title: Comprehensive humoral and cellular immune responses to SARS-CoV-2 variants in diverse Chinese populations: A benefit perspective of national vaccination

abstract: The emerging SARS-CoV-2 variants have made great challenges to current vaccine and pandemic control strategies. B.1.1.529 (Omicron), which was classified as a variant of concern (VOC) by the World Health Organization on November 26th, 2021, has quickly become the dominant circulating variant and causing waves of infections. It is urgent to understand the current immune status of the general population given that pre-existing immunity has been established by national vaccination or exposure to past variants. Using sera from 85 individuals (including 21 convalescents of natural infection, 15 cases suffered a breakthrough infection after vaccination, and 49 vaccinated participants without infection history), we showed that the cross-neutralizing activity against VOCs such as Omicron can be detected in 53 (62.4%) cases, although less potent than against the Wuhan-1 strain (WT), with a 3.9-fold reduction in geometric mean neutralizing titer (GMT) (130.7, 95% CI 88.4-193.3 vs 506, 355.8-719.7, respectively). Subgroup analysis revealed significantly enhanced neutralizing activity against WT and VOCs in Delta convalescent sera. The neutralizing antibodies against Omicron were detectable in 75% of convalescents and 44.9% of healthy donors (p = 0.006), with a GMT of 289.5, 180.9-463.3 and 42.6, 31.3-59, respectively. However, the protective effect against VOCs was weaker in young convalescents (aged < 18y), with a detectable rate of 50% and a GMT of 46.4 against Omicron, similar to vaccinees. The pan-sarbecovirus neutralizing activities were not observed in vaccinated SARS-CoV-1 survivors. A booster dose significantly increased the breadth and magnitude of neutralization against WT and VOCs to different degrees than full vaccination. In addition, we showed that COVID-19 inactivated vaccines can elicit Omicron-specific T cell responses. The positive rates of ELISpot reactions were 26.7% (4/15) and 43.8% (7/16) in the full vaccination group and the booster vaccination group, respectively. The neutralizing antibody titers declined while T-cell responses remain robust over 6 months. These findings will inform the optimization of public health vaccination and intervention strategies to protect diverse populations against SARS-CoV-2 variants.


title: SARS-CoV-2 Omicron triggers cross-reactive neutralization and Fc effector functions in previously vaccinated, but not unvaccinated individuals

abstract: The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We use plasma from 20 unvaccinated and seven vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies target Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization is not extensively cross-reactive for VOCs (14 to 31-fold titer reduction) and we observe 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection was associated with improved cross-neutralization of VOCs, with titers exceeding 1:2,100. This has important implications for vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. While Omicron-based immunogens may be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2 naive individuals.

category: infectious diseases


title: Strength and durability of antibody responses to BNT162b2 and CoronaVac

abstract: We studied 2780 adults in Hong Kong who received CoronaVac inactivated virus vaccine (Sinovac) and BNT162b2 mRNA vaccine ("Comirnaty", BioNTech/Fosun Pharma). We found stronger and more durable antibody responses to two doses of the mRNA vaccine, and slightly stronger initial antibody responses to each vaccine in younger adults and women.


title: Workplace infection control measures and romantic activities of workers during COVID-19 pandemic: a prospective cohort study in Japan

abstract:
BackgroundDue to the COVID-19 pandemic, non-married people are at high risk of loneliness. With social interactions restricted, it is important for non-married people to acquire a new romantic partner for their mental health and quality of life. We hypothesized that infection control efforts in the workplace influence peoples social interactions, including romantic activities.

MethodsWe conducted an internet-based prospective cohort study from December 2020 (baseline) to December 2021, using self-administered questionnaires. Briefly, 27,036 workers completed the questionnaires at baseline, and when followed up after one year, 18,560 (68.7%) participated. A total of 6,486 non-married individuals with no romantic relationship at baseline were included in the analysis. At baseline they were asked about the implementation of infection control measures in the workplace, and at follow-up they were asked about activities they performed with a view to romantic relationships during the period from baseline to follow-up.

ResultsCompared to workers in workplaces with no infection control measures, the OR associated with romance-related activities for those in workplaces with seven or more infection control measures was 1.90 (95% CI: 1.45-2.48, p<0.001), and the OR associated with having a new romantic partner was 1.79 (95% CI: 1.20-2.66, p=0.004).

ConclusionsUnder the COVID-19 pandemic, the implementation of infection control measures in the workplace and the expressed satisfaction with those measures promoted romantic relationships among non-married, single individuals.

category: epidemiology


title: Role of COVID-19 vaccinal status in admitted children during OMICRON variant circulation in Rio de Janeiro, city- Preliminary report

abstract:
ObjectiveTo evaluate COVID-19 vaccination status in admitted children during the OMICRON variant circulation.

DesignObservational retrospective study. Patients with confirmed COVID-19 were compared in two different periods: 2020-2021 when full COVID-19 vaccine were not completed for adolescents between 12 and 18 years and 2022, when Pfizer-BioNTech vaccine full scheme were completed for children older 12 years

SettingTwo paediatric hospitals in Rio de Janeiro, city

PatientsChildren aged <18 years with confirmed COVID-19.

InterventionNone

Main outcomeVaccination status for COVID-19 at the admission.

ResultsThree-hundred patients were admitted with confirmed COVID-19, being 240 in 2020-2021, and 60 in 2022. The distribution of patients according to the age-groups were: 0-2 years (33.3% in 2020-2021 and 53.4% in 2022), 2-5 years (21.7% in 2020-2021 and 10% in 2022), 5-11 years (29.2% in 2020-2021 and 28.3% in 2022) and 12-18 years (15.8% in 2020-2021 and 8.3% in 2022) (p= 0.015). The median of lenght of stay was 6 days in 2020-2021 and 5 days in 2022 (p=0.036). We verified 6 deaths and in the first period of analysis and 1 death in the second one (p=0.777). Of 60 children admitted in 2022, fifty-eigth (96.7%) not received the full scheme of COVID-19 vaccine available

ConclusionsWe verified in a "real world condition" ability of Pfizer-BioNTech vaccine in avoid hospitalization in children older than 12 years

category: pediatrics


title: Australian children's foot, ankle and leg problems in primary care: a secondary analysis of the Bettering the Evaluation and Care of Health (BEACH) data

abstract:
ObjectivesTo explore childrens foot, ankle and leg consultation patterns and management practices in Australian primary care.

DesignCross-sectional, retrospective study

SettingAustralia Bettering the Evaluation and Care of Health program dataset.

ParticipantsData were extracted for GPs and patients [≤]18 years from April 2000 to March 2016 inclusive.

Main outcome measuresDemographic characteristics: sex, GP age groups (i.e. <45, 45-54, 55+ years), GP country of training, patient age grouping (0-4, 5-9, 10-14, 15-18 years), postcode, concession card status, Indigenous status, up to three patient encounter reasons, up to four encounter problems/diagnoses, and the clinical management actioned by the GP.

ResultsChildrens foot, ankle or leg problems were managed at a rate of 2.05 (95% CI 1.99 to 2.11) per 100 encounters during 229,137 GP encounters with children. There was a significant increase in the rate of foot, ankle and leg problems managed per 100 children in the population, from 6.1 (95% CI: 5.3-6.8) in 2005-06 to 9.0 (95% CI: 7.9-10.1) in 2015-16. Management of childrens foot, ankle and leg problems were independently associated with male patients (30% more than female), older children (15-18 years were 7.1 times more than <1 years), male GPs (13% more) and younger GPs (<45 years of age 13% more than 55+). The top four most frequently managed problems were injuries (755.9 per 100,000 encounters), infections (458.2), dermatological conditions (299.4) and unspecified pain (176.3). The most frequently managed problems differed according to age grouping.

ConclusionsChildren commonly present to GPs for foot, ankle, and leg problems. Presentation frequencies varied according to age. Unexpectedly, conditions presenting commonly in adults, but rarely in children, were also frequently recorded. This data highlights the importance of initiatives supporting contemporary primary care knowledge of diagnoses and management of paediatric lower limb problems to minimise childhood burden of disease.

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABS- This study examines the full spectrum of childhood foot, ankle, or leg presentations in primary care and how these are managed
- This study also provides information about how foot, ankle and leg GP presentations and management patterns differ as children get older
- This dataset provides a robust baseline on which future guidelines and implementation studies can measure the outcomes of practice change over time.
- This study may be limited by how GPs coded the presentation and management data

category: primary care research


title: Evaluation of international guidance for the community treatment of complex emotional needs: A systematic review

abstract:
BackgroundGuidelines for the treatment and management of "personality disorder" were introduced to provide guidance on best practice from evidence and views of key stakeholders. However, this guidance varies as there is yet to be an overall, internationally recognised consensus on the best mental health care for people with complex emotional needs (CEN - our preferred working term for the needs of people using services for or related to "personality disorder").

AimsWe aimed to identify and synthesise recommendations made by different mental health organisations from across the world on community treatment for people with CEN.

MethodsThis systematic review consisted of three stages: 1. systematic literature and guideline search, 2. quality appraisal, and 3. data synthesis. We combined a search strategy involving both systematic searching of bibliographic databases and supplementary search methods of grey literature. Key informants were also contacted to further identify relevant guidelines. Codebook thematic analysis was then conducted. The quality of all included guidelines was assessed and considered alongside results.

ResultsAfter synthesising 29 guidelines from 11 countries and 1 international organisation, we identified four main domains, with a total of 27 themes. Important key principles on which there was consensus included continuity of care, equity of access, accessibility of services, availability of specialist care, taking a whole systems approach, trauma informed approaches, and collaborative care planning and decision making.

ConclusionsExisting international guidelines shared consensus on a set of principles for the community treatment of CEN. However, half of the guidelines were of lower methodological quality, with many recommendations not backed by evidence.

category: psychiatry and clinical psychology


title: SARS-CoV-2 seroprevalence in a rural and urban community household cohort in South Africa, after the third wave, April-November 2021

abstract:
By November 2021, after the third SARS-CoV-2 wave in South Africa, seroprevalence was 60% (95%CrI 56%-64%) in a rural and 70% (95%CrI 56%-64%) in an urban community; highest in individuals aged 13-18 years. High seroprevalence prior to Omicron emergence may have contributed to reduced severity observed in the 4th wave.

Article Summary LineIn South Africa, after a third wave of SARS-CoV-2 infections, seroprevalence was 60% in a rural and 70% in an urban community, with case-to-infection, - hospitalization and -fatality ratios similar to the second wave.

category: public and global health


title: Using Blood-Test Parameters to Define Biological Age among Older Adults: Association with Morbidity and Mortality Independent of Chronological Age Validated in Two Separate Birth Cohorts

abstract:
Biomarkers defining biological age are typically laborious or expensive to assess. Instead, in the current study, we identified parameters based on standard laboratory blood tests across metabolic, cardiovascular, inflammatory, and kidney functioning that had been assessed in the Berlin Aging Study (BASE; n = 384) and Berlin Aging Study II (BASE-II, n = 1,517). We calculated biological age using those 12 parameters that individually predicted mortality hazards over 26 years in BASE.

In BASE, older biological age was associated with more physician-observed morbidity and higher mortality hazards, over and above the effects of chronological age, sex, and education. Similarly, in BASE-II, biological age was associated with physician-observed morbidity and subjective health, over and above the effects of chronological age, sex, and education as well as alternative biomarkers including telomere length, DNA methylation age, skin age, and subjective age. We discuss the importance of biological age as one indicator of aging.


title: Predicting COVID-19 outbreak using open mobility data for minimal disruption on the country's economy

abstract: COVID-19 is an infectious disease caused by the SARS-COV-2 coronavirus, which was discovered in late 2019. Within a few months, COVID-19 was declared a global pandemic by the WHO. Several countries adopted social distancing measures, such as self-quarantine, workplace and mobility restrictions, reducing the probability of contact between non-infected and infected people. In general, these measures have a negative impact on low-income economies and small and medium businesses. During the outbreak, several predictive models have been proposed in order to assess the level of saturation that health services might have. Nevertheless, none of them considers information on the peoples mobility to assess the effectiveness of the social distancing policies. In this study, the authors propose a prediction method based on peoples open mobility data from Apple(C) and Google(C) databases to project potential scenarios and monitor case growth. The proposed method shows the importance of monitoring daily case increase for the first 4-6 weeks of the pandemic wave. Active monitoring is crucial to determine the reduction in mobility and proper actions. The results can contribute to health authorities for making timely decisions, preventing the spread of viruses while balancing the reduction of mobility with minimal disruption in peoples economies in future outbreaks.


title: Impact of low-dose intrathecal morphine on orthopedic surgery: a protocol of a systematic review and meta-analysis of randomized controlled trials

abstract:
IntroductionPatients undergoing orthopedic surgery usually suffer considerably from peri-operative pain and intrathecal morphine (ITM) has recently been used as an effective analgesic method. The intrathecal morphine dose achieving optimal analgesia for orthopedic surgery while minimizing side effects has not yet been determined. There is currently a lack of literature synthesis on the safety and effects of low-dose ITM on orthopedic surgery.

Methods and analysisA thorough literature search will be performed on multiple electronic databases and trial registries until January 11th 2022, and reference lists will be examined. Two independent reviewers will select studies, extract data and assess the risk of bias and quality of the included studies. We will select randomized controlled trials comparing low-dose ITM (<100g) with high-dose ITM (<200g) or placebo treatment or other comparatives. We will assess the risk of bias using the Cochrane risk of bias tool and Jadad score will be applied to assess the quality of each included trial. We will also use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to determine the confidence in effect estimates. Publication bias will be evaluated by visually inspecting funnel plots and Egger regression asymmetry test in estimations of more than 10 trials. Standard meta-analysis will be performed using R package meta.

Ethics and disseminationThe results of this systematic review and meta-analysis will be disseminated through peer-reviewed journal and related conferences. The data used in this meta-analysis will not contain individual patient data and ethical approval is therefore not required.

category: surgery


title: Prognosis-related molecular subtypes and immune features associated with hepatocellular carcinoma

abstract: Bioinformatics tools were used to identify prognosis-related molecular subtypes and biomarkers of hepatocellular carcinoma (HCC). Differential expression analysis of four datasets (TCGA, GSE76427, GSE25097, and GSE14520) identified 3,330 genes differentially expressed in the same direction in all four datasets; those genes were involved in the cell cycle, FOXO signaling pathway, as well as complement and coagulation cascades. Based on non-negative matrix decomposition, two molecular subtypes of HCC with different prognosis were identified, with subtype C2 showing better overall survival than subtype C1. Cox regression and Kaplan-Meier analysis showed that 217 of the overlapping DEGs were closely associated with HCC prognosis. The subset of those genes showing an area under the curve > 0.80 was used to construct random survival forest and least absolute shrinkage and selection operator models, which identified seven feature genes (SORBS2, DHRS1, SLC16A2, RCL1, IGFALS, GNA14, and FANCI) that may be involved in HCC occurrence and prognosis. Based on the feature genes, risk score and recurrence models were constructed, while a univariate Cox model identified FANCI as a key gene involved mainly in the cell cycle, DNA replication, and mismatch repair. Further analysis showed that FANCI had two mutation sites and that its gene may undergo methylation. Single-sample gene set enrichment analysis showed that Th2 and T helper cells are significantly upregulated in HCC patients compared to controls. Our results identify FANCI as a potential prognostic biomarker for HCC.

category: oncology


title: Combined oropharyngeal/nares and nasopharyngeal swab sampling remain effective for molecular detection of SARS-CoV-2 Omicron variant

abstract: The world has experienced several waves of SARS-CoV-2 variants of concern (VoCs) throughout the COVID-19 pandemic since the first cases in December 2019. The Omicron VoC has increased transmission, compared to its predecessors, and can present with sore throat and other cold-like symptoms. Given the predominance of throat symptoms, and previous work demonstrating better sensitivity using antigen-based rapid detection tests when a throat swab is included in the standard nasal sampling, this quality improvement project sought to ensure ongoing suitability of both combined oropharyngeal/nares (OPN) and nasopharyngeal (NP) swab sampling used throughout the pandemic. Consenting participants meeting Public Health testing criteria (mostly symptomatic or a close contact of a known case) were enrolled, and paired NP and OPN swabs collections were subjected to nucleic acid amplification testing (NAAT). Comparing paired specimens from 392 participants sensitivity of NP swabs was 89.1% (95% CI, 78.8-94.9), and that of OPN was 98.4% (95% CI: 90.9->99.9) (p-value 0.052). This project demonstrated that both NP and combined OPN swabs detected the Omicron variant with similar sensitivity by NAAT, supporting the continued use of either swab collection for SARS-CoV-2 molecular detection.


title: Clinical and immunological features of SARS-CoV-2 breakthrough infections in vaccinated individuals requiring hospitalization

abstract:
BackgroundWaning immunity and the surge of SARS-CoV-2 variants are responsible for breakthrough infections, i.e. infections in fully vaccinated individuals. Although the majority of vaccinated infected subjects reports mild or no symptoms, some others require hospitalization. The clinical and immunological features of vaccinated hospitalized COVID-19 patients are currently unknown.

Methods29 unvaccinated and 36 vaccinated hospitalized COVID-19 patients were prospectively enrolled and clinical and laboratory data. Immunophenotyping of leukocytes subsets, T and B cell SARS-CoV-2 specific responses were evaluated via flow cytometry. Anti-IFN- autoantibodies were measured via ELISA.

ResultsDespite vaccinated patients were older and with more comorbidities, unvaccinated subjects showed higher levels of pro-inflammatory markers, more severe disease and increased mortality rate. Accordingly, they presented significant alterations in the circulating leukocyte composition, typical of severe COVID-19. Vaccinated patients displayed higher levels of anti-Spike IgGs and Spike-specific B cells. Of all participants, survivors showed higher levels of anti-Spike IgGs and S-specific CD4+ T cells than non-survivors. At hospital admission, 6 out of 65 patients (9.2%) displayed high serum concentrations of autoantibodies targeting IFN-. Remarkably, 3 were unvaccinated and eventually died, while the other 3 were vaccinated and survived.

ConclusionDespite more severe pre-existing clinical conditions, vaccinated patients have good outcome. A rapid activation of anti-SARS-CoV-2-specific immunity is fundamental for the resolution of the infection. Therefore, prior immunization through vaccination provides a significant contribute to prevention of disease worsening and can even overcome the presence of high-risk factors (i.e. older age, comorbidities, anti-IFN- autoantibodies positivity).


title: Evaluation of test-to-return after COVID-19 diagnosis in a Massachusetts public school district

abstract: The Centers for Disease Control allows rapid antigen testing (RAT) towards the end of a 5-day isolation for COVID-19 infection to determine eligibility to leave isolation. The impact of a test-to-return (TTR) program in schools is unknown. In January 2022 a Massachusetts school district initiated a TTR program utilizing a single school-administered RAT on days 5-9 after symptom onset or positive test, whichever was first. Of 636 students with COVID-19 infection, 408 (64.2%) participated in TTR; of these, 128 (31.4%) had a positive TTR rapid antigen test. Students who were symptomatic at any time during their infection were more likely to have a positive TTR than those who were never symptomatic (43.1% vs. 17.3%); positivity rates were lower when TTR was performed later during days 6-9. TTR may identify students who carry higher viral loads after recovery from COVID-19 infection thereby extending their isolation, while facilitating earlier return of those with negative results.


title: Differential durability of humoral and T cell immunity after two and three BNT162b2 vaccinations in adults aged >80 years

abstract: A third mRNA-based "booster" vaccination is the favored strategy to maintain protection against SARS-CoV-2 infection. Yet, significant waning of specific immunity within six months after 2nd vaccination, along with higher incidence of breakthrough infections associated with the time elapsed since 2nd vaccination raises concerns regarding the durability of immunity also after 3rd vaccination. We assessed virus-specific serum antibody and T cell response in the blood after vaccination with the mRNA vaccine BNT162b2 in more than 50 individuals older than 80 years. All old adults demonstrated a strong humoral response to 3rd vaccination which was at average higher and waned slower than the response to 2nd vaccination, indicative of enhanced humoral immunity. In contrast, their respective T cell response quantitatively limited to the level obtained after 2nd vaccination, with similar waning over time and no evidence for enhanced IFNg production. Because BNT162b2-mediated protection from the Omicron variant relies more on T cells than antibodies, our findings raise concern on the durability of protection from the Omicron variant by BNT162b2 in the senior population.


title: Structural risk factors for SARS-CoV-2 infection in an urban slum: Age, gender and income

abstract:
BackgroundThe structural environment of urban slums, including physical, demographic and socioeconomic attributes, renders inhabitants more vulnerable to SARS-CoV-2 infection. Yet, little is known about the specific determinants that contribute to high transmission within these communities.

Methods and findingsWe performed a serosurvey of an established cohort of 2,035 urban slum residents from the city of Salvador, Brazil between November 2020 and February 2021, following the first COVID-19 pandemic wave in the country. We identified high SARS-CoV-2 seroprevalence (46.4%, 95% confidence interval [CI] 44.3-48.6%), particularly among female residents (48.7% [95% CI 45.9-51.6%] vs. 43.2% [95% CI 39.8-46.6%] among male residents), and among children (56.5% [95% CI 52.3-60.5%] vs. 42.4% [95% CI 39.9-45.0%] among adults). In multivariable models that accounted for household-level clustering, the odds ratio for SARS-CoV-2 seropositivity among children was 1.96 (95% CI 1.42-2.72) compared to adults aged 30-44 years. Adults residing in households with children were more likely to be seropositive; this effect was particularly prominent among individuals with age 30-44 and 60 years or more. Women living below the poverty threshold (daily per capita household income <$1.25) and those who were unemployed were more likely to be seropositive.

ConclusionsDuring a single wave of the COVID-19 pandemic, cumulative incidence as assessed by serology approached 50% in a Brazilian urban slum population. In contrast to observations from industrialized countries, SARS-CoV-2 incidence was highest among children, as well as women living in extreme poverty. These findings emphasize the need for targeted interventions that provide safe environments for children and mitigate the structural risks posed by crowding and poverty for the most vulnerable residents of urban slum communities.


title: Demographic Characteristics and Clinical Features of COVID-19 Patients Admitted in a Combined Military Hospital of Bangladesh

abstract:
BackgroundCOVID-19, one of the worst pandemics in humankinds history on December 2019. Clinical presentations of COVID-19 patients are varied and being closely similar to those of seasonal flu, its difficult to differentiate it on first presentation as COVID. Clinical scenario and demographic characteristics provide important guideline in the management of COVID.

Materials and MethodsThe objective of this cross-sectional study was to explore the demographic characteristics and clinical features of COVID-19 patients admitted in a Combined Military Hospital of Bangladesh. Data were collected from treatment records of patients of the CMH Bogura during the period of June 2020 to August 2020. Total 219 RT-PCR positive admitted patients were included as study population.

ResultAmong 219 patients, 78.6% were male and 21.5% female. Mean age of patients was 34.3 {+/-} 12.2. Highest percentages (67.2%) of patients were from age group 21-40 years. 85.4% of the patients had no comorbidities, and hypertension (10.1%) was the most common comorbidity. Most (83.1%) of the admitted patients were diagnosed as mild cases. 96.4% cases were symptomatic and fever (84.5%) was the most common symptoms of COVID, followed by dry cough (46.6%), sore throat (19.6%), headache (18.3%), bodyache (17.8%), loss of appetite (15.5%), tiredness (15.5%) and anorexia (14.2%).

ConclusionThis single center study revealed younger age, male predominance, less presence of comorbidites, mild cases, high proportion of symptomatic patients, and fever and cough as the most common presenting features among the admitted COVID-19 patients in CMH Bogura.


title: Source terms for benchmarking models of SARS-CoV-2 transmission via aerosols and droplets

abstract: There is ongoing and rapid advancement in approaches to modelling the fate of exhaled particles in different environments relevant to disease transmission. It is important that models are verified by comparison with each other using a common set of input parameters to ensure that model differences can be interpreted in terms of model physics rather than unspecified differences in model input parameters. In this paper, we define parameters necessary for such benchmarking of models of airborne particles exhaled by humans and transported in the environment during breathing and speaking.


title: SARS-CoV-2 IgG seroprevalence in blood donors located in three different federal states, Germany, July 2020 to June 2021-a follow-up

abstract: Seroprevalence studies can contribute to better assess the actual incidence of infection. Since long-term data for Germany are lacking, we determined seroprevalence of IgG-antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 3,759 regular blood donors in three German federal states between July 2020 and June 2021. The IgG seroprevalence was 5.48% (95% confidence interval (CI): 4.77-6.25) overall, ranging from 5.15% (95% CI: 3.73-6.89) in Lower Saxony to 5.62% (95% CI: 4.57-6.84) in North Rhine Westphalia.


title: Direct and indirect mortality impacts of the COVID-19 pandemic in the US, March 2020-April 2021

abstract: Excess mortality studies provide crucial information regarding the health burden of pandemics and other large-scale events. Here, we used time series approaches to separate the direct contribution of SARS-CoV-2 infections on mortality from the indirect consequences of pandemic interventions and behavior changes in the United States. We estimated deaths occurring in excess of seasonal baselines stratified by state, age, week and cause (all causes, COVID-19 and respiratory diseases, Alzheimers disease, cancer, cerebrovascular disease, diabetes, heart disease, and external causes, including suicides, opioids, accidents) from March 1, 2020 to April 30, 2021. Our estimates of COVID-19 excess deaths were highly correlated with SARS-CoV-2 serology, lending support to our approach. Over the study period, we estimate an excess of 666,000 (95% Confidence Interval (CI) 556000, 774000) all-cause deaths, of which 90% could be attributed to the direct impact of SARS-CoV-2 infection, and 78% were reflected in official COVID-19 statistics. Mortality from all disease conditions rose during the pandemic, except for cancer. The largest direct impacts of the pandemic were seen in mortality from diabetes, Alzheimers, and heart diseases, and in age groups over 65 years. In contrast, the largest indirect consequences of the pandemic were seen in deaths from external causes, which increased by 45,300 (95% CI 30,800, 59,500) and were statistically linked to the intensity of non-pharmaceutical interventions. Within this category, increases were most pronounced in mortality from accidents and injuries, drug overdoses, and assaults and homicides, while the rate of death from suicides remained stable. Younger age groups suffered the brunt of these indirect effects. Overall, on a national scale, the largest consequences of the COVID-19 pandemic are attributable to the direct impact of SARS-CoV-2 infections; yet, the secondary impacts dominate among younger age groups, in periods of stricter interventions, and in mortality from external causes. Further research on the drivers of indirect mortality is warranted to optimize interventions in future pandemics.


title: Diagnostic Accuracy of Commercially Available Tests for Respiratory Syncytial Virus: A Scoping Literature Review in the COVID-19 Era

abstract:
BackgroundNon-pharmaceutical interventions to prevent the spread of coronavirus disease 2019 also decreased the spread of respiratory syncytial virus (RSV) and influenza. Viral diagnostic testing in patients with respiratory tract infections (RTI) is a necessary tool for patient management; therefore, sensitive and specific tests are required. This scoping literature review evaluated the analytical validity of commercially available sample-to- answer RSV diagnostic tests in different contexts.

ContentPubMed and Embase were queried for studies reporting on the analytical validity of tests for RSV in patients with RTI (published January 2005-January 2021). Sensitivity and specificity of RSV tests and information on study design, patient, and setting characteristics were extracted from 77 studies that met predefined inclusion criteria. A literature gap was identified for studies of RSV tests conducted in adult-only populations (5.3% of total sub- records), and in outpatient (7.5%) or household (0.8%) settings. Overall, RSV tests with analytical time >30 min had higher sensitivity (62.5-100%) versus RSV tests with analytical time [≤] 30 min (25.7-100%), this sensitivity range could be partially attributed to the different modalities (antigen versus molecular) used. Molecular-based rapid RSV tests had higher sensitivity (66.7-100%) and specificity (94.3-100%) than antigen-based RSV tests (25.7- 100%; 80.3-100%).

SummaryMolecular-based RSV tests should be considered for first-line use when possible, given their high sensitivity and specificity and that adults with RTI typically have low viral load, necessitating a highly sensitive test. This review benefits healthcare professionals by summarizing the diagnostic accuracy data available for commercially available RSV tests.

IMPACT STATEMENTViral diagnostic testing in patients with respiratory tract infection is a powerful tool for patient management. This scoping literature review included 77 studies reporting the analytical validity of commercially available respiratory syncytial virus (RSV) diagnostic tests (published January 2005-January 2021) and examined the characteristics of such studies. The data suggest that molecular-based RSV tests have higher sensitivity and specificity than antigen-based tests, thus should be considered for first-line use for timely diagnosis and to detect infections in adults with low level viral load. Future studies should investigate the diagnostic accuracy of RSV tests in adults and in outpatient/household settings.

category: respiratory medicine


title: MUC16 mutation is associated with tumor grade, clinical features, and prognosis in glioma patients

abstract: MUC16 is a member of the attached mucin family that encodes cancer antigen 125 (CA-125), but the association of MUC16 status with grade and subtypes of glioma patients has not yet been established. Data for MUC16 mRNA expression in 37 different cancer types were considered, and genomic data from the Cancer Genome Atlas (TCGA) from 1051 low-grade glioma (LGG) patients and 833 glioblastoma (GBM) patients were analyzed. LGG and GBM has low expression of MUC16, but it is frequently mutated in GBM. Kaplan-Meier survival analysis, glioma subtypes, methylation, and isocitrate dehydrogenase (IDH1) status were all performed. We found that mutated-MUC16 in LGG patients is associated with better prognosis considering overall survival (OS), IDH1, methylation, 1p/19q, and 10q status. Conversely, MUC16 mutation were related with worse prognosis in GBM patients upon analyzing those same parameters. Therefore, MUC16 mutations may assist in glioma diagnosis and prognosis and should be further studied in this tumor type.


title: Users' Reactions on Announced Vaccines against COVID-19 Before Marketing in France: Analysis of Twitter posts

abstract:
BackgroundWithin a few months, the COVID-19 pandemic has spread to many countries and has been a real challenge for health systems all around the world. This unprecedented crisis has led to a surge of online discussions about potential cures for the disease. Among them, vaccines have been at the heart of the debates, and have faced lack of confidence before marketing in France.

ObjectiveThis study aims to identify and investigate the opinion of French Twitter users on the announced vaccines against COVID-19 through sentiment analysis.

MethodsThis study was conducted in two phases. First, we filtered a collection of tweets related to COVID-19 from February to August 2020 with a set of keywords associated with vaccine mistrust using word embeddings. Second, we performed sentiment analysis using deep learning to identify the characteristics of vaccine mistrust. The model was trained on a hand labeled subset of 4,548 tweets.

ResultsA set of 69 relevant keywords were identified as the semantic concept of the word "vaccin" (vaccine in French) and focus mainly on conspiracies, pharmaceutical companies, and alternative treatments. Those keywords enabled to extract nearly 350k tweets in French. The sentiment analysis model achieved a 0.75 accuracy. The model then predicted 16% of positive tweets, 41% of negative tweets and 43% of neutral tweets. This allowed to explore the semantic concepts of positive and negative tweets and to plot the trends of each sentiment. The main negative rhetoric identified from users tweets was that vaccines are perceived as having a political purpose, and that COVID-19 is a commercial argument for the pharmaceutical companies.

ConclusionsTwitter might be a useful tool to investigate the arguments of vaccine mistrust as it unveils a political criticism contrasting with the usual concerns on adverse drug reactions. As the opposition rhetoric is more consistent and more widely spread than the positive rhetoric, we believe that this research provides effective tools to help health authorities better characterize the risk of vaccine mistrust.

category: health informatics


title: Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

abstract:
BackgroundEarly antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early.

MethodsWe conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ClinicalTrials{middle dot}gov: NCT04499677.

FindingsBetween 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm.

InterpretationAt the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations.

FundingLifeArc, UK.


title: Co-infection with SARS-COV-2 Omicron and Delta Variants Revealed by Genomic Surveillance

abstract: We identified the co-infection of the SARS-CoV-2 Omicron and Delta variants in two epidemiologically unrelated patients with chronic kidney disease requiring haemodialysis. Both SARS-CoV-2 variants were co-circulating locally at the time of detection. Amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified Omicron and Delta subpopulations in respiratory samples from the two patients. These findings highlight the importance of genomic surveillance in vulnerable populations.


title: Distinguishing Admissions Specifically for COVID-19 from Incidental SARS-CoV-2 Admissions: A National EHR Research Consortium Study

abstract:
BackgroundAdmissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. EHR-based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. Although the need to improve classification of COVID-19 disease vs. incidental SARS-CoV-2 is well understood, the magnitude of the problems has only been characterized in small, single-center studies. Furthermore, there have been no peer-reviewed studies evaluating methods for improving classification.

ObjectiveThe aims of this study were to: first, quantify the frequency of incidental hospitalizations over the first fifteen months of the pandemic in multiple hospital systems in the United States; and second, to apply electronic phenotyping techniques to automatically improve COVID-19 hospitalization classification.

MethodsFrom a retrospective EHR-based cohort in four US healthcare systems in Massachusetts, Pennsylvania, and Illinois, a random sample of 1,123 SARS-CoV-2 PCR-positive patients hospitalized between 3/2020-8/2021 was manually chart-reviewed and classified as admitted-with-COVID-19 (incidental) vs. specifically admitted for COVID-19 (for-COVID-19). EHR-based phenotyping was used to find feature sets to filter out incidental admissions.

ResultsEHR-based phenotyped feature sets filtered out incidental admissions, which occurred in an average of 26% of hospitalizations (although this varied widely over time, from 0%-75%). The top site-specific feature sets had 79-99% specificity with 62-75% sensitivity, while the best performing across-site feature set had 71-94% specificity with 69-81% sensitivity.

ConclusionsA large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.


title: COVID-19 onset reduced the sex ratio at birth in South Africa

abstract:
BackgroundThe sex ratio at birth [defined as male/(male+female) live births] is anticipated to approximate 0.510 with a slight male excess. Following sudden unexpected stressful events, this ratio has been observed to decrease transiently around 3-5 months following such events. We hypothesised that stress engendered by the onset of the COVID-19 pandemic may have caused such a decrease in South Africa 3-5 months after March 2020 since in this month, South Africa reported its first COVID-19 case, death and nationwide lockdown restrictions were instituted.

MethodsWe used publicly available recorded monthly live birth data from Statistics South Africa. The most recent month for which data was available publicly was December 2020. We analysed live births for a 100-month period from September 2012 to December 2020, taking seasonality into account. Chi-squared tests were applied.

ResultsOver this 100-month period, there were 8,151,364 live births. The lowest recorded monthly sex ratio at birth of 0.499 was in June 2020, 3 months after March 2020. This June was the only month during this period where the sex ratio inverted i.e., fewer male live births occurred. The predicted June 2020 ratio was 0.504. The observed June 2020 decrease was statistically significant p = 0.045.

ConclusionsThe sex ratio at birth decreased and inverted in South Africa in June 2020, for the first time, during the most recent 100-month period. This decline occurred 3 months after the March 2020 onset of COVID-19 in South Africa. As June 2020 is within the critical window when population stressors are known to impact the sex ratio at birth, these findings suggest that the onset of the COVID-19 pandemic engendered population stress with notable effects on pregnancy and public health in South Africa. These findings have implications for future pandemic preparedness and social policy.


title: Identifying the target population for primary Respiratory Syncytial Virus two-step prevention in infants: Normative Outcome of Hospitalisation Assessment for Newborns (NOHAN)

abstract:
BackgroundRespiratory syncytial virus (RSV) is the leading cause of acute respiratory infection related hospitalisations in infants (RSVh). Most of these infants are younger than 6 months old with no known risk factors. An efficient RSVh prevention program should address both mothers and infants, relying on Non-Pharmaceutical (NPI) and Pharmaceutical Interventions (PI). This study aimed at identifying the target population for these two interventions.

MethodsLaboratory-confirmed RSV-infected infants hospitalised during the first 6 months of life were enrolled from the Hospices Civils de Lyon birth cohort (2014 to 2018). Clinical variables related to pregnancy and birth (sex, month of birth, birth weight, gestational age, parity) were used for descriptive epidemiology, multivariate logistic regression, and predictive score development.

FindingsOverall, 616 cases of RSVh in 45 648 infants were identified. Being born before the epidemic season, prematurity, and multiparity were independent predictors of RSVh. Infants born in January or June to August with prematurity and multiparity, and those born in September or December with only one other risk factor (prematurity or multiparity) were identified as moderate-risk, identifying the mothers as candidates for a first level NPI prevention program. Infants born in September or December with prematurity and multiparity, and those born in October or November were identified as high-risk, identifying the mothers and infants as candidates for a second level (NPI and PI) intervention.

InterpretationIt is possible to determine predictors of RSVh at birth, allowing to enrol early the target population in a two-level RSV prevention intervention.

FundingNone.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIn infants, the global burden of disease caused by the respiratory syncytial virus (RSV) is increasingly recognised. Nowadays the prevention programs are limited to the only licensed drug, Palivizumab, a humanised monoclonal antibody that shows some benefit in preventing RSV in high-risk infants. With the recent encouraging progress obtained using a maternal vaccine candidate and long half-life monoclonal antibodies administered to newborns, as well as the impact of Covid-19 non-pharmaceutical interventions on the RSV epidemic, there is an urgent need to revisit this prevention paradigm from a much broader perspective.

Added value of this studyUsing a hospital birth cohort (NOHAN strategy) split into a training and a testing dataset, we were able to determine strong maternal and newborn predictors for the risk of RSV hospitalisation. Month of birth, multiparity, and prematurity were sufficient to accurately identify low-, moderate-, and high-risk groups in the validating cohort.

Implications of all the available evidenceUsing the NOHAN strategy, future parents could be enrolled early during pregnancy follow-up in a health-related behaviour change program and then be proposed a vaccine boost for the pregnant women or neutralizing monoclonal antibodies for the newborns. The thresholds for triggering each intervention can be adjusted to the local epidemiology, the resources available, and the evolving evidence concerning the cost-efficiency of the future interventions. Stakeholders, healthcare professionals and policy makers must acknowledge this opportunity when designing the future of RSV prevention programs.


title: SARS-CoV-2 variants of concern Alpha and Delta show increased viral load in saliva

abstract:
BackgroundHigher viral loads in SARS-CoV-2 infections may be linked to more rapid spread of emerging variants of concern (VOC). Rapid detection and isolation of cases with highest viral loads, even in pre- or asymptomatic individuals, is essential for the mitigation of community outbreaks.

Methods and FindingsIn this study, we analyze Ct values from 1297 SARS-CoV-2 positive patient saliva samples collected at the Clemson University testing lab in upstate South Carolina. Samples were identified as positive using RT-qPCR, and clade information was determined via whole genome sequencing at nearby commercial labs. We also obtained patient-reported information on symptoms and exposures at the time of testing. The lowest Ct values were observed among those infected with Delta (median: 22.61, IQR: 16.72-28.51), followed by Alpha (23.93, 18.36-28.49), Gamma (24.74, 18.84-30.64), and the more historic clade 20G (25.21, 20.50-29.916). There was a statistically significant difference in Ct value between Delta and all other clades (all p.adj<0.01), as well as between Alpha and 20G (p.adj<0.05). Additionally, pre- or asymptomatic patients (n=1093) showed the same statistical differences between Delta and all other clades (all p.adj<0.01); however, symptomatic patients (n=167) did not show any significant differences between clades. Our weekly testing strategy ensures that cases are caught earlier in the infection cycle, often before symptoms are present, reducing this sample size in our population.

ConclusionsCOVID-19 variants Alpha and Delta have substantially higher viral loads in saliva compared to more historic clades. This trend is especially observed in individuals who are pre- or asymptomatic, which provides evidence supporting higher transmissibility and more rapid spread of emerging variants. Understanding the viral load of variants spreading within a community can inform public policy and clinical decision making.


title: Accuracy of rapid point-of-care antigen-based diagnostics for SARS-CoV-2: an updated systematic review and meta-analysis with meta regression analyzing influencing factors

abstract:
BackgroundComprehensive information about the accuracy of antigen rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 is essential to guide public health decision makers in choosing the best tests and testing policies. In August 2021, we published a systematic review and meta-analysis about the accuracy of Ag-RDTs. We now update this work and analyze the factors influencing test sensitivity in further detail.

Methods and findingsWe registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched multiple databases (PubMed, Web of Science Core Collection, medRvix, bioRvix, and FIND) for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 until August 31, 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity with reverse transcription polymerase chain reaction (RT-PCR) testing as a reference. To evaluate factors influencing test sensitivity, we performed 3 different analyses using multivariate mixed-effects meta-regression models. We included 194 studies with 221,878 Ag-RDTs performed. Overall, the pooled estimates of Ag-RDT sensitivity and specificity were 72.0% (95% confidence interval [CI] 69.8 to 74.2) and 98.9% (95% CI 98.6 to 99.1), respectively. When manufacturer instructions were followed, sensitivity increased to 76.4% (95%CI 73.8 to 78.8). Sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values (sensitivity of 97.9% [95% CI 96.9 to 98.9] and 90.6% [95% CI 88.3 to 93.0] for Ct-values <20 and <25, compared to 54.4% [95% CI 47.3 to 61.5] and 18.7% [95% CI 13.9 to 23.4] for Ct-values [≥]25 and [≥]30) and was estimated to increase by 2.9 percentage points (95% CI 1.7 to 4.0) for every unit decrease in mean Ct-value when adjusting for testing procedure and patients symptom status. Concordantly, we found the mean Ct-value to be lower for true positive (22.2 [95% CI 21.5 to 22.8]) compared to false negative (30.4 [95% CI 29.7 to 31.1]) results. Testing in the first week from symptom onset resulted in substantially higher sensitivity (81.9% [95% CI 77.7 to 85.5]) compared to testing after 1 week (51.8%, 95% CI 41.5 to 61.9). Similarly, sensitivity was higher in symptomatic (76.2% [95% CI 73.3 to 78.9]) compared to asymptomatic (56.8% [95% CI 50.9 to 62.4]) persons. However, both effects were mainly driven by the Ct-value of the sample. With regards to sample type, highest sensitivity was found for nasopharyngeal (NP) and combined NP/oropharyngeal samples (70.8% [95% CI 68.3 to 73.2]), as well as in anterior nasal/mid-turbinate samples (77.3% [95% CI 73.0 to 81.0]).

ConclusionAg-RDTs detect most of the individuals infected with SARS-CoV-2, and almost all when high viral loads are present (>90%). With viral load, as estimated by Ct-value, being the most influential factor on their sensitivity, they are especially useful to detect persons with high viral load who are most likely to transmit the virus. To further quantify the effects of other factors influencing test sensitivity, standardization of clinical accuracy studies and access to patient level Ct-values and duration of symptoms are needed.


title: Surveillance of Myopericarditis following COVID-19 Booster Dose Vaccination in a Large Integrated Health System

abstract:
PurposeThe risk of myopericarditis following COVID-19 booster vaccination has not been extensively evaluated. We provide a timely case ascertainment of myocarditis following COVID-19 booster vaccine in individuals age 18-39 years from an integrated health system.

MethodsWe studied a cohort of 65,785 Kaiser Permanente (KP) Northwest Health Plan members aged 18-39 years who received a COVID-19 vaccine booster at least 5 months following completion of the primary series. We identified cases of myopericarditis by searching the electronic health record for the National Center for Health Statistics (NCHS) text label for  myocarditis or  pericarditis diagnosis codes in all inpatient and outpatient encounters through January 18th 2022. The cohort was followed for 21 days after their booster. We excluded anyone with a documented diagnosis of myocarditis or pericarditis before their first COVID-19 vaccination. Two physicians independently reviewed the identified patient records and applied the CDC myocarditis and pericarditis surveillance case definition to classify records as confirmed, probable or excluded based on the prior published definition.

ResultsOur method identified 6 patients who met the confirmed or probable CDC case definition for acute myocarditis or pericarditis within 21 days of COVID-19 booster dose among 65,785 eligible members. Four cases occurred in 27,253 men. Overall, we estimated 9.1 cases (exact 95% CI 3.4 to 19.9) of post-booster myopericarditis per 100,000 booster doses given. In men, we estimated 14.7 cases (exact 95% CI 4.0 to 37.6) per 100,000 booster doses given.

ConclusionWe identified a rate of 9.1 cases of myopericarditis per 100,000 COVID-19 booster doses which is higher than prior estimates reported by the Vaccine Adverse Event Reporting System (VAERS). Myopericarditis occurs following COVID-19 booster vaccine and may be underreported by current surveillance methods. High sensitivity of these case estimates is essential when modeling risk and benefit for sequential COVID-19 vaccinations for the general population.


title: CT-Guided Direct Current Cardioversion for Atrial Arrhythmias During the COVID-19 Pandemic

abstract:
ObjectiveTo assess left atrial appendage (LAA) thrombus detection using a novel cardiac computed tomography (CT) protocol specifically prior to direct current cardioversion (DCCV).

BackgroundTransesophageal echocardiography (TEE) is the gold standard in evaluating the LAA prior to DCCV for atrial fibrillation (AF) or flutter (AFL). The COVID-19 pandemic has restricted availability of TEE and anesthesia support.

MethodsProspective cohort of consecutive patients with uncontrolled AF/AFL referred for DCCV from March 2020 to March 2021 were enrolled. CT evaluation of LAA was performed with an initial arterial and subsequent 30-second delayed acquisition to exclude thrombus prior to DCCV. Primary end points were to assess safety and outcomes.

ResultsA total of 161 patients were included; mean age 69.8 {+/-} 11.1 years; mean CHA2DS2-VASc 3.4 {+/-} 1.7; and HAS-BLED 1.8 {+/-} 0.9. Median follow-up 175 (105-267) days with zero cardiac-related deaths, and no episodes of TIA or embolic stroke. There was no statistically significant change in mean glomerular filtration rate (GFR) in the study population between the pre- and post-GFR measurements (73.9 {+/-} 21.0 vs 72.7 {+/-} 20.3; p=0.104). Overall mean total dose length product (DLP) was 1042.8 {+/-} 447.5 mGy*cm. Modifying the CT protocol to a narrower 8-cm axial coverage had a statistically significant decrease in total DLP (from 1130.6 {+/-} 464.1 mGy*cm to 802.1 {+/-} 286.4 mGy*cm; P<0.0001).

ConclusionCardiac CT is both a safe and feasible alternative imaging to TEE for patients prior to DCCV.

PerspectivesO_ST_ABSCompetency in Medical KnowledgeC_ST_ABSCardiac CT is a powerful tool for the evaluation of left atrial appendage and detection of thrombus prior to direct current cardioversion.

Translational OutlookOur protocol was implemented with the restrictions during COVID-19 in mind, yet CT can be a viable tool beyond the pandemic; future randomized clinical trials can bridge the gap between CT and TEE in the setting of cardioversion and help elucidate its safety profile further.

category: cardiovascular medicine


title: A Novel de novo TP63 Mutation in WholeExome Sequencing of a Syrian Family with Oral Cleft and Ectrodactyly

abstract:
Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly. A paternal side second-degree relative with only an oral cleft was deceased and unavailable for analysis. Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing. Twentyeight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G>T, p.Arg319Leu), and confirmed by Sanger sequencing. A triallelic SNV was also found in HLA-DRB5, which is similar to and overlaps the known oral cleft gene HLA-DRB1.

TP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. A known mutation 1bp upstream (rs121908839, c.955C>T, p.Arg319Cys) causes ectrodactyly, providing evidence that mutating this codon is deleterious. It is unclear whether this patients mutation is responsible for the entire phenotype. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days postfertilization. The embryonic phenotype could not be rescued by injection of zebrafish or human mRNA. Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.

category: dentistry and oral medicine


title: Integrated metagenomic and bile acid metabolomic analysis of human fecal microbiota transplantation for recurrent Clostridioides difficile and/or inflammatory bowel diseases.

abstract:
BackgroundFecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI). In comparison, FMT has more limited efficacy in treating either ulcerative colitis (UC) or Crohns disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and may be normalized by FMT.

AimTo study the effect of single colonoscopic FMT on the microbial composition and function of recipients with rCDI and/or IBD.

MethodsMulti-omic analysis was performed on stools from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials [ClinicalTrials.gov ID:NCT03268213, 479696, (IND) 15642, ClinicalTrials.gov ID: NCT03267238, IND 16795]. Fitted linear mixed models were used to examine the effects of four recipient groups (rCDI - IBD, rCDI + IBD, UC - rCDI, CD - rCDI), FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions.

ResultsFMT was effective in preventing rCDI for up to one year in 92% of the rCDI - IBD group and 75% of the rCDI + IBD recipients. The donor-recipient Sorensen similarity index was < 0.6 in all donor-CDI recipient pairs but > 0.6 in some donor-IBD only recipient pairs at baseline. Increasing post-FMT similarity indices > 0.6 in IBD recipients, was not clearly associated with reduced fecal calprotectin levels. Fecal secondary BA levels were lower in rCDI {+/-} IBD and CD - rCDI recipients compared to donors. FMT restored secondary BA levels in these recipients. Metagenomic baiE gene and some of the 8 bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels.

ConclusionRestoration of multiple secondary BA levels, including those recently implicated in immunomodulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7--dehydroxylation step is rate-limiting.

category: gastroenterology


title: Prior SARS-CoV2 infection in vaccinated solid organ transplant recipients induces potent neutralization responses against variants, including Omicron

abstract: Factors affecting functional antibody responses in solid organ transplant recipients (SOTRs) to current SARS-CoV2 vaccines are not well understood. Here, we measured vaccine-induced neutralizing activities against the D614G-CoV2 baseline virus and eight variants, including Omicron, in a panel of CoV2 infected- (n=13) and uninfected- (n=63) vaccinated kidney and heart transplant recipients. In the CoV2 uninfected-vaccinated subset, only 19% and 35% of two and three-dose vaccinated recipients respectively possessed minimally protective neutralizing plasma antibody titers (IC50>1:50) against D614G. In contrast, all of the CoV2 infected-vaccinated SOTRs who received two vaccine doses possessed titers exceeding minimal protection; 12/13 exhibiting strong protection (IC50>1:600) against D614G with minimal increases provided by a third dose. Omicron was the most resistant variant: only 10% of CoV2 uninfected-vaccinated SOTRs reached the minimally protective neutralization titer, while 76% of CoV2 infected-vaccinated SOTRs exceeded this value. These results indicate that prior infection and vaccination can induce highly protective antibody responses in many SOTRs, and identify important factors (shorter time since transplantation, prednisone administration, and African American ethnicity) that limit these responses. Overall, these results suggest factors to consider in establishing optimum COVID-19 vaccination strategies in these cohorts.

category: transplantation


title: Reliable estimation of SARS-CoV-2 anti-spike protein IgG titers from single dilution optical density values in serologic surveys

abstract:
BackgroundAs the COVID-19 pandemic evolves, there is a need for reliable and scalable seroepidemiology methods to estimate incidence, monitor the dynamics of population-level immunity, and guide mitigation and immunization policies. Our aim was to evaluate the reliability of normalized ELISA optical density (nOD) at a single dilution as a predictor of SARS-CoV-2 immunoglobulin titers derived from serial dilutions.

MethodsWe conducted serial serological surveys of a community-based cohort from the city of Salvador, Brazil after two sequential COVID-19 epidemic waves. Anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S IgG) ELISA (Euroimmun AG) was performed with serial 3-fold dilutions of sera from 54 of the 1101 cohort participants. We estimated interpolated ELISA titers, used parametric models to fit the relationship between nOD at a single 1:100 dilution and interpolated titers, and assessed the correlation between changes in nOD and changes in titers.

ResultsThe relationship between nOD at a single 1:100 dilution and interpolated titers fit a log-log curve, with a residual standard error of 0.304. We derived a conversion table of nOD to interpolated titer values. Additionally, there was a high correlation between changes in nOD and changes in interpolated titers between paired serial samples (r = 0.836, {rho} = 0.873). Changes in nOD reliably predicted increases and decreases in titers, with 98.1% agreement ({kappa} = 95.9%).

ConclusionSingle nOD measurements can reliably estimate SARS-CoV-2 antibody titers, significantly reducing time, labor, and resource needs when conducting large-scale serological surveys to ascertain population-level changes in exposure and immunity.

HighlightsO_LIOptical density at a single dilution reliably estimates SARS-CoV-2 antibody titers
C_LIO_LISerial optical density measurements accurately identify changes in serostatus
C_LIO_LIUsing single optical density values can significantly reduce resource use in serosurveys
C_LI


title: Is chronic pain an affective disorder? Moderation of resting-state functional connectivity within the emotional brain by depressive symptoms

abstract:
BackgroundDepressive symptoms are often comorbid to chronic pain. These conditions share aberrant emotion processing and regulation, as well as common brain networks. However, the relationship between depressive symptoms and chronic pain on emotional brain function is unclear.

MethodsParticipants were 26 individuals with chronic pain (referred to as the Pain group) and 32 healthy controls (HC), who underwent resting-state functional magnetic resonance imaging and completed the Beck Depressive Inventory. Main effects of group, depressive symptom severity (total score), and their interaction were evaluated on functional connectivity from three seed regions (separately, the left and right amygdalae, the medial prefrontal cortex, mPFC) and the rest of the brain. In case of significant interaction, moderation analyses were conducted.

ResultsThe group-by-depressive symptoms interaction was significantly associated with changes in connectivity between the right amygdala and the mPFC (pFWEc<0.001). Moderation analysis indicated that, compared to the HC group, the Pain group showed weaker connectivity between these regions at lower levels of depressive symptoms (p=0.018), and stronger connectivity at higher levels of depressive symptoms (p=0.001). In addition, the strength of connectivity decreased in the HC (p=0.004) and increased in the Pain group (p=0.011) as the severity of depressive symptoms increased. Finally, the Pain group showed significant weaker connectivity between the mPFC seed and the left parahippocampal gyrus compared to the HC group (pFWEc=0.015).

ConclusionsThese results indicate that depressive symptoms moderate the impact of chronic pain on the emotional brain function and highlight potential implications for the choice of treatment for chronic pain.


title: Reward Responsiveness across Autism and Autistic Traits. Evidence from Neuronal, Autonomic, and Behavioural Levels

abstract: Atypicalities in processing of social rewards have been suggested to lie at the root of social difficulties in autism spectrum conditions (ASC). While evidence for atypical reward function in ASC is mounting, it remains unclear whether it manifests specifically in hypo- or hyper-responsiveness, and whether it appears only in the social domain or more generally. Moreover, stimuli used as social rewards in studies often lack familiarity and relevance, which are known to enhance reward-related responses. In this study, we investigated behavioural (reaction times and ratings), neuronal (event-related potentials), and autonomic (pupil sizes) responses to three conditions - relevant social rewards, money, and neutral informative outcomes - in 26 ASC and 53 non-autistic subjects varying in levels of autistic traits, as measured with the Autism Spectrum Quotient (AQ). We used both a population-based approach (low AQ vs. high AQ) and a psychopathological approach (low AQ vs. ASC) to investigate the effects of both sub-clinical and clinical autistic traits on reward responsiveness. As hypothesised and preregistered, autism and autistic traits did not differently influence responses to social, monetary, and neutral outcomes on behavioural, neuronal or autonomic level. Although the ASC group rated the stimulis motivational and rewarding values lower than the other groups, the task performance was similar for all participants. Moreover, the ASC group in contrast to low AQ group showed enhanced brain responses (the CNV) in early anticipation and larger pupil constrictions in reward reception. Both effects were also predicted by autistic traits (AQ). Together, our results do not offer evidence for specifically social reward deficits in ASC. Instead, the data suggest enhanced neuronal and autonomic reward responsiveness linked to autism with simultaneously typical performance and reduced self-reported motivational and rewarding values of stimuli. Together, these results emphasise the need to investigate multiple processing levels for a broader picture of reward responsiveness in ASC.


title: In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis via the ENIGMA Consortium.

abstract:
BackgroundEmerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls (CTR) using diffusion tensor imaging (DTI).

MethodsOur sample included 321 adolescents with EOP (mean age: 16.3 {+/-} 1.4 years, 46.4% females) and 265 adolescent CTR (mean age: 16.0 {+/-} 1.7 years, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures.

ResultsWe found widespread lower FA in EOP compared to CTR, with the largest effect sizes in the superior longitudinal fasciculus (Cohens d = 0.37), posterior corona radiata (d = 0.32), and superior fronto{square}occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status.

ConclusionUsing the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male patients with early-onset schizophrenia and patients with a shorter duration of illness.


title: Supporting first FSH dosage for ovarian stimulation with Machine Learning

abstract:
Research questionIs it possible to identify accurately the optimal first dose of FSH in controlled ovarian stimulation (COS) by means of a machine learning (ML) model?

DesignObservational study (2011 to 2021) including first In Vitro Fertilization (IVF) cycles with own oocytes. 2713 patients from five private reproductive centers were included in the development phase of the model (2011 to 2019), and 774 in the validation phase (2020 to 2021). Predictor variables included: age, Body Mass Index (BMI), Antimullerian Hormone (AMH), Antral Follicle Count (AFC), and previous live births. Performance of the developed model was measured with a proposed score based on the number of MII retrieved and the dose received and/or recommended.

ResultsThe cycles included were from women 37.2{+/-}4.9 years old [18-45], with a BMI of 23.7{+/-}4.2, AMH of 2.4{+/-}2.3, AFC of 11.8{+/-}7.7; and an average number of MII obtained 7.2{+/-}5.3. The model reached a mean performance score of 0.87 (95% CI 0.86 to 0.88) in the development phase; this value was significantly better than the one for the doses prescribed by the clinicians for the same patients (0.83 [0.82, 0.84]; p-value= 2.44 e-10). The mean performance score of the model recommendations was 0.89 (95% CI 0.88 to 0.90) in the validation phase, also significantly better than clinicians (0.84 [0.82, 0.86]; p-value = 3.81 e-05). With these results the model was shown to surpass the performance of the standard practice.

Conclusion(s)The ML model developed could be deployed as a training and learning tool for new clinicians and serve as quality control for experienced ones; further, it could be used as second opinion, for instance by providing information in peer-to-peer case discussions.

Key MessageA Machine Learning model was trained to recommend first FSH doses for ovarian stimulation. When compared to clinicians the model developed had consistently better performance scores. The model could be used as a second opinion and as learning tool for new clinicians; to avoid as many non-optimal outcomes as possible.

category: sexual and reproductive health


title: Is this Herpes or Syphilis?: Latent Dirichlet Allocation Analysis of Sexually Transmitted Disease-Related Reddit Posts During the COVID-19 Pandemic

abstract:
BackgroundSexually Transmitted Diseases (STDs) are common and costly, impacting approximately one in five people annually. Reddit, the sixth most used internet site in the world, is a user-generated social media discussion platform that may be useful in monitoring discussion about STD symptoms and exposure.

ObjectiveThis study sought to define and identify patterns and insights into STD related discussions on Reddit over the course of the COVID-19 pandemic.

MethodsWe extracted posts from Reddit from March 2019 through July 2021. We used a machine learning text mining method, Latent Dirichlet Allocation (LDA), to conduct a text analysis to identify the most common topics discussed in the Reddit posts. We then used word clouds, qualitative topic labelling, and spline regression to characterize the content and distribution of topics observed.

ResultsOur extraction resulted in 24,311 total posts. LDA Coding showed that with 8 topics for each time period we achieved high coherence values (pre-COVID=0.41, pre-vaccine=0.42; post-vaccine=0.44). While most topic categories remained the same over time, the relative proportion of topics changed and new topics emerged. Spline regression revealed some key terms had variability in the percentage of posts that coincided with COVID-19 pre- and post-periods, while others were uniform across the study periods.

ConclusionsOur studys use of Reddit is a novel way to gain insights into STD symptoms experienced, potential exposures, testing decisions, common questions, and behavior patterns (e.g., during lock down periods). For example, reduction in STD screening may result in observed negative health outcomes due to missed cases, which also impacts onward transmission. As Reddit use is anonymous, users may discuss sensitive topics with greater detail, and more freely than in clinical encounters. Data from anonymous Reddit posts may be leveraged to enhance understanding of the distribution of disease and need for targeted outreach/screening programs. This study demonstrates Reddit has feasibility and utility to enhance understanding of sexual behaviors, STD experiences, and needed health engagement with the public.


title: Tau Imaging with 18F-MK6240 across the Alzheimer's Disease spectrum

abstract:
Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimers disease (AD). Recent generation tracers have high target to background ratios giving a wide dynamic range that may improve sensitivity for detection of low levels of tau (Pascoal, Shin et al. 2018). Building on previous evidence, this study aims to characterize the effects of tau deposition as assessed by 18F-MK6240, in a large cohort of patients across the AD disease spectrum.

A total of 464 participants, enrolled in the AIBL-ADNeT study, underwent 18F-MK6240 tau PET, 18F-NAV4964 A{beta} PET, 3D structural MRI (hippocampal and whole-brain cortical volumes) and extensive neuropsychological evaluation. Participants included 266 cognitively unimpaired controls (CU), 112 patients with mild cognitive impairment (MCI), and 86 patients with probable AD dementia. Evaluation included the characterization of the pattern and degree of 18F-MK6240 tracer retention in each clinical group as well as assessment of the relationship between 18F-MK6240 and age, A{beta} imaging, brain volumetrics and cognition in each of the clinical groups. Standard uptake value ratios (SUVR) were estimated in four predefined composite regions of interest (ROIs), reflecting the stereotypical progression of tau pathology in the brain: 1. Mesial-temporal (Me), 2. Temporoparietal (Te), 3. Remainder of neocortex (R), 4. A temporal meta-region termed metaT+.

 18F-MK6240 retention was higher in AD patients compared with all other diagnostic groups, with 18F-MK6240 distinguishing patients with AD from CU individuals, with the highest effect size obtained in the amygdala (Cohens d: 2.07), and Me (Cohens d: 1.99). When considering A{beta} status, 18F-MK6240 not only was able to distinguish between A{beta}+ AD patients and A{beta}- CU (Cohens d: 2.23), but also between A{beta}+ and A{beta}- CU (Cohens d: 1.32). In A{beta}- CU, 18F-MK6240 retention in Me showed a slow age-related increase, while 18F-MK6240 retention was higher in younger elderly A{beta}+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and A{beta}, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical A{beta}. Moreover, a non-linear relationship between A{beta} and tau suggest that detectable cortical A{beta} precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and A{beta} and hippocampal volume in MCI, the main predictor of cognitive decline in the AD group was tau. High tau was associated with faster cognitive decline and clinical progression in the CU and MCI groups.

This large study provides further evidence that 18F-MK6240 discriminates CU from AD and, most importantly, A{beta}+ from A{beta}- CU individuals with high effect sizes, suggesting that 18F- MK6240 can detect lower tau levels than earlier tau tracers, crucial for early detection of tau deposition as well as tracking small tau changes over time. In conclusion, identification of regional cortical tau deposition has critical diagnostic and prognostic implications and should become a standard tool to identify individuals at risk, as well as outcome measure, in both anti- A{beta} and anti-tau trials.

category: neurology


title: Single cell analysis of menstrual endometrial tissues defines phenotypes associated with endometriosis

abstract:
BackgroundEndometriosis is a common, complex disorder which is under-recognized and subject to prolong delays in diagnosis. It is accompanied by significant changes in the eutopic endometrial lining.

MethodsWe have undertaken the first single cell RNA-sequencing (scRNA-Seq) comparison of endometrial tissues in freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) and controls as well as symptomatic subjects.

ResultsWe identify a unique subcluster of proliferating uterine natural killer (uNK) cells in ME-tissues from controls that is almost absent from endometriosis cases, along with a striking reduction of total uNK cells in the ME of cases (p<10-16). In addition, IGFBP1+ decidualized subset of stromal cells are abundant in the shed endometrium of controls when compared to cases (p<10-16) confirming findings of compromised decidualization of cultured stromal cells from cases. By contrast, endometrial stromal cells from cases are enriched in cells expressing a pro-inflammatory phenotype. An enrichment of B cells in the cases (p=5.8 x 10-6) raises the possibility in some subjects of chronic endometritis, a disorder which predisposes to endometriosis.

ConclusionsWe propose that characterization of endometrial tissues in ME will provide an effective screening tool for identifying endometriosis in patients with chronic symptoms suggestive of this disorder. This constitutes a major advance, since delayed diagnosis for many years is a major clinical problem in the evaluation of these patients. Comprehensive analysis of ME is expected to lead to new diagnostic and therapeutic approaches to endometriosis and other associated reproductive disorders such as female infertility.

Brief summaryThe single cell analysis of menstrual effluent reveals differences in the endometrial tissues that may inform new diagnostic approaches to endometriosis.

category: obstetrics and gynecology


title: COVID-19 mortality and excess mortality among working-age Californians, by occupational sector: March 2020 through November 2021

abstract:
BackgroundDuring the first year of the pandemic, essential workers faced higher rates of SARS-CoV-2 infection and COVID-19 mortality than non-essential workers. It is unknown whether disparities in pandemic-related mortality across occupational sectors have continued to occur, amidst SARS-CoV-2 variants and vaccine availability.

MethodsWe obtained data on all deaths occurring in the state of California from 2016 through 2021. We restricted our analysis to California residents who were working age (18-65 years at time of death) and died of natural causes. Occupational sector was classified into 9 essential sectors; non-essential; or not in the labor market. We calculated the number of COVID-19 deaths in total and per capita that occurred in each occupational sector. Separately, using autoregressive integrated moving average models, we estimated total, per-capita, and relative excess natural-cause mortality by week between March 1, 2020, and November 30, 2021, stratifying by occupational sector. We additionally stratified analyses of occupational risk into regions with high versus low vaccine uptake, categorizing high-uptake regions as counties where at least 50% of the population completed a vaccination series by August 1, 2021.

FindingsFrom March 2020 through November 2021, essential work was associated with higher COVID-19 and excess mortality compared with non-essential work, with the highest per-capita COVID-19 mortality in agriculture (131.8 per 100,000), transportation/logistics (107.1), manufacturing (103.3), and facilities (101.1). Essential workers continued to face higher COVID-19 and excess mortality during the period of widely available vaccines (March through November 2021). Between July and November 2021, emergency workers experienced higher per-capita COVID-19 mortality (113.7) than workers from any other sector. Essential workers faced the highest COVID-19 mortality in counties with low vaccination rates, a difference that was more pronounced during the period of the Delta surge in Summer 2021.

InterpretationEssential workers have continued to bear the brunt of high COVID-19 and excess mortality throughout the pandemic, particularly in the agriculture, emergency, manufacturing, facilities, and transportation/logistics sectors. This high death toll has continued during periods of vaccine availability and the delta surge. In an ongoing pandemic without widespread vaccine coverage and anticipated threats of new variants, the US must actively adopt policies to more adequately protect essential workers.

category: occupational and environmental health


title: A novel molecular subtype of hepatocellular carcinoma based on the tumor purity and tumor microenvironment-related polygenic risk scores

abstract:
PurposeThe purpose of the present study was to use malignant cell-related and tumor microenvironment (TME)-related molecules to develop a novel molecular subtype of hepatocellular carcinoma (HCC).

MethodsThe tumor purity (TP)-related and TME-related genes were identified and separately used to construct the TP-related and TME-related polygenic risk score (PRS). According to the two PRSs, we developed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes.

ResultsThe three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGF{beta} and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. These three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies.

ConclusionBy combining the TP-related PRS and TME-related PRS, we proposed and validated the TP-TME risk subtyping system to divide patients with HCC into three subtypes with distinct biological characteristics and prognoses. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for HCC.


title: Assessment of Genetic Susceptibility to Multiple Primary Cancers through Whole-Exome Sequencing in Two Large Multi-Ancestry Studies

abstract: Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large prospective cohorts (6,429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: 1) an overall combined set with at least two cancers across any of 36 organ sites; and 2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis. Further investigation of these findings may lead to new screening strategies for individuals at risk for multiple primary cancers.

category: genetic and genomic medicine


title: Genetic control of body weight by the human brain proteome

abstract: Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with body weight but the biological relevance of most remains unexplored. Given the critical role of the brain in multiple biological processes associated with body weight regulation, we set out to determine whether genetic variants linked with body mass index (BMI) could be mapped to brain proteins. Using genetic colocalization, we mapped 23 loci from the largest BMI GWAS (n=806,834) to brain proteins (obtained from a dataset of >7000 dorsolateral prefrontal cortex proteins measured by mass spectrometry in >400 individuals). We also performed a proteome-wide Mendelian randomization analysis followed by genetic colocalization, which allowed us to identify an additional 48 brain proteins linked with BMI. Multi-trait colocalization suggested that more than 75% of the protein quantitative trait loci (pQTL)-BMI associations are mediated via protein expression and not via RNA expression. Single-cell sequencing from the human brain cortex revealed that the genes expressing the proteins associated with BMI may be predominantly expressed in oligodendrocytes. In the Quebec Family Study, a genetic risk score (GRS) including these brain pQTLs was associated with higher dietary carbohydrate intake and lower lipid intake whereas a GRS including the 67 variants most strongly associated with BMI was not associated with dietary intake. In conclusions, we identified 71 proteins expressed in the prefrontal cortex that may be critical regulators of body weight and possibly dietary intake in humans.


title: Clinical and economic benefits of lenzilumab plus standard of care compared with standard of care alone for the treatment of hospitalized patients with Coronavirus Disease 19 (COVID-19) from the perspective of National Health Service England

abstract:
PurposeEstimate the clinical and economic benefits of lenzilumab plus standard of care (SOC) compared with SOC alone in the treatment of hospitalized COVID-19 patients from the National Health Service (NHS) England perspective.

MethodsA cost calculator was developed to estimate the clinical benefits and costs of adding lenzilumab to SOC in newly hospitalized COVID-19 patients over 28 days. The LIVE-AIR trial results informed the clinical inputs: failure to achieve survival without ventilation (SWOV), mortality, time to recovery, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) use. Base case costs included drug acquisition and administration for lenzilumab and remdesivir and hospital resource costs based on level of care required. Clinical and economic benefits per weekly cohort of newly hospitalized patients were also estimated.

ResultsIn all populations examined, specified clinical outcomes were improved with lenzilumab plus SOC over SOC treatment alone. In a base case population aged <85 years with C-reactive protein (CRP) <150 mg/L, with or without remdesivir, adding lenzilumab to SOC was estimated to result in per-patient cost savings of {pound}1,162. In a weekly cohort of 4,754 newly hospitalized patients, addition of lenzilumab to SOC could result in 599 IMV uses avoided, 352 additional lives saved, and over {pound}5.5 million in cost savings. Scenario results for per-patient cost savings included: 1) aged <85 years, CRP <150 mg/L, and receiving remdesivir ({pound}3,127); 2) Black patients with CRP <150 mg/L ({pound}9,977); and 3) Black patients from the full population ({pound}2,369). Conversely, in the full mITT population, results estimated additional cost of {pound}4,005 per patient.

ConclusionFindings support clinical benefits for SWOV, mortality, time to recovery, time in ICU, time on IMV, and ventilator use, and an economic benefit from the NHS England perspective when adding lenzilumab to SOC for hospitalized COVID-19 patients.

category: health economics


title: Implementing semantic interoperability of gene expression profiles using the HL7 FHIR standard

abstract: High-throughput technologies, especially gene expression analyses can accurately capture the molecular state in patients under different conditions. Thus, their application in clinical routine gains increasing relevance and fosters patient stratification towards individualized treatment decisions. Electronic health records already evolved to capture genomic data within clinical systems and standards like FHIR enable sharing within, and even between institutions. However, FHIR only provides profiles tailored to variations in the molecular sequence, while expression patterns are neglected although being equally important for decision making. Here we provide an exemplary implementation of gene expression profiles of a microarray analysis of patients with acute myeloid leukemia using an adaptation of the FHIR genomics extension. Our results demonstrate how FHIR resources can be facilitated in clinical systems and thereby pave the way for usage for the aggregation and exchange of transcriptomic data in multi-center studies.


title: Adaptation of HL7 FHIR for the exchange of patients' gene expression profiles


title: Mobility restrictions as a pandemic response

abstract: The COVID19 pandemic has caused a large number of infections and fatalities, causing administrations at various levels to use different policy measures to reduce viral spread by limiting public mobility. This paper analyzes the complex association between the stringency of restrictions, public mobility, and reproduction rate (R-value) on a national level for Germany. The goals were to analyze; a) the correlation between government restrictions and public mobility and b) the association between public mobilities and virus reproduction. In addition to correlations, a Gaussian Process Regression Technique is used to fit the interaction between mobility and R-value. The main findings are that: (i) Government restrictions has a high association with reduced public mobilities, especially for non-food stores and public transport, (ii) Out of six measured public mobilities, retail, recreation, and transit station activities have the most significant impact on COVID19 reproduction rates. (iii) A mobility reduction of 30% is required to have a critical negative impact on case number dynamics, preventing further spread.

category: health policy


title: Assessing the Profile of Unvaccinated COVID-19 Individuals in African American and Latinx Communities in Eastern Pennsylvania

abstract:
BackgroundThroughout US history, chronic and infectious diseases have severely impacted minority communities due to lack of accessibility to quality healthcare, accurate information, and underlying racism. These fault lines in the care of minority communities in the US have been further exposed by the rise of COVID-19 pandemic. This study examined the factors associated with COVID-19 vaccine hesitancy among African American and Latinx communities in Eastern Pennsylvania (PA).

MethodsSurvey data was collected in July 2021 in Philadelphia, Scranton, Wilkes-Barre, and Hazleton, PA. The 203 participants (38.7% Black, 27.5% Latinx) completed the 28-question survey of COVID-19 vaccination attitudes in either English or Spanish.

ResultsOut of a total of 181 participants that met inclusion criteria of completed surveys, results indicate that 63.5% (n=115) were acceptant of the COVID-19 vaccine whereas the remainder 36.5% (n=66) were hesitant. Binary logistic regression results showed that age, concern for vaccine efficacy, race, knowledge on the vaccine, and belief that the COVID-19 virus is serious significantly influenced COVID vaccine hesitancy. Minorities were more likely to be hesitant toward vaccination (OR: 2.77, 95% CI: 1.13, 6.79) than non-Hispanic whites. Those who believed the COVID vaccine was ineffective (OR: 8.29, 95% CI: 3.78,18.2), and that the virus is not serious (OR: 8.28, 95% CI: 1.11, 61.8) showed the greatest odds of hesitancy.

ConclusionsContributing factors of vaccine hesitancy in minority communities were age, concern for vaccine efficacy, and education. Understanding and addressing the barriers to COVID-19 vaccination in minority groups is essential to decreasing transmission and controlling this pandemic.

category: infectious diseases