among postpartum women.

"What this study adds?"This is the first study to describe a methodology to analyze the eight-part PRAMS emergency preparedness question. Among recently postpartum women in Hawaii, about 80% practiced at least one of eight emergency preparedness measures assessed and about 10% practiced all behaviors.

category: epidemiology


title: Evolution of case fatality rates in the second wave of coronavirus in England: effects of false positives, a Variant of Concern and vaccination.

abstract:
1ObjectiveTo track the statistical case fatality rate (CFR) in the second wave of the UK coronavirus outbreak, and to understand its variations over time.

DesignPublicly available UK government data and clinical evidence on the time between first positive PCR test and death are used to determine the relationships between reported cases and deaths, according to age groups and across regions in England.

Main Outcome MeasuresEstimates of case fatality rates and their variations over time.

ResultsThroughout October and November 2020, deaths in England can be broadly understood in terms of CFRs which are approximately constant over time. The same CFRs prove a poor predictor of deaths when applied back to September, when prevalence of the virus was comparatively low, suggesting that the potential effect of false positive tests needs to be taken into account. Similarly, increasing CFRs are needed to match cases to deaths when projecting the model forwards into December. The growth of the S gene dropout VOC in December occurs too late to explain this increase in CFR alone, but at 33% increased mortality, it can explain the peak in deaths in January. Seasonal effects could be in part responsible for the early December increase in CFR, and if so, the estimate of increased mortality would be reduced. There is also evidence that the prevalence of B.1.1.7 may have been slower amongst older age groups, and if this is a factor, then 33% could be an underestimate of mortality. From the second half of January, the CFRs for older age groups show a marked decline. Since the fraction of the VOC has not decreased, this decline is likely to be the result of the rollout of vaccination. However, due to the rapidly decreasing nature of the raw cases, any imprecisions in the time-to-death distribution are magnified in this time period, rendering estimates of vaccinations effect less precise.

ConclusionsThe relationship between cases and deaths, even when controlling for age, is not static through the second wave of coronavirus in England. An apparently anomalous low case-fatality ratio in September can be accounted for by a 0.4% false-positive fraction. The rapid growth in CFR in December can be understood in part in terms of a more deadly new variant B.1.1.7, while a decline in January correlates with vaccine roll-out, suggesting that vaccine reduce the severity of infection, as well as the risk.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSThe case fatality rate (CFR) is a useful measure which enables one to estimate future deaths based on current infections. In England, there was a surge in Covid-19 CFR around the beginning of December.

What the study addsUsing it, we monitor the case-fatality rate across time, region and age group from publicly available case data. This quantity is related to the lethality of the virus. It shows a sharp increase in December 2020, which parallels the spread of the B.1.1.7 variant. The January peak in actual deaths matches that predicted by cases if B.1.1.7 is about 33% more deadly; this estimate would be lower if there is a seasonal effect on deaths, and higher if at the peak the variant was less pervasive amongst older age groups. A steady drop in CFR from January suggests that vaccination not only reduces transmission but also the risk of serious illness among those infected. It is notable that these conclusions are reached with publicly available data independent of clinical studies.


title: Quantifying malaria acquired during travel and its role in malaria elimination on Bioko Island

abstract:
BackgroundMalaria elimination is the goal for Bioko Island, Equatorial Guinea. Intensive interventions implemented since 2004 have reduced prevalence, but progress has stalled in recent years. A challenge for elimination has been malaria infections in residents acquired during travel to mainland Equatorial Guinea. We quantify how off-island contributes to remaining malaria prevalence on Bioko Island, and investigate the potential role of a pre-erythrocytic vaccine in making further progress towards elimination.

MethodsWe simulated malaria transmission on Bioko Island using a model calibrated based on data from the Malaria Indicator Surveys (MIS) from 2015-2018, including detailed travel histories and malaria positivity by rapid-diagnostic tests (RDTs), as well as geospatial estimates of malaria prevalence. Mosquito population density was adjusted to fit local transmission, conditional on importation rates under current levels of control and within-island mobility. We evaluated the impact of two pre-erythrocytic vaccine distribution strategies: mass treat and vaccinate, and prophylactic vaccination for off-island travelers. We propagated uncertainty through the model through an ensemble of simulations fit to the Bayesian joint posterior probability distribution of the geospatial prevalence estimates.

ResultsThe simulations suggest that in Malabo, an urban city containing 80% of the population, there are some pockets of residual transmission, but a large proportion of prevalence is attributable to malaria importation by travelers. Outside of Malabo, prevalence was mainly attributable to local transmission. We assess the uncertainty in the local transmission vs. importation to be lowest within Malabo and highest outside. Using a pre-erythrocytic vaccine to protect travelers would have larger benefits than using the vaccine to protect residents of Bioko Island from local transmission. In simulations, mass treatment and vaccination had short-lived benefits, as malaria prevalence returned to current levels as the vaccines efficacy waned. Prophylactic vaccination of travelers resulted in longer-lasting reductions in prevalence. These projections were robust to underlying uncertainty in prevalence estimates.

ConclusionsThe modeled outcomes suggest that the volume of malaria cases imported from the mainland is a partial driver of continued endemic malaria on Bioko Island, and that continued elimination efforts on must account for human travel activity.


title: Strategies for COVID-19 vaccination under a shortage scenario: a geo-stochastic modelling approach.

abstract: In a world being hit by waves of COVID-19, vaccination is a light on the horizon. However, the roll-out of vaccination strategies and their influence on the pandemic are still open problems. In order to compare the effect of various strategies proposed by the World Health Organization and other authorities, a previously developed SEIRS stochastic model of geographical spreading of the virus is extended by adding a compartment for vaccinated people. The parameters of the model were fitted to describe the pandemic evolution in Argentina, Mexico and Spain to analyze the effect of the proposed vaccination strategies. The mobility parameters allow to simulate different social behaviors (e.g. lock-down interventions). Schemes in which vaccines are applied homogeneously in all the country, or limited to the most densely-populated areas, are simulated and compared. The second strategy is found to be more effective. Moreover, under the current global shortage of vaccines, it should be remarked that immunization is enhanced when mobility is reduced. Additionally, repetition of vaccination campaigns should be timed considering the immunity lapse of the vaccinated (and recovered) people. Finally, the model is extended to include the effect of isolation of detected positive cases, shown to be important to reduce infections.


title: Preliminary study on the pathogenesis of anal fistula

abstract:
BACKGROUNDAnal gland infection is one of the main pathogenic factors of anal fistula. The anal gland is mainly consist of columnar epithelial cells and goblet cells. Goblet cells could secrete mucins which maintain the surface mucous gel layer of intestine to prevent columnar epithelial cells from the direct acting of bacteria. The absence or diminished secretion of goblet cells could lead to the exposure of columnar epithelial cells to bacteria. In recent years, studies have found that most of the microorganisms in perianal abscess and anal fistula are intestinal bacteria. So, it can be considered that the occurrence and development of anal fistula is closely related to gut microbiota. However, the molecular mechanism of gut microbiota acting on the epithelial cells of anal gland leading to the occurrence and development of anal fistula has not been explored.

METHODSAnal fistula tissues were collected from 30 patients, and HE staining was employed to observe pathological changes of anal gland. Stool specimens were collected from normal group (14 normal subjects), preoperative group (21 subjects before surgery) and postoperative group (16 subjects after surgery). High-throughput 16S rRNA gene sequencing was performed to explore differences among different groups.

RESULTSIt was found by HE staining that normal anal gland is composed of a large number of columnar epithelial cells as well as goblet cells, while the anal gland of patients with anal fistula is seriously lack of goblet cells. In the normal ones, a large number of vacuoles formed by the dye dissolution of mucin particles can be seen at the top of the goblet cells, and a large amount of mucin secretion can be seen in the center of the anal gland. The results of high-throughput 16S rRNA gene sequencing showed that there were significant statistical differences in species richness, species evenness and species composition between the preoperation group and the normal group (P1 =0.00004), and between the preoperative group and the postoperative group (P2 =0.00003). It also showed that PWY-6471 metabolic pathway was the most significant difference between the preoperative group and the postoperative group (P=0.0033).

CONCLUSIONSThe occurrence of anal fistula may be related to the abnormal permeability of mucus layer and the change of intestinal flora composition. The absence or diminished secretion of goblet cells may cause exception of the permeability of mucus layer which makes the columnar epithelial cells of anal gland exposed to the direct contact of peptidoglycan. The metabolite of pathogenic microorganisms could activate the signal pathway (i.g. NLR/NF-{kappa}B) which leading to the overexpression of inflammatory factors and cause anal fistula.

category: gastroenterology


title: Post-vaccination SARS-CoV-2 infections and incidence of the B.1.427/B.1.429 variant among healthcare personnel at a northern California academic medical center

abstract:
BackgroundDistribution of mRNA-based SARS-CoV-2 vaccines to healthcare personnel (HCP) in the United States began in December 2020, with efficacy > 90%. However, breakthrough infections in fully vaccinated individuals have been reported. Meanwhile, multiple SARS-CoV-2 variants of concern have emerged worldwide, including the B.1.427/B.1.429 variant first described in California. Little is known about the real-world effectiveness of the mRNA-based SARS-CoV-2 vaccines against novel variants including B.1.427/B.1.429.

MethodsIn this quality improvement project, post-vaccine SARS-CoV-2 cases (PVSCs) were defined as individuals with positive SARS-CoV-2 nucleic acid amplification test (NAAT) after receiving at least one dose of a SARS-CoV-2 vaccine. Chart extraction of demographic and clinical information was performed, and available specimens meeting cycle threshold value criteria were tested for L452R, N501Y and E484K mutations by RT-PCR.

ResultsFrom December 2020 to March 2021, 189 PVSCs were identified out of 22,729 healthcare personnel who received at least one dose of an mRNA-based SARS-CoV-2 vaccine. Of these, 114 (60.3%) occurred within 14 days of first vaccine dose (early post-vaccination), 49 (25.9%) within 14 days of the second vaccine dose (partially vaccinated), and 26 (13.8%) >14 days after the second dose (fully vaccinated). Of 115 samples available for mutation testing, 42 were positive for L452R alone, presumptive of B.1.427/B.1.429; three had N501Y mutation alone and none were found with E484K mutation. Though on univariate analysis partially- and fully-vaccinated PVSCs were more likely than early post-vaccination PVSCs to be infected with presumptive B.1.427/B.1.429, when adjusted for community prevalence of B.1.427/B.1.429 at the time of infection, partially- and fully-vaccinated PVSC did not have statistically significantly elevated risk ratios for infection with this variant (RR 1.40, 95% CI 0.81-2.43 and RR 1.13, 95% CI 0.59-2.16, respectively).

ConclusionsThe great majority of PVSCs occurred prior to the expected onset of full, vaccine-derived immunity. Although the B.1.427/B.1.429 variant did not represent a significantly higher proportion of PVSCs than expected, numbers were small and there was a trend towards higher representation in the partially- and fully-vaccinated subset. Continued infection control measures in the workplace and in the community including social distancing and masking, particularly in the early days post-vaccination, as well as continued variant surveillance in PVSCs, is imperative in order to anticipate and control future surges of infection.


title: Previous COVID-19 infection but not Long-COVID is associated with increased adverse events following BNT162b2/Pfizer vaccination

abstract:
ImportanceUnderstanding Adverse Events (AEs) associated with SARS-CoV-2 vaccination has public health implications, especially with regards to vaccine hesitancy.

ObjectiveTo establish whether individuals with prior history of COVID-19 were more likely to experience AEs after BNT162b2/Pfizer vaccination, than those without previous COVID-19, and whether COVID-19-vaccination interval influenced AE severity.

DesignAn observational study explored AEs after vaccination. Participants were invited to complete an electronic survey, capturing self-reported COVID-19 symptoms, PCR/antibody results, and AEs following first dose of BNT162b2/Pfizer vaccine. In a subset where PCR/antibody results could be verified, a sensitivity analysis was conducted.

SettingThree North-East England hospital Trusts in the United Kingdom.

ParticipantsHealthcare workers formed an opportunistic sample - 265 of 974 reported prior positive SARS-CoV-2 PCR and/or antibody.

ExposureAll participants had received their first dose of BNT162b2/Pfizer vaccine.

Main Outcomes and MeasuresNature, severity, duration, and onset of self-reported AEs (reported via a modified version of the FDA Toxicity Grading Scale for vaccine-associated AEs), was compared between those with and without a prior history of COVID-19, using 2-way ANCOVA and logistic regression. Effects of age, gender, illness-vaccine interval, and ongoing symptoms ( Long-COVID) on AEs, were also explored.

ResultsOf 974 respondents (81% female, mean age 48), 265 (27%) reported previous COVID-19 infection. Within this group (symptoms median 8.9 months pre-vaccination), 30 (11%) complained of Long-COVID. The proportion reporting one moderate/severe symptom was higher in the previous COVID-19 group (56% v 47%, OR=1.5 [95%CI, 1.1-2.0], p=.009), with fever, fatigue, myalgia-arthralgia and lymphadenopathy significantly more common. There was no significant relationship between illness-vaccine interval and symptom composite score (rs=0.09, p=.44). Long-COVID was not associated with worse AEs in comparison to the group without previous COVID-19. In the smaller sensitivity analysis cohort (412 people) similar findings were obtained although only myalgia and arthralgia remained significant.

Conclusions and RelevancePrior COVID-19 infection but not ongoing Long-COVID symptoms were associated with an increase in the risk of self-reported adverse events following BNT162b2/Pfizer vaccination. COVID-19 illness-vaccination interval did not significantly influence AEs. This data can support education around vaccine-associated AEs and, through improved understanding, help to combat vaccine hesitancy.

Key PointsO_ST_ABSQuestionC_ST_ABSDoes previous COVID-19 infection or  Long-COVID increase the frequency of Adverse Events (AEs) following first dose of BNT162b2/Pfizer vaccination?

FindingsIn a survey-based observational study, healthcare workers in the United Kingdom reported AEs experienced after their first dose of BNT162b2/Pfizer vaccine. Prior COVID-19 infection, but not Long-COVID, were associated with increased risk of self-reported AEs including lymphadenopathy post-vaccination. Duration since COVID-19 infection did not affect severity of AEs.

MeaningOur study can inform education and understanding of AEs associated with COVID-19 vaccination and help to combat vaccine hesitancy.


title: Association of in-hospital use of ACE-I/ARB and COVID-19 outcomes in African American population

abstract:
ImportanceThe ACE D allele is more prevalent among African Americans (AA) compared to other races/ethnicities and has previously been associated with severe COVID-19 pathogenesis through excessive ACE1 activity. ACE-I/ARBs may counteract this mechanism, but their association with COVID-19 outcomes has not been specifically tested in the AA population.

ObjectivesTo determine whether the use of ACE-I/ARBs is associated with COVID-19 in-hospital mortality in AA compared with non-AA population.

Design, Setting, and ParticipantsIn this observational, retrospective study, patient-level data were extracted from the Mount Sinai Health Systems (MSHS) electronic medical record (EMR) database, and 6,218 patients with a laboratory-confirmed COVID-19 diagnosis from February 24 to May 31, 2020 were identified as ACE-I/ARB users.

ExposuresPatients with an active prescription from January 1, 2019 up to the date of admission for ACE-I/ARB (outpatient use) and patients administered ACE-I/ARB during hospitalization (in-hospital use) were identified.

Main Outcomes and MeasuresThe primary outcome was in-hospital mortality, assessed in the entire, AA, and non-AA population.

ResultsOf the 6,218 COVID-19 patients, 1,138 (18.3%) were ACE-I/ARB users. In a multivariate logistic regression model, ACE-I/ARB use was independently associated with reduced risk of in-hospital mortality in the entire population (OR, 0.655; 95% CI, 0.505-0.850; P=0.001), AA population (OR, 0.44; 95% CI, 0.249-0.779; P=0.005), and non-AA population (OR, 0.748, 95% CI, 0.553-1.012, P=0.06). In the AA population, in-hospital use of ACE-I/ARBs was associated with improved mortality (OR, 0.378; 95% CI, 0.188-0.766; P=0.006) while outpatient use was not (OR, 0.889; 95% CI, 0.375-2.158; P=0.812). When analyzing each medication class separately, ARB in-hospital use was significantly associated with reduced in-hospital mortality in the AA population (OR, 0.196; 95% CI, 0.074-0.516; P=0.001), while ACE-I use was not associated with impact on mortality in any population.

Conclusion and RelevanceIn-hospital use of ARBs was associated with a significant reduction in in-hospital mortality among COVID-19-positive AA patients. These results support further investigation of ARBs to improve outcomes in AA patients at high risk for COVID-19-related mortality.


title: Mid-Regional pro-Adrenomedullin (MR-proADM), C-Reactive Protein (CRP) and Other Biomarkers in the Early Identification of Disease Progression in COVID-19 Patients in the Acute NHS Setting

abstract:
AimsThere is a lack of biomarkers validated for assessing clinical deterioration in COVID-19 patients upon presentation to secondary or tertiary care. This evaluation looked at the potential clinical application of C-Reactive Protein, Procalcitonin, Mid-Regional pro-adrenomedullin (MR-proADM) and White Cell Count to support prediction of clinical outcomes.

Methods135 patients presenting to Hampshire Hospitals NHS Foundation Trust between April and June 2020 confirmed to have COVID-19 via RT-qPCR were included. Biomarkers from within 24 hours of admission were used to predict disease progression by Cox regression and area under the receiver operating characteristic (AUROC) curves. The endpoints assessed were 30-day all-cause mortality, intubation and ventilation, critical care admission and non-invasive ventilation (NIV) use.

ResultsElevated MR-proADM was shown to have the greatest ability to predict 30-day mortality adjusting for age, cardiovascular, renal and neurological disease. A significant association was also noted between raised MR-proADM and CRP concentrations and the requirement for critical care admission and non-invasive ventilation.

ConclusionsThe measurement of MR-proADM and CRP in patients with confirmed COVID-19 infection upon admission shows significant potential to support clinicians in identifying those at increased risk of disease progression and need for higher level care, subsequently enabling prompt escalation in clinical interventions.


title: Impact of COVID-19 restrictions on diabetes health checks and prescribing for people with type 2 diabetes: a UK-wide cohort study involving 618,161 people in primary care

abstract:
OBJECTIVETo compare rates of performing NICE-recommended health checks and prescribing in people with type 2 diabetes (T2D), before and after the first COVID-19 peak in March 2020, and to assess whether trends varied by age, sex and deprivation.

METHODSWe constructed a cohort of 618,161 people with T2D followed between March and December 2020 from 1744 UK general practices registered with the Clinical Practice Research Datalink (CPRD; Aurum and GOLD databases). We focused on the following six health checks and prescribing: HbA1c, serum creatinine, cholesterol, urinary albumin excretion, blood pressure and BMI assessment, comparing trends using regression models and 10-year historical data.

RESULTSIn April 2020, in English practices, rates of performing health checks were reduced by 76-88% when compared to 10-year historical trends, with older people from deprived areas experiencing the greatest reductions. Between May and December 2020, the reduced rates recovered gradually but overall remained 28% and 47% lower compared to historical trends, with similar findings in other UK nations. In England, rates of prescribing of new medication fell during April with reductions varying from 10% (4-16%) for antiplatelet agents to 60% (58-62%) for antidiabetic medications. Overall, between March and December 2020, the overall rate of prescribing new diabetes medications was reduced by 19% (15-22%) and new antihypertensive medication by 22% (18-26%). Similar trends were observed in other UK nations, except for a reduction in new lipid-lowering therapy prescribing March to December 2020 (reduction: 16% (10-21%)).

CONCLUSIONSOver the coming months, healthcare services will need to manage this backlog of testing and prescribing. Effective communications should ensure that patients remain engaged with diabetes services, monitoring and opportunities for prescribing, and make use of home monitoring and remote consultations.


title: COVID-19 risk assessment for the Tokyo Olympic Games

abstract:
ObjectivesTo explore effective prevention and control measures for Coronavirus Disease 2019 (COVID-19) in large international events through simulations of different interventions according to risk assessment.

MethodsWe used random model to calculate the number of initial infected patients. And Poisson distribution was used to determine the number of initial infected patients based on the number of countries involved. Further, to simulate the COVID-19 transmission, the susceptible-exposed-symptomatic-asymptomatic-recovered-hospitalized (SEIARH) model was established based on susceptible-exposed-infectious-recovered (SEIR) mathematical model of epidemic diseases. According to risk assessment indicators produced by different scenarios of the simulated interventions, the risk of COVID-19 transmission in Tokyo Olympic Games was assessed.

ResultsThe large-scale vaccination will effectively control the spread of COVID-19. If the effective rate of vaccine is 100%, and the vaccination rate of athletes reaches 80%, an epidemic prevention barrier can be established.

ConclusionsThe current COVID-19 prevention measures proposed by the Japan Olympic Committee were needed to be enhanced. For the vaccination intervention had the best control effect, a mass vaccination serves was an effective way to control COVID-19.

category: public and global health


title: Understanding the barriers to pooled SARS-CoV-2 testing in the United States

abstract: Pooled testing for SARS-CoV-2 detection is instrumental for increasing test capacity while decreasing test cost, key factors for sustainable, long-term surveillance measures. While numerous pooled approaches have been described, uptake by labs has been limited. We surveyed 90 US labs to understand the barriers to implementing pooled testing.


title: Patient symptoms and experience following COVID-19: results from a UK wide survey

abstract:
ObjectivesTo investigate the experience of people who continue to be unwell after acute COVID-19, often referred to as  long COVID, both in terms of their symptoms and their interactions with healthcare.

DesignWe conducted a mixed-methods analysis (quantitative and qualitative) of responses to a survey accessed through a UK online post-COVID support and information hub between April 2020 and December 2020 about peoples experiences after having acute COVID-19.

ParticipantsOf 3290 respondents, 78% were female, median age range 45-54 years, 92.1% reported white ethnicity; 12.7% had been hospitalised. 494 respondents (16.5%) completed the survey between 4 and 8 weeks of the onset of their symptoms, 641 (21.4%) between 8 and 12 weeks and 1865 (62.1%) more than 12 weeks after.

ResultsThe ongoing symptoms most frequently reported were; breathing problems (92.1%), fatigue (83.3%), muscle weakness or joint stiffness (50.6%), sleep disturbances (46.2%), problems with mental abilities (45.9%) changes in mood, including anxiety and depression (43.1%) and cough (42.3%). Symptoms did not appear to be related to the severity of the acute illness or to the presence of pre-existing medical conditions. Analysis of free text responses revealed three main themes (1) Experience of living with COVID-19 - physical and psychological symptoms that fluctuate unpredictably; (2) Interactions with healthcare; (3) Implications for the future - their own condition, society and the healthcare system and the need for research

ConclusionPeople living with persistent problems after the acute phase of COVID-19 report multiple and varying symptoms that are not necessarily associated with initial disease severity or the presence of pre-existing health conditions. Many have substantial unmet needs and experience barriers to accessing healthcare. Consideration of patient perspective and experiences will assist in the planning of services to address this.

Ethical approvalEthical approval was granted by Imperial College Research and Integrity Team (IREC; 20IC6625).

What we already know on this subjectO_LIMany people who develop COVID-19 will go on to endure persistent symptoms past the acute phase of the disease, commonly termed long-COVID.
C_LIO_LIKnowledge gaps exist regarding the lived experience and symptom frequency, in people with long-COVID, particularly in those who were not admitted to hospital during the acute phase of their illness.
C_LI

What this study addsO_LIThe findings from this large population, many of whom were not hospitalised during the acute phase of their illness, demonstrate the varying patterns and persistence of symptoms of long-COVID, which do not appear to be associated with severity of the acute phase of the disease or pre-existing medical conditions.
C_LIO_LIQualitative findings revealing the patient experience of long-COVID symptoms, healthcare, and suggestions for future research and service adaptation.
C_LI


title: Effects of BNT162b2 mRNA vaccine on Covid-19 infection and hospitalisation among older people: matched case control study for England

abstract:
BackgroundThe BNT162b2 mRNA vaccine has been shown to be effective at preventing serious Covid-19 events in clinical trials. There is less evidence on effectiveness in real-world settings, especially for older people. The rapid roll-out of the NHS vaccination programme in England based on age thresholds offers an opportunity to make unbiased comparisons of outcomes between vaccinated and unvaccinated populations.

Methods and FindingsWe matched older (aged 80-83 years) vaccine recipients with younger (aged 76-79 years) persons not yet eligible to receive the vaccine on gender, area of residence, area deprivation, health status, living arrangements, acute illness, and history of seasonal flu vaccination. We also adjusted for the over-representation of Covid-19 positive individuals in the control population because eligibility for vaccination required no Covid-19 symptoms in the previous two weeks. The study population included 170,226 individuals between the ages of 80 and 83 years from community settings outside care homes who received one dose of BNT162b2 mRNA between the 15th and 20th December 2020 and were scheduled a second dose 21 days later.

We found emergency hospital admissions were 51.0% (95% confidence interval: 19.9% to 69.5%) lower and positive Covid-19 tests were 55.2% (40.8% to 66.8%) lower for vaccinated individuals compared to matched controls 21 to 27 days after first vaccination. Emergency admissions were 75.6% (52.8% to 87.6%) lower and positive Covid-19 tests were 70.1% (55.1% to 80.1%) lower 35 to 41 days after first vaccination when 79% of participants had received a second dose within 26 days of their first dose.

ConclusionsReceipt of the BNT162b2 mRNA vaccine is effective at reducing Covid-19 hospitalisations and infections. The nationwide vaccination of older adults in England with the BNT162b2 mRNA vaccine reduced the burden of Covid-19.


title: Modelling to inform the COVID-19 response in Bangladesh

abstract:
BackgroundNon-pharmaceutical interventions (NPIs) used to limit SARS-CoV-2 transmission vary in their feasibility, appropriateness and effectiveness in different contexts. In Bangladesh a national lockdown implemented in March 2020 exacerbated poverty and was untenable long-term, and a resurgence in 2021 warranted renewed NPIs.

MethodsWe developed an SEIR model for Dhaka District, parameterised from literature values and calibrated to data from Bangladesh. We discussed scenarios and parameterisations with policymakers with the aid of an interactive app. These discussions guided modelling of lockdown and two post-lockdown measures considered feasible to deliver; symptoms-based household quarantining and compulsory mask-wearing. We examined how testing capacity affects case detection, and compared NPI scenarios on deaths, hospitalisations relative to capacity, working days lost, and cost-effectiveness.

ResultsLockdowns alone were predicted to delay the first epidemic peak but could not prevent overwhelming of the health service and were costly in lost working days. Impacts of post-lockdown interventions depended heavily on compliance. Assuming 80% compliance, symptoms-based household quarantining alone could not prevent hospitalisations exceeding capacity, whilst mask-wearing prevented overwhelming health services and was cost-effective given masks of high filtration efficiency. Combining masks with quarantine increased their impact. Even at maximum testing capacity, confirmed cases far underestimate total cases. Recalibration to surging cases in 2021 suggests potential for another wave later in 2021, dependent on uncertainties in case reporting and immunity.

ConclusionsMasks and symptoms-based household quarantining synergistically prevent transmission, and are cost-effective in Bangladesh. Our interactive app was valuable in supporting decision-making, with mask-wearing being mandated early, and community teams being deployed to support quarantining across Dhaka. These measures likely contributed to averting the worst public health impacts, but delivering an effective response at scale has been challenging. Messaging to increase compliance with mask-wearing and quarantine is needed to reduce the risk and impacts from another wave.


title: Spatial aggregation choice in the era of digital and administrative surveillance data

abstract:
BackgroundTraditional disease surveillance is increasingly being complemented by data from non-traditional sources like medical claims, electronic health records, and participatory syndromic data platforms. As non-traditional data are often collected at the individual-level and are convenience samples from a population, choices must be made on the aggregation of these data for epidemiological inference. Our study seeks to understand the influence of spatial aggregation choice on our understanding of disease spread with a case study of influenza-like illness in the United States.

MethodsUsing U.S. medical claims data from 2002 to 2009, we examined the epidemic source location, onset and peak season timing, and epidemic duration of influenza seasons for data aggregated to the county and state scales. We also compared spatial autocorrelation and tested the relative magnitude of spatial aggregation differences between onset and peak measures of disease burden.

ResultsWe found discrepancies in the inferred epidemic source locations and estimated influenza season onsets and peaks when comparing county and state-level data. Spatial autocorrelation was detected across more expansive geographic ranges during the peak season as compared to the early flu season, and there were greater spatial aggregation differences in early season measures as well.

ConclusionsEpidemiological inferences are more sensitive to spatial scale early on during U.S. influenza seasons, when there is greater heterogeneity in timing, intensity, and geographic spread of the epidemics. Users of non-traditional disease surveillance should carefully consider how to extract accurate disease signals from finer-scaled data for early use in disease outbreaks.


title: Public Perception of COVID-19 Vaccines through Analysis of Twitter Content and Users

abstract: Twitter is a robust medium to understand wide-scale, organic public perception about the COVID-19 vaccine. In this cross-sectional observational study, we evaluated 2.4 million English tweets from nearly 1 million user accounts matching keywords (( covid* OR  coronavirus) AND  vaccine) during vaccine development from Feb 1st through Dec 11th, 2020. We applied topic modeling, sentiment and emotion analysis, and demographic inference of users on the COVID-19 vaccine related tweets to provide insight into the evolution of public attitudes. Individuals generated 87.9% (n=834,224) of tweets. Of individuals, men (n=560,824) outnumbered women (n=273,400) by 2:1 and 39.5% (n=329,776) of individuals were [≥] 40 years old. Daily mean sentiment fluctuated congruent with news events, but overall trended positively. Trust, anticipation, and fear were the three most predominant emotions; while fear was the most predominant emotion early in the study period, trust outpaced fear from April 2020 onward. Fear was more prevalent in tweets by individuals (26.3% vs. organizations 19.4%; p<0.001), specifically among women (28.4% vs. males 25.4%; p <0.001). Multiple topics had a monthly trend towards more positive sentiment. Tweets comparing COVID-19 to the influenza vaccine had strongly negative early sentiment but improved over time. Our findings are concerning for COVID-19 vaccine hesitancy, but also identify targets for educational interventions.


title: Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants

abstract:
BackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.

MethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.

ResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.

ConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.

category: ophthalmology


title: Pathogenic Neurofibromatosis type 1 (NF1) RNA-splicing resolved by targeted RNAseq

abstract:
PurposeNeurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. A targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants.

MethodsRNA was extracted from lymphocytes, followed by targeted NF1 RNAseq. An in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event.

ResultsThis method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%).

ConclusionTargeted NF1 RNAseq can be successfully used to detect pathogenic RNA splicing variants, complementary to DNA based diagnostics.


title: Genetic liability for substance use associated with medical comorbidities in electronic health records of African- and European-ancestry individuals

abstract: Polygenic risk scores (PRS) represent an individuals summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record-based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N=18,612). Finally, we conducted phenome-wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross-trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes, however they are not yet predictive enough to be useful diagnostically. The cross-trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse.


title: Assessing genetic overlap and causality between blood plasma proteins and Alzheimer's Disease

abstract:
Background Blood plasma proteins are modifiable and have been associated with Alzheimers disease (AD), but understanding which proteins are on the causal pathway remains challenging.

ObjectiveInvestigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian Randomization (MR).

MethodsFollowing a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritised proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR.

ResultsFor APOE e3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p-value <0.00017). No protein APOE-PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p-value=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p-value=0.025, protein APOE-PRS p-value=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the 5 proteins demonstrated a causal association (p-value<0.05) in either direction.

ConclusionApolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, modifiable risk factor. Whilst evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.


title: Dissatisfaction with family members' medical care: the relationship with trust in personal physicians and physicians generally in Japan

abstract: Negative experiences with medical care have long-term effects on family members attitudes and emotions. However, the impact of family members experiences on patients trust in their physicians and in physicians generally is poorly understood. We aimed to quantify these associations. Our cross-sectional online survey, conducted in Japan during April 2020, involved adults with non-communicable diseases (cardiac disease, diabetes, cancer, depression, and rheumatic disease). The main exposure variable was dissatisfaction with the medical care that family members had received. The main outcomes were patients (N=661) trust in their personal physicians and in physicians generally. The study adopted the Japanese version of the Abbreviated Wake Forest Physician Trust Scales. We translated and validated both 5-item scales (general and individual physician trust) for the study. The results showed a lower rating for trust in physicians generally compared to trust in the respondents personal physician. Furthermore, dissatisfaction with a family members medical care was associated with lower trust in physicians generally. Interestingly, dissatisfaction with a family members care was also associated with lower trust in the respondents personal physician, but the magnitude of this association was weaker. The lower trust in personal physicians may be mediated by reduced trust in physicians generally. We suggest that physicians enquire about past patients negative experiences, including dissatisfaction with family members medical care, to repair hidden loss of trust, when they sense that patients doubt them or physicians generally.

category: health systems and quality improvement


title: Evaluation of a novel, rapid antigen detection test for the diagnosis of SARS-CoV-2

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is currently finally determined in laboratory settings by real-time reverse-transcription polymerase-chain-reaction (rt-PCR). However, simple testing with immediately available results are crucial to gain control over COVID-19. The aim was to evaluate such a point-of-care antigen rapid test (AG-rt) device in its performance compared to laboratory-based rt-PCR testing in COVID-19 suspected, symptomatic patients.

MethodsFor this prospective study, two specimens each of 541 symptomatic female (54.7%) and male (45.3%) patients aged between 18 and 95 years tested at five emergency departments (ED, n=296) and four primary healthcare centres (PHC, n=245), were compared, using AG-rt (positive/negative/invalid) and rt-PCR (positive/negative and cycle threshold, Ct) to diagnose SARS-CoV-2. Diagnostic accuracy, sensitivity, specificity, positive predictive values (PPV), negative predictive value (NPV), and likelihood ratios (LR+/-) of the AG-rt were assessed.

ResultsDifferences between ED and PHC were detected regarding gender, age, symptoms, disease prevalence, and diagnostic performance. Overall, 174 (32.2%) were tested positive on AG-rt and 213 (39.4%) on rt-PCR. AG correctly classified 91.7% of all rt-PCR positive cases with a sensitivity of 80.3%, specificity of 99.1%, PPV of 98.3, NPV of 88.6%, LR(+) of 87.8, and LR(-) of 0.20. The highest sensitivities and specificities of AG-rt were detected in PHC (sensitivity: 84.4%, specificity: 100.0%), when using Ct of 30 as cut-off (sensitivity: 92.5%, specificity: 97.8%), and when symptom onset was within the first three days (sensitivity: 82.9%, specificity: 99.6%).

ConclusionsThe highest sensitivity was detected with a high viral load. Our findings suggest that AG-rt are comparable to rt-PCR to diagnose SARS-CoV-2 in COVID-19 suspected symptomatic patients presenting both at emergency departments and primary health care centres.

SUMMARYThe rapid SARS-Cov-2 antigen test (SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics), was compared in symptomatic patients with PCR testing both in emergency departments and primary health care centres. It showed an overall sensitivity of 80.3% and specificity of 99.1%; these were higher with lower PCR cycle threshold numbers and with a shorter onset of symptoms.


title: Verification of the Abbott Alinity m Resp-4-Plex Assay for detection of SARS-CoV-2, influenza A/B, and respiratory syncytial virus

abstract: COVID-19 symptomology may overlap with other circulating respiratory viruses that may also cause severe disease and for which there are specific and potentially life-saving treatments. The Abbott Alinity m Resp-4-Plex assay is a multiplex PCR assay that simultaneously detects and differentiates infection with SARS-CoV-2, influenza A, influenza B, and respiratory syncytial virus (RSV). We characterized its accuracy, precision, and analytical sensitivity. All were found to be robust for measures examined. In the context of sample-to-answer, near random access automation on the Alinity m platform, we believe that the Resp-4-Plex assay offers significant utility in addressing the current needs of the SARS-CoV-2 pandemic and future needs during anticipated endemic circulation of SARS-CoV-2 with other respiratory viruses.


title: Genetic mismatch explains sizable variation of COVID-19 vaccine efficacy in clinical trials

abstract: Timely evaluation of the protective effects of COVID-19 vaccines is challenging but urgently needed to inform the pandemic control planning. Based on vaccine efficacy/effectiveness (VE) data of 11 vaccine products and 297,055 SARS-CoV-2 sequences collected in 20 regions, we analyzed the relationship between genetic mismatch of circulating viruses against the vaccine strain and VE. Variations from technology platforms are controlled by a mixed-effects model. We found that the genetic mismatch measured on the RBD is highly predictive for vaccine protection and accounted for 72.0% (p-value < 0.01) of the VE change. The NTD and S protein also demonstrate significant but weaker per amino acid substitution association with VE (p-values < 0.01). The model is applied to predict vaccine protection of existing vaccines against new genetic variants and is validated by independent cohort studies. The estimated VE against the delta variant is 79.3% (95% prediction interval: 67.0 - 92.1) using the mRNA platform, and an independent survey reported a close match of 83.0%; against the beta variant (B.1.351) the predicted VE is 53.8% (95% prediction interval: 39.9 - 67.4) using the viral-vector vaccines, and an observational study reported a close match of 48.0%. Genetic mismatch provides an accurate prediction for vaccine protection and offers a rapid evaluation method against novel variants to facilitate vaccine deployment and public health responses.


title: Rapid evaluation of COVID-19 vaccine effectiveness against VOC/VOIs by genetic mismatch


title: Genetic determinants of interventricular septal anatomy and the risk of ventricular septal defects and hypertrophic cardiomyopathy

abstract:
BackgroundThe interventricular septum (IVS) plays a primary role in cardiovascular physiology and a large proportion of genetic risk remains unexplained for structural heart disease involving the IVS such as hypertrophic cardiomyopathy (HCM) and ventricular septal defects (VSD).

ObjectivesWe sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to two rare diseases of the IVS.

MethodsWe performed machine learning to estimate the cross-sectional area of the interventricular septum (IVS.csad) obtained from the 4-chamber view of cardiac MRI in 32,219 individuals from the UK Biobank. Using these extracted measurement of IVS.csad we performed phenome-wide association to relate this proxy measure to relevant clinical phenotypes, followed by genome-wide association studies and Mendelian Randomization.

ResultsAutomated measures of IVS.csad were highly accurate, and strongly correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. A Single nucleotide polymorphism in the intron of CDKN1A was associated with IVS.csad (rs2376620, Beta 8.4 mm2, 95% confidence intervals (CI) 5.8 to 11.0, p=2.0e-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure was associated with an increase in IVS.csad (Beta 8.6 mm2, 95% CI 6.3-10.9, p=1.3e-13). Mendelian Randomization suggested that inheritance of a larger IVS.csad was causal for HCM (Beta 2.45 log odds ratio (OR) HCM per increase in SD of IVS.csad, standard error (SE) 0.48, pIVW = 2.8e-7) while inheritance of a smaller IVS.csad was causal for VSD (Beta -2.06 log odds ratio (OR) VSD per decrease in SD of IVS.csad, SE 0.75, pIVW = 0.006)

ConclusionAutomated derivation of the cross sectional area of the IVS from the 4-chamber view allowed discovery of loci mapping to genes related to cardiac development and Mendelian disease. Inheritance of a genetic liability for either large or small interventricular septum, appears to confer risk for HCM or VSD respectively, which suggests that a considerable proportion of risk for structural and congenital heart disease may be localized to the common genetic determinants of cardiovascular anatomy.

category: cardiovascular medicine


title: In-silico clinical trial using high performance computational modeling of a virtual human cardiac population to assess drug-induced arrhythmic risk

abstract:
Drug-induced arrhythmia continues to be a major health issue worldwide. The need for reliable pro-arrhythmic predictors became relevant during early phases of the SarsCoV2 pandemic, when it was uncertain whether the use of hydroxychloroquine (HCQ) and azithromycin (AZM) could be more harmful than beneficial due to their reported pro-arrhythmic effects.

In this work we describe a computational framework that employs a gender-specific, in-silico cardiac population to assess cardiac drug-induced QT-prolongation after the administration of a single or a combination of potentially cardiotoxic drugs as HCQ and AZM. This novel computational methodology is capable of reproducing the complex behavior of the clinical electrocardiographic response to drug-induced arrhythmic risk, in-silico. Using high performance computing, the computational framework allows the estimation of the arrhythmic risk in a population, given a variety of doses of one or more drugs in a timely manner and providing markers that can be directly related to the clinical scenario. The pro-arrhythmic behavior observed in subjects within the in-silico trial, was also compared to supplemental in-vitro experiments on a reanimated swine hearts. Evidence of transmurally heterogeneous action potential prolongation after the administration of a large dose of HCQ was an observed mechanism of arrhythmia, both in the in-vitro and the in-silico model. The virtual clinical trial also provided remarkably similar results to recent published clinical data. In conclusion, the in-silico clinical trial on the cardiac population is capable of reproducing and providing evidence of the normal phenotype variants that produce distinct arrhythmogenic outcomes after the administration of one or various drugs.


title: Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers

abstract: Therapeutic targets for halting the progression of Alzheimers disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the cyclophilin A matrix metalloproteinase-9 (CypA MMP9) pathway in the cerebrospinal fluid, leading to an accelerated breakdown of the blood brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence that CypA or MMP9 affected the risk of Alzheimers disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in APOE4 carriers.


title: Mutation-specific SARS-CoV-2 PCR Screen: Rapid and Accurate Detection of Variants of Concern and the Identification of a Newly Emerging Variant with Spike L452R Mutation

abstract: The emergence of more transmissible and/or more virulent SARS-CoV-2 variants of concern (VOCs) has triggered intensive genomic surveillance, which is costly and difficult to sustain operationally over the long-term. To address this problem, we developed a set of four multiplex mutation-specific PCR-based assays with same-day reporting that can detect five VOCs and three variants of interest (VOIs), as defined in the March 2021 guidelines from the United States (US) Centers for Disease Control and Prevention. The screening results were compared to the whole genome sequencing (WGS) and showed 100% concordance for strain typing for B.1.1.7 (25) and P.1 (5) variants using Spike (S) mutations N501Y, E484K and H69_V70del assays. The S L450R assay, designed to detect the B.1.427/429 VOCs, also identified multiple isolates of a newly emerging multiply-mutated B.1.526.1 variant that is now rapidly increasing in the Eastern US. PCR approaches can be easily adopted in clinical laboratories, provide rapid screening methods to allow early detection of newly emergent variants and to efficiently triage cases for full genomic sequencing.


title: Dynamics of neurotransmitter and extracellular vesicle-derived microRNA landscapes during heroin and methamphetamine withdrawal

abstract: Circulating miRNAs in small vesicles known as exosomes within blood have been emerging as a new research hotspot in the field of psychiatric disorders. The aim of this work was to characterize the changes in exosomal microRNA profiles, both short-term and long-term, during substance withdrawal using a cross-sectional study design. Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal microRNAs were identified as being associated with withdrawal stage and key neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are associated with developmental and intellectual abnormalities. Notably, a set of dysregulated microRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting patients with substance use disorders. Furthermore, hsa-miR-744a-5p was positively correlated with serotonin, and its important role in maintaining neuronal development and function was revealed using an in vitro human induced pluripotent stem cells derived neuronal model. Taken together, these data suggest that the microRNA content of circulating exosomes represent a biomolecular "fingerprint" of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal microRNAs contribute to central nervous system development and function.

category: psychiatry and clinical psychology


title: Dysregulation in EGF/ERBB signaling pathway may explain abnormalities in cellular migration in bipolar disorder in patient-derived neural precursors

abstract:
Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and is believed to contribute to the pathology of bipolar disorder (BD). We studied the migration patterns of induced pluripotent stem cell (IPSC)-derived neural precursor cells (NPCs) from individuals with familial BD, in comparison with healthy control. The BD patients also had morphological brain abnormalities in magnetic resonance imaging. Time-lapse analysis of migrating cells was conducted, through which we were able to identify several parameters to be abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind aberrant cellular phenotype identified. Our analysis showed downregulation of a network of genes, centering on EGF/ERBB proteins. Present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype; which could contribute to the functional and structural changes in the brain, reported in bipolar disorder.

SUMMARY STATEMENTAberrant migration patterns in NPCs derived from bipolar disorder patients could be attributed to the downregulation of genes related to EGF/ERBB signaling pathway.


title: Abnormalities in migration of neural precursor cells in familial bipolar disorder


title: A normative model representing autistic individuals amidst Autism Spectrum Disorders phenotypic heterogeneity

abstract:
Approaches to deal and understand Autism Spectrum Disorder (ASD) phenotypic heterogeneity, quantitatively and multidimensionally, are in need. Being able to access a specific individual relative to a normative reference ASD sample would provide a severity estimate that takes into account the spectrum variance. We propose such an approach analyzing the principal components of variance observable in a clinical reference sample. Using phenotypic data available in a comprehensive reference sample, the Simons Simplex Collection (n=2744 individuals), we performed Principal Component Analysis (PCA). The PCA considered ASD core-symptoms (accessed by ADI-R), important clinical features (accessed by VABS and CBCL) and IQ. PCA-projected dimensions supported a normative modeling where a multivariate normal distribution was used to calculate percentiles. An additional phenotypically homogeneous sample (ASD, IQ<75, 6-7yr, n=60) is presented as a case study to illustrate the phenotypic heterogeneity assessment and individual placement under the normative modeling approach. Three PCs embedded 72% of the normative sample variance, interpreted based on correlations (>0.50) with clinical features as: Social Functionality (39%), Behavioral Disturbance (18%) and Communication Problems (15%). A Multidimensional Severity Score (MSS) to evaluate new prospective single subjects was developed based on percentiles. Additionally, the disequilibrium among PCA-projected dimensions gave rise to an individualized Imbalance Score (ImS). The approach, named TEAplot, is implemented in user-friendly free software and was illustrated in a homogenous independent sample. Our approach proposes a basis for patient monitoring in clinical practice, guides research sample selection and pushes the field towards personalized precision medicine.

Lay SummaryMost families or clinicians already heard the now adage: "If youve met one person with autism, youve met one person with autism". The phenotypic heterogeneity presented by the Autism Spectrum Disorders (ASD) is a challenge to research and clinical practice. Here in this work we summon established mathematical tools from the Machine Learning field to help one to organize the principal components of such variability. These mathematical tools were applied to a comprehensive database of autistic individuals mensurable profiles (cognitive, emotional, behavioural, and so on) maintained by the Simons Foundation Autism Research Initiative (SFARI). Using this normative model one can quantitatively estimate how a given individual person fits into the whole, as pediatricians often do by evaluating growth charts, a tool we named TEAplot. We made freely available Excel/Libreoffice spreadsheets that calculate our proposed Multidimensional Severity Score in order to effectively engage the research and clinical communities. The TEAplot model is a step towards a personalized precision medicine approach for ASD.


title: Regional atrophy and cognitive decline depend on definition of subjective cognitive decline

abstract:
BackgroundPeople with subjective cognitive decline (SCD) may be at increased risk for Alzheimers disease (AD). However, not all studies have observed this increased risk. Inconsistencies may be related to different methods used to define SCD. The current project examined whether four methods of defining SCD (applied to the same sample) results in different patterns of atrophy and future cognitive decline between cognitively normal older adults with (SCD+) and without SCD (SCD-).

MethodsMRI scans and questionnaire data for 273 cognitively normal older adults from Alzheimers Disease Neuroimaging Initiative were examined. To operationalize SCD we used four common methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry only. A previously validated MRI analysis method (SNIPE) was used to measure hippocampal volume and grading. Deformation-based morphometry was performed to examine volume at regions known to be vulnerable to AD. Logistic regressions were completed to determine whether diagnostic method was associated with volume differences between SCD- and SCD+. Linear mixed effects models were performed to examine the relationship between the definitions of SCD and future cognitive decline.

ResultsResults varied between the four methods of defining SCD. Left hippocampal grading was lower in SCD+ than SCD-when using the CCI (p=.041) and Worry (p=.021) definitions. The right (p=.008) and left (p=.003) superior temporal regions were smaller in SCD+ than SCD-, but only with the ECog. SCD+ was associated with greater future cognitive decline measured by Alzheimers Disease Assessment Scale, but only with the CCI definition. In contrast, only the ECog definition of SCD was associated with future decline on the Montreal Cognitive Assessment.

ConclusionThe current findings suggest that the various methods used to differentiate between SCD- and SCD+ influence whether volume differences and findings of cognitive decline are observed between groups in this retrospective analysis.

category: radiology and imaging


title: Anxiety and Depression in Patients with Pulmonary Hypertension and its Impact on Health-Related Quality of Life

abstract:
BackgroundPulmonary Hypertension (PH) is a chronic progressive disease which affects quality of life. The prevalence of mood disorders in PH patients in Saudi Arabia is not known.

ObjectivesThis is a prospective observational study to investigate the prevalence of anxiety and depression in patients with pulmonary hypertension and its effect on health-related quality of life (HRQoL).

MethodsForty-two PH patients were evaluated for mood disorders by using Hospital Anxiety and Depression Scale (HADS) and health related quality of life was assessed with The Short Form 36 (SF-36) Health Survey questionnaire.

ResultsMean age for the cohort was 42.8 ({+/-}13.3) years and 31(73%) were female. Mean pulmonary artery pressure was 46.4 ({+/-} 15) mm Hg and 25 (60%) patients had severe PH (mPAP [≥]45 mmHg). Thirty-eight (90%) patients were in World Health Organization Functional Class (WHO-FC) II/III and 5 (10%) class IV. HADS anxiety and depression score was positive (11-21) in 4 (10%) and 6 (14%) patients respectively. Presence of anxiety and/or depression affected HRQoL.

ConclusionPrevalence of anxiety and depression in PH patients in Saudi Arabia is low (10% and 14% respectively) compared to published studies. The low prevalence may be explained by cultural and social differences and strong family support.

category: respiratory medicine


title: Classifying chronic pain using multidimensional pain-agnostic symptom assessments and clustering analysis

abstract: Chronic pain conditions present in various forms, yet all feature symptomatic impairments in physical, mental, and social domains. Rather than assessing symptoms as manifestations of illness, we used them to develop a chronic pain classification system. A cohort of real-world treatment-seeking patients completed a multidimensional patient-reported registry as part of a routine initial evaluation in a multidisciplinary academic pain clinic. We applied hierarchical clustering on a training subset of 11448 patients using nine pain-agnostic symptoms. We then validated a three-cluster solution reflecting a graded scale of severity across all symptoms and eight independent pain-specific measures in additional subsets of 3817 and 1273 patients. Negative affect-related factors were key determinants of cluster assignment. The smallest subset included follow-up assessments that were predicted based on baseline cluster assignment. Findings provide a cost-effective classification system that promises to improve clinical care and alleviate suffering by providing putative markers for personalized diagnosis and prognosis.

category: pain medicine


title: Prevalence of Metabolic Syndrome in the United States National Health and Nutrition Examination Survey (NHANES) 2011-2018

abstract:
ImportanceMetabolic syndrome (MetS) is a cluster of risk factors presaging the development of cardiovascular diseases and diabetes. It is a risk factor for severe coronavirus disease 2019 (COVID-19).

ObjectiveTo estimate the prevalence of MetS in the US National Health and Nutrition Examination Survey (NHANES) 2011-2018.

Design, Setting, and ParticipantsThis cohort study included 22370 eligible participants aged [≥]20 years from the NHANES 2011-2018.

Main Outcome and MeasureMetS was defined as the presence of at least three of these components: central obesity, reduced high-density lipoprotein, elevated triglycerides, elevated blood pressure and elevated fasting blood glucose. The prevalence of MetS was estimated taking into account the complex sampling. The time trend was evaluated using logistic regression. Annual percentage changes (APC) were used to measure the trends in MetS prevalence.

ResultsThe prevalence of MetS was 36.2% (95% CI, 32.3-40.3), 34.8% (95% CI, 32.3-37.4), 39.9% (95% CI, 36.6-43.2) and 38.3% (95% CI, 35.3-41.3) in 2011-2, 2013-4, 2015-6, 2017-8, respectively (P for trend =.08). Among the MetS components, the prevalence of elevated glucose increased from 48.7% (95% CI, 45.9-51.5) in 2011-2 to 64.3% (95% CI, 61.0-67.4) in 2017-8 [P for trend <.001; APC=11.7, (95% CI, 3.5-21.0)]. The prevalence of MetS in non-Hispanic Asian increased from 21.8% (95% CI, 16.7-28.0) in 2011-2 to 31.2% (95% CI, 27.4-35.3) in 2017-8 [P for trend <.001; APC=14.6, (95% CI, 2.5-34.8)].

Conclusion and RelevanceThe prevalence of MetS remained stable from 2011 to 2018, but increased among non-Hispanic Asians. Lifestyle modification is needed to prevent metabolic syndrome and the associated risks of diabetes and cardiovascular disease.


title: Effect of asymptomatic transmission and emergence time on multi-strain viral disease severity

abstract:
BackgroundIn a viral epidemic, the emergence of a novel strain with increased transmissibility (larger value of basic reproduction number R0) sparks the fear that the increase in transmissibility is likely to lead to an increase in disease severity. It is required to investigate if a new, more contagious strain will be necessarily dominant in the population and resulting in more disease severity.

MethodsThe impact of the asymptomatic transmission and the emergence time of a more transmissible variant of a multi-strain viral disease on the disease prevalence, disease severity, and the dominant variant in an epidemic was investigated by a proposed 2-strain epidemic model, called 2-SEICARD model, that is an extension of the SEIRD model.

ResultsThe simulation results showed that considering only R0, is insufficient to predict the outcome of a new, more contagious strain in the population. A more transmissible strain with a high fraction of asymptomatic cases can substantially reduce the mortality rate. If the emergence time of the new strain is closer to the start of the epidemic, the new, more contagious variant has more chance to win the viral competition and be the dominant strain; otherwise, despite being more contagious, it cannot dominate previous strains.

ConclusionsThree factors of R0, the fraction of asymptomatic transmission, and the emergence time of the new strain are required to correctly determine the prevalence, disease severity, and the winner of the viral competition.


title: Multidimensional Sleep Health: Concepts, Advances, and Implications for Research and Intervention.

abstract: The new paradigm of multidimensional sleep health ( sleep health) offers both challenges and opportunities for sleep science. Buysse (2014) has described sleep health to be multidimensional, framed as positive attributes, operationalizable into composite measures of global sleep health, sensitive to upstream exposures, and consequential for downstream health. We highlight two paradigm-shifting effects of a multidimensional sleep health perspective. The first is the use of composite sleep metrics which i) enable quantification of population shifts in sleep health, ii) with possibly reduced measurement error, iii) greater statistical stability, and iv) reduced multiple-testing burdens. The second is that sleep dimensions do not occur in isolation, that is, they are commonly biologically or statistically dependent. These dependencies complicate hypothesis tests yet can be leveraged to inform scale construction, model interpretation, and inform targeted interventions. To illustrate these points, we i) extended Buysses Ru SATED model; ii) constructed a conceptual model of sleep health; and iii) showed exemplar analyses from the Multi-Ethnic Study of Atherosclerosis (n=735). Our findings support that sleep health is a distinctively useful paradigm to facilitate interpretation of a multitude of sleep dimensions. Nonetheless, the field of sleep health is still undergoing rapid development and is currently limited by: i) a lack of evidence-based cut-offs for defining optimal sleep health; ii) longitudinal data to define utility for predicting health outcomes; and iii) methodological research to inform how to best combine multiple dimensions for robust and reproducible composites.


title: Emotional symptoms, mental fatigue and behavioral adherence after 72 continuous days of strict lockdown during the COVID-19 pandemic in Argentina

abstract:
BackgroundAn early, total, and prolonged lockdown was adopted in Argentina during the first wave of COVID-19 as the main sanitary strategy to reduce the spread of the virus in the population. The aim of this study was to explore emotional symptoms, mental fatigue, and behavioral adherence associated with the COVID-19 pandemic after an average of 72 days of continuous lockdown in Argentina. Specifically, we intended to know: 1) if the prolongation of the lockdown was associated with elevated emotional symptoms; 2) if the prolonged lockdown affected adherence, a phenomenon called "behavioral fatigue"; and 3) how financial concerns in a developing country affected adherence to the lockdown and emotional status of the population.

MethodA survey was designed to evaluate the psychological impact of the pandemic and lockdown. The survey included standardized questionnaires to assess the severity of depressive (PHQ-9) and anxious (GAD-7) symptoms, a questionnaire to evaluate mental fatigue, and several additional instruments to assess other variables of interest: risk perception, lockdown adherence, financial concerns, daily stress, loneliness, intolerance to uncertainty, negative repetitive thinking, and cognitive problems. Three LASSO regression analyses were carried to evaluate the predictive role of the different variables over depression, anxiety, and lockdown adherence

ResultsThe survey was responded by 3617 individuals over the age of 18 (85.2% female) from all the provinces of Argentina. Using the Oxford stringency index, Argentina had one of the most stringent and prolonged lockdowns when the sample was collected with 63 to 77 continuous days with a stringency index of more than 85/100. 45.6% of the sample met the cut-off for depression and 27% for anxiety. Previous mental health treatment, low income, being younger, and being female were associated with higher levels of emotional symptoms. Mental fatigue, cognitive failures, and financial concerns were also associated with emotional and subjective complaints, but not with adherence to the lockdown. In the regression models, mental fatigue, cognitive failures, and loneliness were the most important variables to predict depression, meanwhile intolerance to uncertainty and lockdown difficulty were the most important in the case of anxiety. Perceived threat was the most important variable predicting lockdown adherence.

ConclusionsEmotional symptoms persisted and even increased during the extended lockdown, but we found no evidence of behavioral fatigue. Instead, mental fatigue, cognitive difficulties, and financial concerns were expressions of the emotional side of the pandemic and the restrictive measures.


title: Specific concussion curriculum: Does it improve residents' comfort, Knowledge and In-Training Examination Scores? A pilot study.

abstract:
BackgroundConcussion is defined as aberrant brain function consequent to traumatic injury characterized by disorientation or loss of consciousness or memory. If concussions are not recognized and treated appropriately, they can cause significant morbidity. Because [~]20% of sports-related concussions occur in juveniles, pediatricians must be able to treat this injury. Our primary objective was to assess the comfort and competence of pediatric residents in managing patients with concussions. Secondary objective was to assess the change in the In-Training Examination (ITE) scores after instituting a novel multimodal concussion curriculum.

MethodFrom February to June 2019, all pediatric residents (N = 24) were required to complete a multimodal concussion curriculum, including board review-style questions, lectures, and rotation in a concussion clinic. Residents voluntarily participated in a pre-and post-curriculum survey. ITE scores from 2018 and 2019 were compared.

ResultsTwenty-three of 24 (96%) residents completed both pre- and post-curriculum surveys; of those, 17 (74%) had matched identifiers. Most residents (82%) want more education about concussion management. Residents scores on knowledge-based questions increased an average of 0.64 questions, with PGY-1 showing the most improvement. The proportion of residents who correctly answered the ITE head injury/concussion questions increased from 0.33 to 0.88. The concussion clinic was identified as the most helpful tool.

ConclusionTo better educate pediatric residents about concussions, we propose a unique multimodal curriculum. We found improved self-assessed comfort and performance on knowledge-based questions and the ITE. We recommend that pediatric and other residency training programs consider implementing this type of curriculum.

category: medical education


title: Socio-demographic and knowledge-related determinants of vitamin D supplementation in the context of the COVID-19 pandemic: assessment of an educational intervention

abstract: Vitamin D is a pro-hormone, essential for musculo-skeletal health, normal immune system, and numerous other body functions. Vitamin D deficiency is considered a risk factor in many conditions, and there is growing evidence of its potential role in the severity of COVID-19 outcomes. However, an alarmingly high prevalence of vitamin D deficiency is reported in many regions, and vitamin D supplementation is commonly recommended, particularly during wintertime. To reduce the risk for vitamin D deficiency in the Slovenian population during the COVID-19 pandemic, we conducted mass media intervention with an educational campaign. The objective of this study was to investigate vitamin D supplementation practices in Slovenia before and during the COVID-19 pandemic, and to determine the effects of the educational intervention on supplementation practices. Two data collections were conducted using an online panel with quota sampling for age, sex, and geographical location. A pre-intervention (N=602, April 2020) and post-intervention (N=606) sampling were done during the first and second COVID-19 lockdown, respectively. We also focused on the identification of different factors connected to vitamin D supplementation, with a particular emphasis on vitamin D-related knowledge. Study results showed significant changes in vitamin D supplementation in the population. Penetration of the supplementation increased from 33% in April to 56% in December 2020. The median daily vitamin D intake in supplement users was 25 {micro}g, with about 95% of supplement users taking safe intake levels below 100 {micro}g/daily. Vitamin D-related knowledge (particularly about dietary sources of vitamin D, the health-related impact of vitamin D, and the prevalence of deficiency) was identified as a key independent predictor of vitamin D supplementation. Based on the study findings, we prepared recommendations, which will enable the development of effective awareness campaigns for increasing supplementation of vitamin D.


title: Associations of SARS-CoV-2 serum IgG with occupation and demographics of military personnel

abstract:
BackgroundCountries across the globe have mobilized their armed forces in response to COVID-19, placing them at increased risk for viral exposure. Humoral responses to SARS-CoV-2 among military personnel serve as biomarkers of infection and provide a basis for disease surveillance and recognition of work-related risk factors.

MethodsEnzyme-linked immunosorbent assays (ELISA) were used to measure SARS-CoV-2 spike antigen-specific IgG in serum obtained from N=995 US National Guard soldiers between April-June 2020. Occupational information, e.g. military operating specialty (MOS) codes, and demographic data were obtained via questionnaire. Plaque assays with live SARS-CoV-2 were used to assess serum neutralizing capacity for limited subjects (N=12).

ResultsThe SARS-CoV-2 IgG seropositivity rate among the study population was 10.3% and significantly associated with occupation and demographics. Odds ratios were highest for those working in MOS 2T-Transportation (3.6; 95% CI 0.7-18) and 92F-Fuel specialist/ground and aircraft (6.8; 95% CI 1.5-30), as well as black race (2.2; 95% CI 1.2-4.1), household size [≥]6 (2.5; 95% CI 1.3-4.6) and known COVID-19 exposure (2.0; 95% CI 1.2-3.3). Seropositivity tracked along major interstate highways and clustered near the international airport and the New York City border. SARS-CoV-2 spike IgG+ serum exhibited low to moderate SARS-CoV-2 neutralizing capacity with IC50s ranging from 1:15 to 1:280. In limited follow-up testing SARS-CoV-2 serum IgG levels remained elevated up to 7 months.

ConclusionsThe data highlight increased SARS-CoV-2 seroprevalence among National Guard vs. the local civilian population in association with transportation-related occupations and specific demographics.

category: occupational and environmental health