title: Health impact of routine immunisation service disruptions and mass vaccination campaign suspensions caused by the COVID-19 pandemic: Multimodel comparative analysis of disruption scenarios for measles, meningococcal A, and yellow fever vaccination in 10 low- and lower middle-income countries

abstract:
BackgroundChildhood immunisation services have been disrupted by COVID-19. WHO recommends considering outbreak risk using epidemiological criteria when deciding whether to conduct preventive vaccination campaigns during the pandemic.

MethodsWe used 2-3 models per infection to estimate the health impact of 50% reduced routine vaccination coverage and delaying campaign vaccination for measles, meningococcal A and yellow fever vaccination in 3-6 high burden countries per infection.

ResultsReduced routine coverage in 2020 without catch-up vaccination may increase measles and yellow fever disease burden in the modelled countries. Delaying planned campaigns may lead to measles outbreaks and increases in yellow fever burden in some countries. For meningococcal A vaccination, short term disruptions in 2020 are unlikely to have a significant impact.

ConclusionThe impact of COVID-19-related disruption to vaccination programs varies between infections and countries.

FundingBill & Melinda Gates Foundation and Gavi, the Vaccine Alliance

Impact statementRoutine and campaign vaccination disruption in 2020 may lead to measles outbreaks and yellow fever burden increases in some countries, but is unlikely to greatly increase meningococcal A burden.

SummaryO_ST_ABSBackgroundC_ST_ABSChildhood immunisation services have been disrupted by the COVID-19 pandemic. WHO recommends considering outbreak risk using epidemiological criteria when deciding whether to conduct preventive vaccination campaigns during the pandemic.

MethodsWe used 2-3 models per infection to estimate the health impact of 50% reduced routine vaccination coverage in 2020 and delay of campaign vaccination from 2020 to 2021 for measles vaccination in Bangladesh, Chad, Ethiopia, Kenya, Nigeria, and South Sudan, for meningococcal A vaccination in Burkina Faso, Chad, Niger, and Nigeria, and for yellow fever vaccination in the Democratic Republic of Congo, Ghana, and Nigeria. Our counterfactual comparative scenario was sustaining immunisation services at coverage projections made prior to COVID-19 (i.e. without any disruption).

FindingsReduced routine vaccination coverage in 2020 without catch-up vaccination may lead to an increase in measles and yellow fever disease burden in the modelled countries. Delaying planned campaigns in Ethiopia and Nigeria by a year may significantly increase the risk of measles outbreaks (both countries did complete their supplementary immunisation activities (SIAs) planned for 2020). For yellow fever vaccination, delay in campaigns leads to a potential disease burden rise of >1 death per 100,000 people per year until the campaigns are implemented. For meningococcal A vaccination, short term disruptions in 2020 are unlikely to have a significant impact due to the persistence of direct and indirect benefits from past introductory campaigns of the 1 to 29-year-old population, bolstered by inclusion of the vaccine into the routine immunisation schedule accompanied by further catch-up campaigns.

InterpretationThe impact of COVID-19-related disruption to vaccination programs varies between infections and countries. Planning and implementation of campaigns should consider country and infection-specific epidemiological factors and local immunity gaps worsened by the COVID-19 pandemic when prioritising vaccines and strategies for catch-up vaccination.

FundingBill & Melinda Gates Foundation and Gavi, the Vaccine Alliance

category: public and global health


title: Impact of COVID-19-related disruptions to measles, meningococcal A, and yellow fever vaccination in 10 countries


title: Impact of social restrictions during the COVID-19 pandemic on the physical activity levels of older adults: an analysis of the CHARIOT COVID-19 Rapid Response Study

abstract:
ObjectivesPhysical inactivity is more common in older adults, is associated with social isolation and loneliness, and contributes to increased morbidity and mortality. We examined the effect of social restrictions, implemented to reduce transmission of COVID-19 in the UK (lockdown), on physical activity (PA) levels of older adults, and the demographic, lifestyle and social predictors of this change.

DesignBaseline analysis of a survey-based prospective cohort study

SettingAdults enrolled in the Cognitive Health in Ageing Register for Investigational and Observational Trials (CHARIOT) cohort from GP practices in North West London were invited to participate from April to July 2020.

Participants6,219 cognitively healthy adults aged 50 to 92 years completed the survey.

Main outcome measuresSelf-reported PA before and after lockdown, as measured by Metabolic Equivalent of Task (MET) minutes. Associations of PA with demographic, lifestyle and social factors, mood and frailty.

ResultsMean PA was significantly lower following lockdown, from 3,519 MET minutes/week to 3,185 MET minutes/week (p<0.001). After adjustment for confounders and pre-lockdown PA, lower levels of PA after lockdown were found in those who were over 85 years old (640 [95% CI: 246 to 1034] MET minutes/week less); were divorced or single (240 [95% CI: 120 to 360] MET minutes/week less); living alone (277 [95% CI: 152 to 402] MET minutes/week less); reported feeling lonely often (306 [95% CI: 60 to 552] MET minutes/week less); and showed symptoms of depression (1007 [95% CI: 1401 to 612] MET minutes/week less) compared to those aged 50-64 years, married, co-habiting, and not reporting loneliness or depression, respectively.

Conclusions and ImplicationsMarkers of social isolation, loneliness and depression were associated with lower PA following lockdown in the UK. Interventions to improve PA in older adults should take account of social and community factors, and targeted strategies to increase physical activity in socially isolated, lonely and depressed older adults should be considered.


title: The impact of social restrictions during the COVID-19 pandemic on the physical activity levels of older adults: a baseline analysis of the CHARIOT COVID-19 Rapid Response prospective cohort study


title: Clinical impact of the Predict Prostate risk communication tool in men newly diagnosed with non-metastatic prostate cancer: a multi-centre randomised controlled trial.

abstract:
IntroductionPredict Prostate is a freely-available online personalised risk communication tool for men newly diagnosed with non-metastatic prostate cancer. Its accuracy has been assessed in multiple validation studies but the clinical impact of the tool on patient decision-making had not previously been evaluated.

MethodsA multi-centre randomised controlled trial was performed across 8 UK centres, wherein newly diagnosed men considering either active surveillance or radical treatment, were randomised to either standard of care (SOC) information or SOC and presentation of Predict Prostate. Validated questionnaires were completed assessing impact of the tool on decisional conflict, uncertainty, anxiety and understanding of survival.

Results156 patients were included; mean age 67 years (range 44-80) and PSA of 6.9ng/ml (range 0.5-59.8). 81 were randomised to the Predict Prostate arm, and 75 to SOC information only. Mean decisional conflict scores were 26% lower in the Predict Prostate group (mean = 15.9) than in the SOC group (mean = 21.5) (p=0.01). Scores on the  effective decision,  uncertainty and  value clarity subscales all indicated that the Predict Prostate group felt more informed and clear about their decision (all p<0.05). There was no significant difference in anxiety between the two groups.

Patient perceptions of 15-year prostate cancer specific mortality (PCSM) and overall survival benefit from radical treatment were considerably lower among men in the Predict Prostate group (p<0.0001). 58% of men reported the Predict Prostate estimates for PCSM were lower than expected, and 35% reported being less likely to select radical treatment. Over 90% of patients in the Predict Prostate group found it useful and 94% would recommend it to others.

ConclusionPredict Prostate reduces decisional conflict and uncertainty in non-metastatic prostate cancer and shifts patient perceptions around prognosis to be more realistic. This is the first randomised study of such a tool in this context; it demonstrates Predict Prostate can directly inform the complex decision-making process in prostate cancer.

category: urology


title: Elevated HScore is Associated with Poor Clinical Outcomes in COVID-19, Even in the Absence of Secondary Hemophagocytic Lymphohistiocytosis.

abstract:
IntroductionPatients with Coronavirus Disease 2019 (COVID-19) frequently experience a hyperinflammatory syndrome, that leads to unfavorable outcomes. This condition resembles Secondary Hemophagocytic Lymphohistiocytosis (sHLH) described in neoplastic, rheumatic and other infectious diseases. However, it has not been prospectively studied on these patients. A scoring system (HScore) has been validated for sHLH, and recently proposed to evaluate hyperinflammation in COVID-19.

Methods143 patients aged [≥]18 years admitted because of COVID-19 were enrolled in a prospective, single-center, cohort study. HScore was calculated within the 72 hours since admission. The incidence of sHLH during hospitalization was evaluated. Additionally, the relationship between HScore [≥]130 points and either the requirement of mechanical ventilation or 60-days mortality was explored.

ResultsThe median age of enrolled patients was 57 (21-100), and 63.6% were male. The median HScore was 96 (33-169). One patient was diagnosed with sHLH (incidence 0,7%), due to a HScore of 169. After adjusting for age, sex, comorbidities and obesity, HScore [≥]130 was independently associated with the composite clinical outcome (HR 2.13, p=0.022).

ConclusionsHLH is not frequent among COVID-19 patients. HScore can efficiently predict the risk for poor outcomes.

category: hematology


title: A Community-Based Participatory Research to Assess the Feasibility of Ayurveda Intervention in Patients with Mild-to-Moderate COVID-19

abstract:
Innovative strategies are required to manage COVID-19 in the communities. Back to Roots was a collaborative, community-based pilot intervention project in the British Asian community. To assess the efficacy and safety of Ayurveda intervention in relieving symptoms of mild-to-moderate COVID-19, a community based participatory research framework was used. Twenty-eight patients were enrolled with confirmed COVID-19 clinical stages of mild-to-moderate COVID-19, symptomatic, and between 20 to 70{square}years of age. Routine management was followed by all patients managing at home, additionally patents taking Ayurveda intervention for 14 consecutive days. The efficacy and safety of Ayurveda intervention were evaluated. There were suggestions of Ayurvedas advantage in improved symptoms relief, clinical recovery in 7 days. However, a control group was not included but data triangulations from separate usual care found the difference statistically significant. Ayurveda intervention may potentially have a beneficial effect on patients with COVID-19, especially for those with mild to moderate symptoms. A further definitive large-scale clinical trial is necessary.

ClinicalTrials.gov IdentifierNCT04716647

category: infectious diseases


title: Home-based management of COVID-19 by identification of low-risk features

abstract:
BackgroundCovid-19 is a triphasic disorder characterized by a viral phase lasting 7-10 days from onset of symptoms. In approximately 20% it is followed by a second stage heralded by elevation of pro-inflammatory markers such as ferritin, IL-6, CRP, LDH and D-dimers. We hypothesized that those with few abnormalities would have a low risk for progression to respiratory insufficiency and hence could be monitored at home without treatment.

MethodsInclusion criteria included Covid infection, age >21, Oxygen saturation >90%. To be observed without treatment, patients could have no more than 1 of the following: CRP > 10 mg/dL, high LDH, ferritin > 500 ng/ml, D-dimer > 1 mg/L, IL-6 > 10 pg/ml, absolute lymphocyte count <1,000, Oxygen saturation <94%, or CT chest evidence of pneumonia. Primary endpoint was progression to respiratory failure and secondary endpoints was 28-day survival.

ResultsOf 208 entered, 132 were low-risk and hence were monitored without therapy. None progressed to respiratory failure or died.

ConclusionsWe have shown that our approach can identify cases who can safely be observed without treatment, thus avoiding expensive, potentially toxic therapies, and circumventing unnecessary, costly hospitalizations. These results support our hypothesis that applying our criteria, 64% of Covid-19 cases can be monitored as outpatients without therapy.

What is already known about this subjectO_LICOVID-19 is a triphasic disorder first typified by an infectious or viral phase that lasts from the first onset of symptoms until 7-10 days later. This is followed by a second phase considered as the inflammatory stage, characterized initially by the appearance of lung infiltrates which is followed in some cases by hypoxemia.
C_LIO_LIApproximately 80% of patients never proceed to the second phase but currently there is no reliable and objective method to accurately predict those that are cured spontaneously without any treatment and who could be managed at home.
C_LI

What this study addsO_LIWe have developed an approach, based essentially on blood-based inflammatory markers which identifies low-risk cases that do not require therapy and can be managed at home. This method showed an excellent correlation with clinical outcome and has encouraging financial and psychological effects.
C_LIO_LIOf 208 patients, 132, fulfilled criteria for low-risk disease that justified monitoring at home without therapy and none of these developed respiratory failure or any other significant complication.
C_LIO_LIIncluded in this low-risk group were many cases with comorbidities, with COVID-19 pneumonia, as well as patients older than 65 and with more than two symptoms at presentation. These characteristics would usually portend an unfavourable prognosis, yet all these patients had an excellent outcome.
C_LI


title: Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection

abstract:
BackgroundThe search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.

MethodsBronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry.

ResultsThe bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, {gamma}{delta} T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p=0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants.

ConclusionThis observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.

category: allergy and immunology


title: Colder and drier winter conditions are associated with greater SARS-CoV-2 transmission: a regional study of the first epidemic wave in north-west hemisphere countries.

abstract:
Higher transmissibility of SARS-CoV-2 in cold and dry weather conditions has been hypothesized since the onset of the COVID-19 pandemic but the level of epidemiological evidence remains low.

During the first wave of the pandemic, Spain, Italy, France, Portugal, Canada and USA presented an early spread, a heavy COVID-19 burden, and low initial public health response until lockdowns. In a context when testing was limited, we calculated the basic reproduction number (R0) in 63 regions from the growth in regional death counts. After adjusting for population density, early spread of the epidemic, and age structure, temperature and humidity were negatively associated to SARS-CoV-2 transmissibility. A reduction of mean absolute humidity by 1g/m3 was associated with a 0.15-unit increase of R0. Below 10{degrees}C, a temperature reduction of 1{degrees}C was associated with a 0.16-unit increase of R0.

Our results confirm a dependency of SARS-CoV-2 transmissibility to weather conditions in the absence of control measures during the first wave. The transition from summer-to winter-like conditions likely contributed to the intensification of the second wave in north-west hemisphere countries. Adjustments of the levels of social mobility restrictions need to account for increased SARS-CoV-2 transmissibility in winter conditions.

category: epidemiology


title: A flexible, pan-species, multi-antigen platform for the detection and monitoring of SARS-CoV-2-specific antibody responses

abstract:
The SARS-CoV-2 pandemic and the vaccination effort that is ongoing has created an unmet need for accessible, affordable, flexible and precise platforms for monitoring the induction, specificity and maintenance of virus-specific immune responses. Herein we validate a multiplex (Luminex-based) assay capable of detecting SARS-CoV-2-specific antibodies irrespective of host species, antibody isotype, and specimen type (e.g. plasma, serum, saliva or blood spots). The well-established precision of Luminex-based assays provides the ability to follow changes in antibody levels over time to many antigens, including multiple permutations of the most common SARS-CoV-2 antigens. This platform can easily measure antibodies known to correlate with neutralization activity as well as multiple non-SARS-CoV-2 antigens such as vaccines (e.g. Tetanus toxoid) or those from frequently encountered agents (influenza), which serve as stable reference points for quantifying the changing SARS-specific responses. All of the antigens utilized in our study can be made in-house, many in E. coli using readily available plasmids. Commercially sourced antigens may also be incorporated and newly available antigen variants can be rapidly produced and integrated, making the platform adaptable to the evolving viral strains in this pandemic.

Brief SummaryA multi-antigen assay for monitoring SARS-CoV-2-specific antibodies irrespective of host species, antibody isotype, and specimen type was developed.


title: The Association Between Hypoglycemic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis

abstract:
BackgroundDuring the current Coronavirus Disease 2019 (COVID-19) pandemic, diabetic patients face disproportionately more. Anti-inflammatory effects of hypoglycemic agents have been reported, and their beneficial or harmful effects in patients with diabetes and COVID-19 remain controversial.

PurposeThis study was performed to clarify this association.

Data SourcesRelevant literature was searched on China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, Chinese periodical service platform VIP Database, Sinomed (China Biology Medicine, CBM), MedRxiv, PubMed, ScienceDirect, Web of Science, Ovid Databases (LWW), Springer Link, Wiley Online Library, Oxford Academic, Nature Press Group, Cochrane Library and BMJ Evidence-Based Medicine up to November 14, 2020.

Study SelectionOnly observational studies of hypoglycemic agents vs. drugs or therapy without hypoglycemic agents in adult diabetic patients with COVID-19 were included.

Data ExtractionData of death and poor composite outcomes were extracted.

Data SynthesisThe pooled effects were calculated using the fixed-effects or random-effects models based on heterogeneity assessment.

LimitationMost studies were retrospective cohort studies with relative weak capability to verify causality.

ConclusionHome use of metformin might be beneficial in decreasing mortality in diabetic patients infected with SARS-CoV-2. There is insufficient evidence to conclude that metformin and other hypoglycemic agents are associated with poor composite outcomes. More prospective studies, especially RCTs are needed.

Registration-PROSPEROCRD42020221951.

category: endocrinology


title: COVID-19-related disruptions to routine vaccination services in India: perspectives from pediatricians

abstract:
Background and ObjectiveThe COVID-19 pandemic has led to disruptions to routine immunization programs in India and around the world, setting the stage for potentially serious outbreaks of vaccine-preventable diseases.

MethodsWe surveyed pediatric healthcare providers in India in 2 rounds in April-June and September 2020 to understand how COVID-19 control measures may have impacted routine vaccination.

ResultsRespondents were predominantly pediatricians working in primary, secondary or tertiary healthcare centers, across 21 Indian states and two union territories. Among the 424 (survey 1) and 141 (survey 2) respondents, 33.4% and 7.8%, respectively, reported near complete suspension of vaccination services due to COVID-19. A 50% or greater drop in vaccination services was reported by 83.1% of respondents in June, followed by 32.6% four months later, indicating slow recovery of services. By September 2020, 83.6% were aware of updated guidelines on safe provision of immunization services, although awareness of specific catch-up vaccination plans was low, and 76.6% expressed concern about a vaccine coverage gap that could potentially lead to increased non-COVID-19 illnesses and deaths.

ConclusionsPandemic-related disruptions to vaccination services were reported by pediatricians across India. Concerted efforts are needed from governing and academic groups to ensure that routine immunization and catch-up programs are implemented during this pandemic, which can sustain gains in vaccination coverage and provide a robust blueprint for the national roll-out of the COVID-19 vaccine.

category: pediatrics


title: PERIPHERAL INOTROPES IN CRITICALLY ILL CHILDREN - IS IT SAFE?

abstract:
Many children needing paediatric intensive care units care require inotropes, which are started peripherally prior to securing a central venous access. However, many hospitals in low- and middle-income countries may not have access to central lines and the vasoactive medications are frequently given through a peripheral venous access.

AimThe aim of our study was to estimate the safety of peripheral vasoactive inotropes in children.

MethodsChildren requiring peripheral vasoactive medications were included in this study. We retrospectively collected data at two time points on use and complications of peripheral vasoactive medications.

ResultsEighty-four children (51 pre-COVID era and 33 COVID pandemic) received peripheral vasoactive medications. Only 3% of children (3/84) developed extravasation injury, all of whom recovered completely.

ConclusionsResults from our study suggest that extravasation injury due to peripheral inotrope infusion is very low (3%) and it can be safely administered in children at a diluted concentration.


title: SCLERODERMA AND MALIGNANCY

abstract:
Background/ObjectivesDescribe clinical characteristics of malignancy-associated scleroderma in a regional population.

MethodsScleroderma patients with current or past malignancy were prospectively identified from a cohort of 125 scleroderma subjects of a largely Hispanic population. Demographic information included scleroderma subtype, serologies, cancer diagnosis, age at diagnosis, co-morbid conditions, therapies, and survival outcomes.

Results16.0% (20/125) of scleroderma patients were identified as having a malignancy. The mean age of malignancy onset and scleroderma onset were 55.6{+/-}10.3 and 52.7{+/-}12.9 years respectively (95% CI of difference: -4.6 <2.9< 10.4, p=0.44). Antinuclear antibody was positive in 70%, anticentromere antibody in 35.0%, and anti-topoisomerase antibodies in 25%. Tumor proportions were adenocarcinomas 55.0% (11/20) (1 gastric, 2 pancreatic, 1 lung, 2 thyroid, 5 breast), 15% (3/20) squamous cell carcinoma (1 skin, 1 uterine cervical, and 1 rectal), and 20% (4/20) benign tumors (2 meningiomas, 1 renal adenoma, 1 plasma cell). Age of onset of scleroderma greater than 42 years respectively accounted for 85% of all cancer cases. The standardized incidence ratio (SIR) was 2.0 (CI at 95%: 1.2<2<3.1), indicating 100% increase in cancer risk. Treatment of the malignancy did not resolve the scleroderma in any of the cases. Five-year survival after cancer diagnosis was 70.0%, although 2 of the survivors had tumor recurrence.

ConclusionsMalignancy, especially adenocarcinoma, occurs frequently in scleroderma in minority populations with up to 16% of patients affected. High-risk patients are those with scleroderma-onset greater than 42 years in whom routine screening for common cancers should be undertaken.

category: rheumatology


title: Impact of COVID-19 on education, health and lifestyle behaviour of Brazilian urology residents

abstract:
ObjectivesTo evaluate the impact of COVID-19 on clinical and surgical practice, educational activities, health and lifestyle behavior of Brazilian urology residents.

Materials and MethodsA web-based survey was sent to 468 Brazilian urology residents from postgraduate years (PGY) 3 to 5 to collect data on clinical practice and training after 4 months of COVID-19. We also assessed health-related and behavior changes, rate of infection by SARS-CoV-2, deployment to the front line of COVID-19, residents concerns, and access to personal protective equipment (PPE).

ResultsMassive reductions in elective and emergency patient consultations, diagnostic procedures and surgeries were reported across the country, affecting PGY 3 to 5 alike. Most in-person educational activities were abolished. The median damage to the urological training expected for 2020 was 6.0 [3.4 -7.7], on a scale from 0 to 10, with senior residents estimating a greater damage (P< 0.001). Educational interventions developed included online case-based discussions, subspeciality conferences and lectures, and grand rounds. Most senior residents favored extending residency to compensate for training loss and most younger residents favored no additional training (p< 0.001). Modifications in health and lifestyle included weight gain (43.8%), reduced physical activity (68.6%), increased alcoholic intake (44.9%) and cigarette consumption (53.6%), worsening of sexual life (25.2%) and feelings of sadness or depression (48,2%). Almost half were summoned to work on the COVID-19 front-line and 24.4% had COVID-19. Most residents had inadequate training to deal with COVID-19 patients and most reported a shortage of PPE. Residents concerns included the risk of contaminating family members, being away from residency program, developing severe COVID-19 and overloading colleagues.

ConclusionsCOVID-19 had a massive impact in Brazilian urology residents training, health and lifestyle behavior, which may reflect what happened in other medical specialties. Studies should confirm these findings to help developing strategies to mitigate residents losses.


title: Perceived disrespect and abuse among women delivering at a rural tertiary care center in Nepal

abstract:
BackgroundOf the children born every year in Nepal, 57.4% are delivered in health facilities. Disrespect and abuse of women during maternity care are problems that can significantly impact womens willingness to seek out life-saving maternity care. However, evidence suggests ongoing disrespectful maternity care worldwide. This study aims to identify perceived disrespect and abuse during labor and delivery among postnatal women delivering at Bheri Hospital, Nepal.

MethodsA cross sectional study was conducted among 445 purposively selected women admitted in postnatal ward of Bheri Hospital, Nepal from February to March 2020. Ethical approval was obtained from Nepal Health Research Council. Informed written consent was obtained from each participant and a face-to-face interview was conducted for data collection. A semi-structured questionnaire consisting of demographic information and a pre-validated Respectful Maternity Care (RMC) tool was used. The information was then checked, coded, and entered in SPSS for descriptive and inferential analysis.

ResultsIn this study, the participants perceived very high friendly care, abuse-free care and discrimination-free care but moderate timely care only. Timely care was found to be significantly associated with age, ethnicity, occupation, monthly income, gravida, type of delivery, and complications. On multinomial regression, monthly income and type of delivery were the only factors found to be significant. Those mothers who had spontaneous vaginal delivery were 2.07 times more likely to have neutral RMC, and those who earn less than twenty thousand Nepalese rupees per month were likely to perceive high timely RMC.

ConclusionThis study concludes that disrespectful or abusive maternal care is not perceived among women delivering at Bheri Hospital in terms of friendly care, abuse-free care and non- discriminatory care. However, timely care is less reported. Appropriate interventions to provide timely care to delivering women must be instituted.

category: obstetrics and gynecology


title: U.S. Public Views about COVID-19 "Immunity Passports"

abstract:
ImportanceDiscovery of effective vaccines and increased confidence that infection confers extended protection against COVID-19 have renewed discussion of using immunity certificates or "passports" to selectively reduce ongoing public health restrictions.

ObjectiveTo determine public views regarding government and private conferral of immunity privileges.

Design and SettingNational on-line survey fielded in June 2020. Participants were randomly asked about either government "passports" or private "certificates" for COVID-19 immunity.

ParticipantsAdults from a standing panel maintained for academic research, selected to approximate national demographics.

Main Outcomes/MeasuresLevel of support/opposition to immunity privileges, and whether views vary based on: government vs. private adoption; demographics; political affiliation or views; or various COVID19-related attitudes and experiences.

ResultsOf 1315 respondents, 45.2% supported immunity privileges, with slightly more favoring private certificates than government passports (48.1% vs 42.6%, p=0.04). Support was greater for using passports or certificates to enable returns to high-risk jobs or attendance at large recreational events than for returning to work generally. Levels of support did not vary significantly according to age groups, socioeconomic or employment status, urbanicity, political affiliation or views, or whether the respondent had chronic disease(s). However, estimates from adjusted analyses showed less support among women (Odds Ratio, 0.64; 95% Confidence Interval, 0.51 to 0.80), and among Hispanics (0.56; 0.40 to 0.78) and other minorities (0.58; 0.40 to 0.85) compared with whites, but not among blacks (0.83; 0.60 to 1.15). Support was much higher among those who personally wanted a passport or certificate (75.6% vs 24.4%) and much lower among those who believed this would harm the social fabric of their community (22.9% vs 77.1%).

Conclusions and RelevancePublic views are divided on either government or private use of immunity certificates, but, prior to any efforts to politicize the issues, these views do not vary along usual political lines, nor by characteristics that indicate individual vulnerability to infection. Social consensus on the desirability of an immunity privileges programs may be difficult to achieve.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the publics views on government or private use of immunity "passports" to selectively lift COVID-19 restrictions?

FindingsViews are divided and do not vary substantially according to political affiliation or many demographic factors. Support is greater among men but lower among Hispanics and those who believe that immunity privileges would harm the social fabric of society.

MeaningSocial consensus will be difficult to achieve on the appropriateness of immunity privileges.

category: health policy


title: The King's College London Coronavirus Health and Experiences of Colleagues at King's Study: SARS-CoV-2 antibody response in a higher education sample

abstract:
ObjectiveTo assess the feasibility of home antibody testing as part of large-scale study, the Kings College London Coronavirus Health and Experiences of Colleagues at Kings (KCL CHECK).

MethodsParticipants of the KCL CHECK study were sent a SureScreen Diagnostics COVID-19 IgG/IgM Rapid Test Cassette to complete at home in June 2020 (phase 1) and September 2020 (phase 2). Participants were asked to upload a test result image to a study website. Test result images and sociodemographic information were analysed by the research team.

ResultsA total of n=2716 participants enrolled in the KCL CHECK study, with n=2003 (73.7%) and n=1825 (69.3%) consenting and responding to phase 1 and 2. Of these, n=1882 (93.9%; phase 1) and n=1675 (91.8%; phase 2) returned a valid result. n=123 (6.5%; phase 1) and n=91 (5.4%; phase 2) tested positive for SARS-CoV-2 antibodies. A total of n=1488 participants provided a result in both phases, with n=57 (3.8%) testing positive for SARS- CoV-2 antibodies across both phases, suggesting a reduction in the number of positive antibody results over time. Initial comparisons showed variation by age group, gender and clinical role.

ConclusionsOur study highlights the feasibility of rapid, repeated and low-cost SARS-CoV-2 serological testing without the need for face-to-face contact.

What is already known about this subject?Higher education institutions have a duty of care to minimise the spread and transmission of COVID-19 in its campuses, and among staff and students. The reopening of higher education buildings and campuses has brought about a mass movement of students, academics and support staff from across the UK. Serological antibody studies can assist by highlighting groups of people and behaviours associated with high risk of COVID-19.

What are the new findings?We report a framework for SARS-CoV-2 serological antibody testing in an occupational group of postgraduate research students and current members of staff at Kings College London. Over two phases of data collection, 6.5% (phase 1) and 5.4% (phase 2) tested positive for SARS-CoV-2 antibodies, with only 3.8% testing positive for antibodies in both phases, suggesting a reduction in positive antibody results over time.

How might this impact on policy or clinical practice in the foreseeable future?Our study highlights the feasibility of rapidly deploying low-cost and repeatable SARS-CoV-2 serological testing, without the need for face-to-face contact, to support the higher education system of the UK.


title: Lack of trust and social media echo chambers predict COVID-19 vaccine hesitancy

abstract: As COVID-19 vaccines are rolled out across the world, there are growing concerns about the role that trust, belief in conspiracy theories and spread of misinformation through social media impact vaccine hesitancy. We use a nationally representative survey of 1,476 adults in the UK between December 12 to 18, 2020 and five focus groups conducted in the same period. Trust is a core predictor, with distrust in vaccines in general and mistrust in government raising vaccine hesitancy. Trust in health institutions and experts and perceived personal threat are vital, with focus groups revealing that COVID-19 vaccine hesitancy is driven by a misunderstanding of herd immunity as providing protection, fear of rapid vaccine development and side effects, belief the virus is man- made and related to population control. Particularly those who obtain information from relatively unregulated social media sources such as YouTube that have recommendations tailored by watch history are less likely to be willing to become vaccinated. Those who hold general conspiratorial beliefs are less willing to be vaccinated. Since an increasing number of individuals use social media for gathering health information, interventions require action from governments, health officials and social media companies. More attention needs to help people understand their own risks, unpack complex concepts and fill knowledge voids.


title: Non-invasive Diagnosis of Deep Vein Thrombosis from Ultrasound with Machine Learning

abstract:
Deep Vein Thrombosis (DVT) is a blood clot most found in the leg, which can lead to fatal pulmonary embolism (PE). Compression ultrasound of the legs is the diagnostic gold standard, leading to a definitive diagnosis. However, many patients with possible symptoms are not found to have a DVT, resulting in long referral waiting times for patients and a large clinical burden for specialists. Thus, diagnosis at the point of care by non-specialists is desired.

We collect images in a pre-clinical study and investigate a deep learning approach for the automatic interpretation of compression ultrasound images. Our method provides guidance for free-hand ultrasound and aids non-specialists in detecting DVT.

We train a deep learning algorithm on ultrasound videos from 246 healthy volunteers and evaluate on a sample size of 51 prospectively enrolled patients from an NHS DVT diagnostic clinic. 32 DVT-positive patients and 19 DVT-negative patients were included. Algorithmic DVT diagnosis results in a sensitivity of 93.8% and a specificity of 84.2%, a positive predictive value of 90.9%, and a negative predictive value of 88.9% compared to the clinical gold standard.

To assess the potential benefits of this technology in healthcare we evaluate the entire clinical DVT decision algorithm and provide cost analysis when integrating our approach into a diagnostic pathway for DVT. Our approach is estimated to be cost effective at up to $150 per software examination, assuming a willingness to pay $26 000/QALY.


title: Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

abstract:
BackgroundTo assess the outcomes of ivermectin in ambulatory and hospitalized patients with COVID-19.

MethodsFive databases and websites for preprints were searched until January 2021 for randomized controlled trials (RCTs) and retrospective cohorts assessing ivermectin versus control in ambulatory and hospitalized participants. The primary outcome was overall mortality. Secondary outcome was recovered patients. For meta-analysis, random-effects and inverse variance meta-analyses with logarithmic transformation were performed. ROBINS-I for cohort studies, and the Cochrane Risk of Bias 2.0 tool for trials were used. The strength of evidence was assessed using GRADE.

ResultsAfter the selection, twelve studies (five retrospective cohort studies, six randomized clinical trials and one case series), were included. In total, 7412 participants were reported, the mean age was 47.5 (SD 9.5) years, and 4283 (58%) were male. Ivermectin was not associated with reduced mortality (logRR: 0.89, 95% CI 0.09 to 1.70, p = 0.04, I2= 84.7%), or reduced patient recovery (logRR 5.52, 95% CI -24.36 to 35.4, p = 0.51, I2 = 92.6%). All studies had a high risk of bias, and showed a very low certainty of the evidence.

ConclusionsThere insufficient certainty and quality of evidence to recommend the use of ivermectin to prevent or treat ambulatory or hospitalized patients with COVID-19.


title: Association between COVID-19 mortality and population level health and socioeconomic indicators

abstract: With the availability of multiple COVID-19 vaccines and the predicted shortages in supply for the near future, it is necessary to allocate vaccines in a manner that minimizes severe outcomes. To date, vaccination strategies in the US have focused on individual characteristics such as age and occupation. In this study, we assess the utility of population-level health and socioeconomic indicators as additional criteria for geographical allocation of vaccines. Using spatial autoregressive models, we demonstrate that 43% of the variability in COVID-19 mortality in US counties can be explained by health/socioeconomic factors, adjusting for case rates. Of the indicators considered, prevalence of chronic kidney disease and proportion of population living in nursing homes were found to have the strongest association. In the context of vaccine rollout globally, our findings indicate that national and subnational estimates of burden of disease could be useful for minimizing COVID-19 mortality.


title: Diurnal brain temperature rhythms and mortality after brain injury: a prospective and retrospective cohort study

abstract:
ObjectiveTo determine the clinical relevance of brain temperature (TBr) variation in patients after traumatic brain injury (TBI).

DesignCohort study with prospective (healthy participant) and retrospective (TBI patient) arms.

SettingSingle neuroimaging site in the UK (prospective arm); intensive care sites contributing to the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) High Resolution ICU (HR ICU) Sub-Study (retrospective arm).

Participants40 healthy adults aged 20-40 years recruited for non-invasive brain thermometry and all patients up to May 2020 that had TBr measured directly and were not subjected to Targeted Temperature Management (TTM).

Main outcome measuresA diurnal change in TBr (healthy participants); death in intensive care (patients).

ResultsIn healthy participants, mean TBr (38.5 SD 0.4{degrees}C) was higher than oral temperature (36.0 SD 0.5{degrees}C), and 0.36{degrees}C higher in luteal females relative to follicular females and males (95% confidence interval 0.17 to 0.55, P=0.0006 and 0.23 to 0.49, P<0.0001, respectively). TBr increased with age, most notably in deep brain regions (0.6{degrees}C over 20 years; 0.11 to 1.07, P=0.0002). The mean maximal spatial TBr range was 2.41 (SD 0.46){degrees}C, with highest temperatures in the thalamus. TBr varied significantly by time of day, especially in deep brain regions (0.86{degrees}C; 0.37 to 1.26, P=0.0001), and was lowest in the late evening. Diurnal TBr in cortical white matter across participants ranged from 37.0 to 40.3{degrees}C. In TBI patients (n=114), mean TBr (38.5 SD 0.8{degrees}C) was significantly higher than body temperature (TBo 37.5 SD 0.5{degrees}C; P<0.0001) and ranged from 32.6 to 42.3{degrees}C. Only 25/110 patients displayed a diurnal temperature rhythm; TBr amplitude was reduced in older patients (P=0.018), and 25/113 patients died in intensive care. Lack of a daily TBr rhythm, or an age increase of 10 years, increased the odds of death 12-fold and 11-fold, respectively (OR for death with rhythm 0.09; 0.01 to 0.84, P=0.035 and for death with ageing by 1 year 1.10; 1.05 to 1.16, P=0.0002). Mean TBr was positively associated with survival (OR for death 0.45 for 1{degrees}C increase; 0.21 to 0.96, P=0.040).

ConclusionsHealthy TBr exceeds TBo and varies by sex, age, menstrual cycle, brain region, and time of day. Our 4-dimensional reference resource for healthy TBr can guide interpretation of TBr data in multiple clinical settings. Daily temperature variation is frequently disrupted or absent in TBI patients, in which TBr variation is of greater prognostic use than absolute TBr. Older TBI patients lacking a daily TBr rhythm are at greatest risk of death in intensive care. Appropriately controlled trials are needed to confirm the predictive power of TBr rhythmicity in relation to patient outcome, as well as the clinical utility of TTM protocols in brain-injured patients.

RegistrationUK CRN NIHR CPMS 42644; ClinicalTrials.gov number, NCT02210221.

SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIBrain temperature (TBr) can be measured directly in brain-injured patients via intracranial probe, but this method cannot be used in healthy individuals.
C_LIO_LITBr can be measured non-invasively using magnetic resonance spectroscopy (MRS), but this method is not appropriate for most brain-injured patients.
C_LIO_LISince physiological reference ranges for TBr in health have not been established, the clinical relevance of TBr variation in patients is unknown, and the use of TTM in neurocritical care remains controversial.
C_LI

What this study addsO_LIA reference map for healthy adult TBr at three clinically-relevant time points that can guide interpretation of TBr measured directly, or by MRS, in multiple clinical settings.
C_LIO_LIOur results suggest that loss of diurnal TBr rhythmicity after TBI increases the odds of intensive care death 12-fold; some TTM strategies may be clinically inappropriate.
C_LI

category: intensive care and critical care medicine


title: Fallow time determination in dentistry using aerosol measurement.

abstract:
AimTo calculate fallow time (FT) required following dental aerosol generating procedures (AGPs) in both a dental hospital (mechanically ventilated) and primary care (non-mechanically ventilated). Secondary outcomes were to identify spread and persistence of aerosol in open clinics compared to closed surgeries (mechanically ventilated environment), and identify if extra-oral scavenging (EOS) reduces production of aerosol and FT.

MethodsIn vitro simulation of fast handpiece (FHP) cavity preparations using a manikin was conducted in a mechanically and non-mechanically ventilated environment using Optical Particle Sizer and NanoScan at baseline, during the procedure and fallow period.

ResultsAGPs carried out in the non-mechanically, non-ventilated environment failed to achieve baseline particle levels after one hour. In contrast, when windows were opened after AGP, there was an immediate reduction in all particle sizes.

In mechanically ventilated environments the baseline levels of particles were very low and particle count returned to baseline within 10 minutes following AGP. There was no detectable difference between particles in mechanically ventilated open bays and closed surgeries.

The effect of the EOS was greater in non-mechanically ventilated environment on reducing the particle count; additionally, it also reduced the spikes in particle counts in mechanically ventilated environments.

ConclusionHigh-efficiency particulate air filtered mechanical ventilation along with mitigating factors (high-volume suction) resulted in reduction of FT (10 minutes). Non-ventilated rooms failed to reach baseline level even after one hour of FT. There was no difference in particle counts in open bay or closed surgeries in mechanically ventilated settings. The use of an EOS device can reduce the particulate spikes during procedures in both mechanical and non-mechanical environments.

This study confirms that AGPs are not recommended in dental surgeries where no ventilation is possible. No difference was demonstrated in FT required in open bays and closed surgeries in mechanically ventilated settings.

Clinical significanceAGPs should not be carried out in surgeries where ventilation is not possible. Mechanical ventilation for AGPs should be gold standard; where not available or practical then the use of natural ventilation with EOS helps reduce FT. AGPs can be carried out in open bay environment with a minimum of 6 air changes per hour of mechanical ventilation. Four-handed dentistry with high-volume suction and saliva ejector are essential mitigating factors during AGPs.

category: dentistry and oral medicine


title: Water, sanitation, and hygiene practices and challenges during the COVID-19 pandemic: a cross-sectional study in rural Odisha, India

abstract: Water, sanitation, and hygiene (WASH) practices emerged as a critical component to controlling and preventing the spread of the COVID-19 pandemic. We conducted 131 semi-structured phone interviews with households in rural Odisha, India to understand behavior changes made in WASH practices as a result of the pandemic and challenges that would prevent best practices. Interviews were conducted from May-July 2020 with 73 heads of household, 37 caregivers of children less than five years old, and 21 members of village water and sanitation committees in villages with community-level piped water and high levels of latrine ownership. The majority of respondents (86%, N=104) reported a change in their handwashing practice due to COVID-19 or the related government lockdown, typically describing an increase in handwashing frequency, more thorough washing method, and/or use of soap. These improved handwashing practices remained in place a few months after the pandemic began and were often described as a new consistent practice after additional daily actions (such as returning home), suggesting new habit formation. Few participants (13%) reported barriers to handwashing. Some respondents also detailed improvements in other WASH behaviors including village-level cleaning of water tanks and/or treatment of piped water (48% of villages), household water treatment and storage (17% of respondents), and household cleaning (41% of respondents). However, there was minimal change in latrine use and child feces management practices as a result of the pandemic. We provide detailed thematic summaries of qualitative responses to allow for richer insights into these WASH behavior changes, or lack thereof, during the pandemic. The results also highlight the importance of ensuring communities have adequate WASH infrastructure to enable the practice of safe behaviors and strengthen resilience during a large-scale health crisis.


title: The genetic architecture of obsessive-compulsive disorder: alleles across the frequency spectrum contribute liability to OCD

abstract:
ObjectiveObsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of common genetic variation across the allele frequency spectrum to this heritability remains uncertain. We use two new, homogenous cohorts to estimate heritability of OCD from common genetic variation and contrast results with prior studies.

MethodsThe sample consisted of 2096 Swedish-born individuals diagnosed with OCD and 4609 controls, all genotyped for common genetic variants, specifically >400,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) [≥] 0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, we estimated heritability of OCD, both overall and partitioned according to MAF bins.

ResultsWe estimated narrow-sense heritability of 28% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 8% of heritability and estimated heritability per bin roughly follows expectations based on a simple model for SNP-based heritability.

ConclusionsThese results indicate that common inherited risk variation (MAF [≥] 0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD and the results are consistent with expectation under the "infinitesimal model," where risk is influenced by a large number of loci across the genome and across MAF bins.

category: psychiatry and clinical psychology


title: Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19

abstract:
BackgroundEvidence suggests the role of an inflammatory storm in COVID-19 complications. Colchicine is an orally administered, anti-inflammatory medication beneficial in gout, pericarditis and coronary disease.

MethodsWe performed a randomized, double-blind trial involving non-hospitalized patients with COVID-19 diagnosed by polymerase chain reaction (PCR) testing or clinical criteria. The patients were randomly assigned to receive colchicine (0.5 mg twice daily for 3 days and once daily thereafter) or placebo for 30 days. The primary efficacy endpoint was the composite of death or hospitalization for COVID-19.

ResultsA total of 4488 patients were enrolled. The primary endpoint occurred in 4.7% of the patients in the colchicine group and 5.8% of those in the placebo group (odds ratio, 0.79; 95.1% confidence interval (CI), 0.61 to 1.03; P=0.08). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 4.6% and 6.0% of patients in the colchicine and placebo groups, respectively (odds ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04). In these patients with PCR-confirmed COVID-19, the odds ratios were 0.75 (95% CI, 0.57 to 0.99) for hospitalization due to COVID-19, 0.50 (95% CI, 0.23 to 1.07) for mechanical ventilation, and 0.56 (95% CI, 0.19 to 1.66) for death. Serious adverse events were reported in 4.9% and 6.3% in the colchicine and placebo groups (P=0.05); pneumonia occurred in 2.9% and 4.1% of patients (P=0.02). Diarrhea was reported in 13.7% and 7.3% in the colchicine and placebo groups (P<0.0001).

ConclusionAmong non-hospitalized patients with COVID-19, colchicine reduces the composite rate of death or hospitalization. (COLCORONA ClinicalTrials.gov number: NCT04322682)


title: The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial

abstract:
BackgroundAlthough several therapies have been evaluated for treatment of COVID-19, the morbidity and mortality in COVID-19 are still significant, and the need for safe and effective drugs remains high even after launch of vaccine programs.

MethodsWe conducted a double-blind, randomized, placebo-controlled trial with the novel oral angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients with C-reactive protein 50-150 mg/L but not needing mechanical ventilation. Patients were randomly assigned to oral C21 (100 mg twice daily) or placebo for 7 days in addition to standard of care, including glucocorticoids and remdesivir.

Results106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated.

ConclusionsAs studied in hospitalized COVID-19 patients, C21 on top of standard of care led to a clinically beneficial improvement in respiratory function compared to placebo, paving the way for a pivotal randomised controlled trial.

This study is registered at ClinicalTrials.gov with identifier NCT04452435.

category: respiratory medicine


title: Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy

abstract: Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL-2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL-2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors.

category: oncology


title: A cross-disorder dosage sensitivity map of the human genome

abstract: Rare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum of human diseases. To date, most disease-association studies of rCNVs have focused on recognized genomic disorders or on the impact of haploinsufficiency caused by deletions. By comparison, our understanding of duplications in disease remains rudimentary as very few individual genes are known to be triplosensitive (i.e., duplication intolerant). In this study, we meta-analyzed rCNVs from 753,994 individuals across 30 primarily neurological disease phenotypes to create a genome-wide catalog of rCNV association statistics across disorders. We discovered 114 rCNV-disease associations at 52 distinct loci surpassing genome-wide significance (P=3.72x10-6), 42% of which involve duplications. Using Bayesian fine-mapping methods, we further prioritized 38 novel triplosensitive disease genes (e.g., GMEB2 in brain abnormalities), including three known haploinsufficient genes that we now reveal as bidirectionally dosage sensitive (e.g., ANKRD11 in growth abnormalities). By integrating our results with prior literature, we found that disease-associated rCNV segments were enriched for genes constrained against damaging coding variation and identified likely dominant driver genes for about one-third (32%) of rCNV segments based on de novo mutations from exome sequencing studies of developmental disorders. However, while the presence of constrained driver genes was a common feature of many pathogenic large rCNVs across disorders, most of the rCNVs showing genome-wide significant association were incompletely penetrant (mean odds ratio=11.6) and we also identified two examples of noncoding disease-associated rCNVs (e.g., intronic CADM2 deletions in behavioral disorders). Finally, we developed a statistical model to predict dosage sensitivity for all genes, which defined 3,006 haploinsufficient and 295 triplosensitive genes where the effect sizes of rCNVs were comparable to deletions of genes constrained against truncating mutations. These dosage sensitivity scores classified disease genes across molecular mechanisms, prioritized pathogenic de novo rCNVs in children with autism, and revealed features that distinguished haploinsufficient and triplosensitive genes, such as insulation from other genes and local cis-regulatory complexity. Collectively, the cross-disorder rCNV maps and metrics derived in this study provide the most comprehensive assessment of dosage sensitive genomic segments and genes in disease to date and set the foundation for future studies of dosage sensitivity throughout the human genome.

category: genetic and genomic medicine


title: Individual factors underlie temperature variation in sickness and in health: influence of age, BMI and genetic factors in a multi-cohort study

abstract:
IntroductionAgeing affects immune function resulting in aberrant fever response to infection. We assess the effects of biological variables on basal temperature and temperature in COVID-19 infection, proposing an updated temperature threshold for older adults.

MethodsParticipants:

O_LIUnaffected twin volunteers: 1089 adult TwinsUK participants.
C_LIO_LILondon hospitalised COVID-19+: 520 adults with emergency admission.
C_LIO_LIBirmingham hospitalised COVID-19+: 757 adults with emergency admission.
C_LIO_LICommunity-based COVID-19+: 3972 adults self-reporting a positive test using the COVID Symptom Study mobile application.
C_LI

AnalysisHeritability assessed using saturated and univariate ACE models; Linear mixed-effect and multivariable linear regression analysing associations between temperature, age, sex and BMI; multivariable logistic regression analysing associations between fever ([≥]37.8{degrees}C) and age; receiver operating characteristic (ROC) analysis to identify temperature threshold for adults [≥] 65 years.

ResultsAmong unaffected volunteers, lower BMI (p=0.001), and older age (p<0.001) associated with lower basal temperature. Basal temperature showed a heritability of 47% (95% Confidence Interval 18-57%).

In COVID-19+ participants, increasing age associated with lower temperatures in cohorts (c) and (d) (p<0.001). For each additional year of age, participants were 1% less likely to demonstrate a fever (OR 0.99; p<0.001).

Combining healthy and COVID-19+ participants, a temperature of 37.4{degrees}C in adults [≥]65 years had similar sensitivity and specificity to 37.8{degrees}C in adults <65 years for discriminating fever in COVID-19.

ConclusionsAgeing affects temperature in health and acute infection. Significant heritability indicates biological factors contribute to temperature regulation.

Our observations indicate a lower threshold (37.4{degrees}C) should be considered for assessing fever in older adults.

Key PointsO_LIOlder adults, particularly those with lower BMI, have a lower basal temperature and a lower temperature in response to infection
C_LIO_LIBasal temperature is heritable, suggesting biological factors underlying temperature regulation
C_LIO_LIOur findings support a lower temperature threshold of 37.4{degrees}C for identifying possible COVID-19 infection in older adults
C_LIO_LIThis has implications for case detection, surveillance and isolation and could be incorporated into observation assessment
C_LI

category: geriatric medicine


title: Immune response to SARS-CoV-2 in the nasal mucosa in children and adults

abstract:
RationaleDespite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms.

ObjectivesTo investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults.

MethodsClinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls.

ResultsIn both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 - key entry factors for SARS-CoV-2 - did not correlate with age or presence or absence of viral infection.

ConclusionsOur findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.


title: Trajectories of Hypoxemia & Respiratory System Mechanics of COVID-19 ARDS in the NorthCARDS dataset

abstract:
RationaleThe preliminary reports of COVID Acute Respiratory Distress Syndrome (COVIDARDS) suggest the existence of a subset of patients with higher lung compliance despite profound hypoxemia. Understanding heterogeneity seen in patients with COVIDARDS and comparing to non-COVIDARDS may inform tailored treatments.

ObjectivesTo describe the trajectories of hypoxemia and respiratory compliance in COVIDARDS and associations with outcomes.

MethodsA multidisciplinary team of frontline clinicians and data scientists created the Northwell COVIDARDS dataset (NorthCARDS) leveraging over 11,542 COVID-19 hospital admissions. Data was summarized to describe differences based on clinically meaningful categories of lung compliance, and compared to non-COVIDARDS reports. A sophisticated method of extrapolating PaO2 from SpO2, as well estimating FiO2 from non invasive oxygen delivery devices were utilized to create meaningful trends of derived PaO2 to FiO2 (P/F).

Measurements and Main ResultsOf the 1595 COVIDARDS patients in the NorthCARDS dataset, there were 538 (34{middle dot}6%) who had very low lung compliance (<20ml/cmH2O), 982 (63{middle dot}2%) with low-normal compliance (20-50ml/cmH2O), and 34 (2{middle dot}2%) with high lung compliance (>50ml/cmH2O). The very low compliance group had double the median time to intubation compared to the low-normal group (107 hours(IQR 26{middle dot}3, 238{middle dot}3) vs. 37{middle dot}9 hours(IQR 4{middle dot}8, 90{middle dot}7)). Oxygenation trends have improved in all groups after a nadir immediately post intubation. The P/F ratio improved from a mean of 109 to 155, with the very low compliance group showing a smaller improvement compared to low compliance group. The derived P/F trends closely correlated with blood gas analysis driven P/F trends, except immediately post intubation were the trends diverge as illustrated in the image. Overall, 67{middle dot}5% (n=1049) of the patients died during the hospitalization. In comparison to non-COVIDARDS reports, there were less patients in the high compliance category (2.2%vs.12%, compliance [≥]50mL/cmH20), and more patients with P/F [≤] 150 (57{middle dot}8% vs. 45.6%). No correlation was apparent between lung compliance and P/F ratio. The Oxygenation Index was similar, (11{middle dot}12(SD 5{middle dot}67)vs.12{middle dot}8(SD 10{middle dot}8)).

ConclusionsHeterogeneity in lung compliance is seen in COVIDARDS, without apparent correlation to degree of hypoxemia. Notably, time to intubation was greater in the very low lung compliance category. Understanding ARDS patient heterogeneity must include consideration of treatment patterns in addition to trajectories of change in patient-level data and demographics.


title: Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19

abstract:
Although T cells are likely players in SARS-CoV-2 immunity, little is known about the phenotypic features of SARS-CoV-2-specific T cells associated with recovery from severe COVID-19. We analyzed T cells from longitudinal specimens of 34 COVID-19 patients with severities ranging from mild (outpatient) to critical culminating in death. Relative to patients that succumbed, individuals that recovered from severe COVID-19 harbored elevated and increasing numbers of SARS-CoV-2-specific T cells capable of homeostatic proliferation. In contrast, fatal COVID-19 displayed elevated numbers of SARS-CoV-2-specific regulatory T cells and a time-dependent escalation in activated bystander CXCR4+ T cells. Together with the demonstration of increased proportions of inflammatory CXCR4+ T cells in the lungs of severe COVID-19 patients, these results support a model whereby lung-homing T cells activated through bystander effects contribute to immunopathology, while a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/21250054v2_ufig1.gif" ALT="Figure 1">
View larger version (73K):
org.highwire.dtl.DTLVardef@c82ec8org.highwire.dtl.DTLVardef@778d7forg.highwire.dtl.DTLVardef@ea9130org.highwire.dtl.DTLVardef@1e21805_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIGHLIGHTSO_LIDysfunctional spike-specific T cells are characteristic of severe COVID-19
C_LIO_LISpike-specific CD127+ Th1 cells are increased in survivors of severe COVID-19
C_LIO_LISpike-specific Tregs and IL6+ CD8+ T cells are increased in fatal COVID-19
C_LIO_LIEscalation of activated lung-homing CXCR4+ T cells associates with fatal COVID-19
C_LI

BRIEF SUMMARYBy conducting CyTOF on total and SARS-CoV-2-specific T cells from longitudinal specimens spanning the entire spectrum of COVID-19 diseases, Neidleman et al. demonstrate that spike-specific Th1 cells capable of IL7-dependent homeostatic proliferation predict survival from severe COVID-19, while Tregs and IL6+ CD8+ T cells recognizing spike predict fatal outcome. Fatal COVID-19 is characterized by escalating activation of bystander CXCR4+ T cells in the lungs. Boosting SARS-CoV-2-specific CD4+ T effector responses while diminishing CXCR4-mediated homing may help recovery from severe disease.


title: Lack of Accuracy of the GRACE score to Predict Coronary Anatomy in Acute Coronary Syndromes.

abstract:
IntroductionCoronary anatomy is one of the strongest risk predictors in Acute Coronary Syndromes (ACS), which justifies early coronary angiography. Diagnostic scores for predicting outcomes are usually superior to clinical judgment. Despite being validated for prognosis, the GRACE score has been used to discriminate patients with high or low probability of anatomical severity.

ObjectiveTo test the hypothesis that the GRACE score actually predicts anatomical severity.

MethodsThe study was carried out by assessing consecutive patients with ACS who underwent invasive angiography. Severe anatomical disease was defined as obstructive involvement ([≥] 70% in diameter) in (1) left main coronary artery or (2) double or triple vessel disease involving proximal left anterior descending artery or (3) subocclusion. The GRACE score was evaluated under numerical and dichotomous tests.

ResultsA total of 733 patients were evaluated, aged 63 {+/-} 14 years, 61% male and GRACE score of 119 {+/-} 37. Obstructive coronary disease was observed in 81% of the patients, classified as one, two or three vessel disease, or left main coronary artery involvement in 28%, 23%, 26% and 4%, respectively. The area under the ROC curve of the GRACE score was 0.65 (95% CI = 0.61 - 0.69) for predicting severe disease. The cutoff point below which the first GRACE tertile is defined (109) was used to dichotomize low-risk (N = 318) and medium-high-risk (N = 415) samples. This standard definition of intermediate-high risk by the GRACE score (> 109) revealed sensitivity of 67% in detecting severe anatomy (95% CI = 61% - 72%) and specificity of 50% (95% CI = 46% - 55%), resulting in positive likelihood ratio of 1.3 (95% CI = 1.2 - 1.5) and negative likelihood ratio of 0.66 (95% CI = 0.55 - 0.80). There was a weak correlation between GRACE and anatomical scores such as SYNTAX (r = 0.36, P < 0.001) and Gensini (r = 0.36, P < 0.001).

ConclusionDespite statistical association with extent of anatomical coronary disease, the GRACE Score is not accurate to predict severity of disease before coronary angiography.

category: cardiovascular medicine


title: Prevalence of chronic kidney disease in the general population in Latin America and the Caribbean: Protocol for a systematic review and meta-analysis

abstract:
BackgroundChronic kidney disease (CKD) is a global health issue with a general prevalence of 9%. Although the most affected populations are in low- and middle-income countries, the epidemiology of CKD in these countries remains poorly understood and prevalence estimates come from global efforts informed by data from high-income countries; these prevalence estimates need to be compared -and if needed updated-with local estimates.

ObjectiveTo estimate the prevalence of CKD in adults in Latin America and the Caribbean (LAC).

MethodsSystematic review and meta-analysis. We will search Embase, Medline, Global Health (these three through Ovid), Scopus and LILACS. No date or language restrictions will be set. We seek observational studies with a random sample of the general population. We will screen titles and abstracts, we will then study the selected reports. Both phases will be done by two reviewers independently. Data extraction will be performed by two researchers independently using a pre-specified Excel form. We will evaluate the risk of bias with the scale proposed by Hoy et al. for prevalence studies. We will conduct a meta-analysis of prevalence estimates, if there are at least three reports homogeneous enough to be pooled; we will use a random-effects model.

ConclusionsThis systematic review and meta-analysis will provide the prevalence of CKD in adults in countries of LAC. Currently, information regarding CKD in the region is limited. This work will provide evidence to elucidate the magnitude of CKD prevalence in LAC. In so doing, we will provide evidence to inform the scientific community about the burden of CKD in LAC so that research, policies and health interventions can be planned accordingly.


title: Detecting therapy-guiding RNA aberrations in platelets of non-small cell lung cancer patients

abstract:
BackgroundNowadays, the detection of therapy-guiding aberrations such as EGFR mutations and ALK fusion genes in tumor tissue is common practice for lung cancer patients. The aim of this study is to explore the feasibility of detecting common therapy-guiding aberrations in RNA isolated from platelets.

MethodsWe applied a single primed enrichment-based targeted next generation sequencing (NGS) approach on 10 platelet RNA samples isolated from patients with active disease. In parallel, we applied RNA-based ddPCR focusing on EGFR p.(T790M), p.(L858R) and E19del, on KRAS codon 12 and 13 and on ALK-EML4/KIF5B fusions on 22 platelet RNA samples from patients with tumors known to harbor one of these drivers. For 11 cases ddPCR analysis of circulating cell free (cf)DNA from the same blood sample was performed in parallel.

ResultsDespite having good quality NGS data, none of the variants detected in the tumor biopsy were observed in platelet-derived RNA samples. Using the more sensitive ddPCR, we detected known aberrations in three of 22 platelet-derived RNA samples. EGFR mutant droplets were not observed in any of the seven platelet samples, while these mutations were detected in three of six cfDNA samples of which five were extracted from the same blood sample. KRAS mutant droplets were detected in three out of nine platelet RNA samples with fractional abundances of 0.07%, 0.11% and 0.55%. Analysis of five cfDNA samples from the same blood samples revealed KRAS-mutant droplets in four of them. Two of the four corresponding platelet RNA samples were also positive for mutant KRAS. No ALK fusion droplets were detected in seven platelet derived RNA samples.

ConclusionsThe level of tumor-derived RNA transcripts in platelets of non-small cell lung cancer patients was too low to be measured reliably for clinically relevant alterations in EGFR, KRAS and ALK fusion gene transcripts.

category: pathology


title: Discernment of Mediator and Outcome Measurement in the PACE trial

abstract:
BackgroundWhen measuring latent traits, such as those used in psychology and psychiatry, it can be unclear whether the instruments used are measuring different concepts. This issue is particularly important in context of mediation analysis, since for a sound mediation hypothesis the mediator and outcome should be distinct. We sought to assess the extent of measurement overlap between mediators and outcomes in the PACE trial (n=640).

MethodsPotential measurement overlap was assessed using generalised linear latent variable models where confirmatory factor models quantified the extent to which the addition of cross-loading items resulted in significant improvements in model fit.

ResultsOut of 26 mediator-outcome pairs considered, only six showed evidence of cross-loading items, supporting the suggestion that mediator and outcome constructs in the PACE trial were conceptually distinct.

ConclusionsThis study highlights the importance of assessing measurement overlap in mediation analyses with latent traits to ensure mediator and outcome instruments are distinct.


title: High-fidelity discrimination of ARDS versus other causes of respiratory failure using natural language processing and iterative machine learning

abstract: Despite the high morbidity and mortality associated with Acute Respiratory Distress Syndrome (ARDS), discrimination of ARDS from other causes of acute respiratory failure remains challenging, particularly in the first 24 hours of mechanical ventilation. Delay in ARDS identification prevents lung protective strategies from being initiated and delays clinical trial enrolment and quality improvement interventions. Medical records from 1,263 ICU-admitted, mechanically ventilated patients at Northwell Health were retrospectively examined by a clinical team who assigned each patient a diagnosis of "ARDS" or "non-ARDS" (e.g., pulmonary edema). We then applied an iterative pre-processing and machine learning framework to construct a model that would discriminate ARDS versus non-ARDS, and examined features informative in the patient classification process. Data made available to the model included patient demographics, laboratory test results from before the initiation of mechanical ventilation, and features extracted by natural language processing of radiology reports. The resulting model discriminated well between ARDS and non-ARDS causes of respiratory failure (AUC=0.85, 89% precision at 20% recall), and highlighted features unique among ARDS patients, and among and the subset of ARDS patients who would not recover. Importantly, models built using both clinical notes and laboratory test results out-performed models built using either data source alone, akin to the retrospective clinician-based diagnostic process. This work demonstrates the feasibility of using readily available EHR data to discriminate ARDS patients prospectively in a real-world setting at a critical time in their care and highlights novel patient characteristics indicative of ARDS.


title: The Addiction Genetic Factor a(g): A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates

abstract: Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology.

category: addiction medicine


title: The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates


title: Activation of the vagal anti-inflammatory reflex by remote ischaemic conditioning in humans: experimental cross-over study.

abstract:
BACKGROUNDNon-invasive approaches in humans that may activate the vagal anti-inflammatory reflex are lacking. Neurons within the dorsal motor vagal nucleus (DMVN) activate both the vagal anti-inflammatory reflex (which regulates leukocyte trafficking by controlling neutrophil surface CD11b expression) and cardioprotection afforded by remote ischemic conditioning (RIC). We tested the hypothesis that RIC recruits vagal activity and activates the anti-inflammatory reflex in humans by reducing neutrophil (CD16+)CD11b expression.

METHODSParticipants (age:50{+/-}19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 37x8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate variability) before, and 10 minutes after, the last RIC cycle. The primary outcome was RR-interval, compared between RICblock and RIC. Secondary outcomes were time-domain, frequency-domain, and flow cytometric quantification of CD16+CD11b expression in whole blood (incubated with lipopolysaccharide (LPS) or saline) compared between RICblock and RIC.

RESULTSRIC increased RR-interval (lowered heart rate) by 40ms (95% confidence intervals (95%CI):13-66; n=17; P=0.003). RR-interval did not change after RICblock (mean difference:20ms (95%CI:-11 to 50); P=0.19). High-frequency (vagal) modulation of heart rate was reduced after RICblock, but preserved after RIC (P<0.001). indicating RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression was lower after RIC (3615 median fluorescence units (95%CI:475-6754); P=0.026), compared with 2331 units (95%CI:-3921 to 8582); P=0.726) after RICblock.

CONCLUSIONRIC recruits the vagal anti-inflammatory reflex, which requires intact afferent signalling from the peripheral tissue undergoing ischaemia/reperfusion to increase vagal tone and reduce neutrophil activation.

TRIAL REGISTRATIONresearchregistry6482.


title: Left ventricular strain does not differentiate amyloidogenic profiles in at-risk individuals with TTR Val142Ile

abstract:
ObjectivesTo identify echocardiographic signatures featuring left ventricular longitudinal strain (LS) associated with genetic risk for cardiac amyloidosis (CA) due to the TTR Val142Ile (V142I) variant in African American (AA) and Hispanic/Latinx (H/L) individuals.

BackgroundHereditary transthyretin amyloidosis (hATTR) can cause CA in [~]60-70% of older V142I carriers, but amyloid deposition progresses over many years. Disease-modifying therapy for CA is now available and early initiation is a priority for improving outcomes. Genomic screening programs and familial cascade genetic testing uncover pre-symptomatic V142I carriers, yet no guidelines exist for early CA detection.

MethodsExome sequencing data linked to electronic health records (EHRs) of BioMe biobank participants were queried for AA or H/L TTR- and TTR+ (V142I) subjects without hATTR diagnoses and with prior echocardiograms suitable for retrospective LS analysis. Systemic "red flag" features of ATTR were extracted from EHRs of TTR+ subjects. Speckle tracking echocardiography was retrospectively applied to determine global (GLS) and segmental LS. Relative apical sparing (RAS) was calculated.

Results57 TTR+ and 46 TTR-age- and ancestry-matched subjects were included. GLS declined with age in females but not males, and was abnormal (<16%) in 18 (31.6%) TTR+ and 7 (15.2%) TTR-subjects (p = 0.066). Apical sparing was observed in 13 (22.8%) TTR+ and 11 (23.9%) TTR-subjects (p = 1.0). After adjusting for relevant demographic and echocardiographic covariates, neither GLS nor RAS was associated with TTR+ V142I status. Red flag features were not associated with GLS or RAS in TTR+ subjects.

ConclusionsNeither GLS nor RAS were significantly different between TTR+ and TTR-subjects. Since >50% of TTR+ subjects were [≥] 60 years old, penetrance of CA by echocardiography among unselected V142I carriers may be lower than previously estimated. These findings indicate that surveillance for CA in individuals at increased genetic risk due to V142I should not rely solely on echocardiography, even with LS.


title: Reduction of respiratory syncytial virus burden of disease observed in primary care diagnosis of children under 5 years old during the COVID-19 pandemic: a time-series analysis using routinely collected data from primary care electronic health records in Catalonia (Spain).

abstract: We observed an unusual pattern of respiratory syncytial virus (RSV) in children under 5 years in Catalonia (Spain). We observed a nearly absence during winter months and a subsequent surge late spring. Primary care electronic health records combined with hospital RSV laboratory confirmations could be a useful surveillance system to monitorize trends of respiratory pathogens.


title: Unusual trend of respiratory syncytial virus burden of disease observed in primary care diagnosis of children under 5 years old in Catalonia during the COVID-19 pandemic.


title: Post-Mendelian genetic model in COVID-19

abstract:
Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical "threshold model". Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc).

The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity - nmildness) + F (mseverity - mmildness)

where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model "post-Mendelian". The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.


title: Noninvasive Detection of Fetal Genetic Variations through Polymorphic Sites Sequencing of Maternal Plasma DNA

abstract: Non-invasive prenatal testing (NIPT) for common fetal aneuploidies using circulating cell free DNA in maternal plasma has been widely adopted in clinical practice for its sensitivity and accuracy. However, the detection of subchromosomal abnormalities or monogenetic variations showed no cost-effectiveness or satisfactory accuracy. Here we developed an assay, the goodness-of-fit and graphical analysis of polymorphic sites based non-invasive prenatal testing (GGAP-NIPT), to simultaneously detect fetal chromosomal/subchromosomal and nucleotide level abnormalities. In each sample, fetal fraction was estimated using allelic counts of reference polymorphic sites and a robust linear regression model. Then the genotype of each polymorphic site was estimated using allelic goodness of fit test. Finally, monogenic mutations were detected using allelic wildtype and mutant counts of each target site, and chromosomal/subchromosomal abnormalities were identified by collective analysis of all target polymorphic sites. Such an analytic approach was highly accurate for detecting aneuploidies, microdeletions or microduplications and monogenic mutations for simulated samples with different fetal fractions and sequencing depths. Moreover, more than 93% of fetal monogenic mutations were correctly identified for target hotspot sites amplified using circulating or barcode-enabled single-molecule assays. With the aid of sample replicates, higher detection accuracy was observed. Through target polymorphic sites sequencing, all chromosomal/subchromosomal and monogenic abnormalities could be detected simultaneously, facilitating the extension of NIPT to an expanded panel of genetic disorders in a cost-effective manner.


title: Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV

abstract:
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.

Following in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.


title: Structuring clinical text with AI: old vs. new natural language processing techniques evaluated on eight common cardiovascular diseases

abstract: Mining the structured data in electronic health records(EHRs) enables many clinical applications while the information in free-text clinical notes often remains untapped. Free-text notes are unstructured data harder to use in machine learning while structured diagnostic codes can be missing or even erroneous. To improve the quality of diagnostic codes, this work extracts structured diagnostic codes from the unstructured notes concerning cardiovascular diseases. Five old and new word embeddings were used to vectorize over 5 million progress notes from Stanford EHR and logistic regression was used to predict eight ICD-10 codes of common cardiovascular diseases. The models were interpreted by the important words in predictions and analyses of false positive cases. Trained on Stanford notes, the model transferability was tested in the prediction of corresponding ICD-9 codes of the MIMIC-III discharge summaries. The word embeddings and logistic regression showed good performance in the diagnostic code extraction with TF-IDF as the best word embedding model showing AU-ROC ranging from 0.9499 to 0.9915 and AUPRC ranging from 0.2956 to 0.8072. The models also showed transferability when tested on MIMIC-III data set with AUROC ranging from 0.7952 to 0.9790 and AUPRC ranging from 0.2353 to 0.8084. Model interpretability was showed by the important words with clinical meanings matching each disease. This study shows the feasibility to accurately extract structured diagnostic codes, impute missing codes and correct erroneous codes from free-text clinical notes with interpretable models for clinicians, which helps improve the data quality of diagnostic codes for information retrieval and downstream machine-learning applications.

category: health informatics


title: A prediction model for COVID-19 prevalence based on demographic and healthcare parameters in Iran

abstract: Coronavirus Disease 2019 (COVID-19) pandemic has become the greatest threat to global health in only a matter of months. Iran struggling with COVID-19 coincidence with Nowruz vacations has led to horrendous consequences for both people and the public health workforce. Modeling approaches have been proved to be highly advantageous in taking appropriate actions in the early stages of the pandemic. To this date, no study has been conducted to model the disease to investigate the disease, especially after travel restrictions in Iran. In this study, we exploited the opportunities that Artificial neural networks offer to investigate contributing factors of early-stage coronavirus spread via generating a model to predict daily confirmed cases in Iran. We collected publicly available data of confirmed cases in 24 provinces from April 4, 2020, to May 2, 2020, with a list of explanatory factors. The factors were checked separately for any linear associations and to train and validate a multilayer perceptron network. The accuracy of the models was evaluated, the R2 scores were 0.842 for population distribution, 0.822 for health index, and 0.864 for the population in the provinces. Our results suggest the significant impact of the mentioned factors on disease spread in the time of travel restrictions when the vacation ended. Accordingly, this information can be implicated in assessing the risk of epidemics and future policy makings in this area.

category: infectious diseases


title: Disentangling the association of hydroxychloroquine treatment with mortality in Covid-19 hospitalized patients through Hierarchical Clustering

abstract:
The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and intervention studies reporting contrasting results.

To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ.

We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster*HCQ interaction (p<0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome.

These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute clarifying the current controversy on HCQ efficacy in Covid-19 treatment.


title: Lumipulse G SARS-CoV-2 Ag Assay Evaluation for SARS-CoV-2 Antigen Detection Using 594 Nasopharyngeal Swab Samples from Different Testing Groups

abstract: Compared to RT-PCR, lower performance of antigen detection assays, including the Lumipulse G SARS-CoV-2 Ag assay, may depend on specific testing scenarios. We tested 594 nasopharyngeal swab samples from individuals with COVID-19 (RT-PCR cycle threshold [Ct] values [≤]40) or non-COVID-19 (Ct values [≤]40) diagnoses. RT-PCR positive samples were assigned to diagnostic, screening, or monitoring groups of testing. With a limit of detection of 1.2 x 104 SARS-CoV-2 RNA copies/ml, Lumipulse showed positive percent agreement (PPA) of 79.9% (155/194) and negative percent agreement of 99.3% (397/400), whereas PPAs were 100% for samples with Ct values of <18 or 18-<25 and 92.5% for samples with Ct values of 25-<30. By three groups, Lumipulse showed PPA of 87.0% (60/69), 81.1% (43/53), or 72.2% (52/72), respectively, whereas PPA was 100% for samples with Ct values of <18 or 18-<25, and was 94.4%, 80.0%, or 100% for samples with Ct values of 25-<30, respectively. RT-PCR positive samples were also tested for SARS-CoV-2 subgenomic RNA and, by three groups, testing showed that PPA was 63.8% (44/69), 62.3% (33/53), or 33.3% (24/72), respectively. PPAs dropped to 55.6%, 20.0%, or 41.7% for samples with Ct values of 25-<30, respectively. All 101 samples with a subgenomic RNA positive result had a Lumipulse assays antigen positive result, whereas only 54 (58.1%) of remaining 93 samples had a Lumipulse assays antigen positive result. In conclusion, Lumipulse assay was highly sensitive in samples with low RT-PCR Ct values, implying repeated testing to reduce consequences of false-negative results.