title: The role of mouthwash sampling in SARS-CoV-2 diagnosis

abstract:
BackgroundThe current practice of COVID-19 diagnosis worldwide is the use of oro-nasopharyngeal (ONP) swabs. Our study aim was to explore mouthwash (MW) as an alternative diagnostic method, in light of the disadvantages of ONP swabs.

MethodsCovid-19 outpatients molecular-confirmed by ONP-swab were repeatedly examined with ONP-swab and MW with normal-saline (0.9%). Other types of fluids were compared to normal-saline. The Cq values obtained with each method were compared.

ResultsAmong 137 pairs of ONP-swabs and MW samples, 84.6% (116/137) of ONP-swabs were positive by at least one of the genes (N, E, R). However MW detected 70.8% (97/137) of samples as positive, which means 83.6% (97/116) out of positive ONP-swabs, missing mainly Cq value>30. In both methods, the N gene was the most sensitive one. Therefore MW samples targeting N-gene, which was positive in 95/137 (69.3%), is comparable to ONP-swabs targeting E and R genes which gave equal results - 95/137 (69.3%) and 90/137 (65.7%) respectively.

Comparing saline MW to distilled-water gave equal results, while commercial mouth-rinsing solutions were less sensitive.

ConclusionsMW with normal-saline, especially when tested by N gene, can effectively detect COVID-19 patients. Furthermore, this method was not inferior when compared to R and E genes of ONP-swabs, which are common targets in many laboratories around the world.

category: infectious diseases


title: Air travel-related outbreak of multiple SARS-CoV-2 variants

abstract:
BackgroundA large cluster of 59 cases were linked to a single flight with 146 passengers from New Delhi to Hong Kong in April 2021. This outbreak coincided with early reports of exponential pandemic growth in New Delhi, which reached a peak of >400,000 newly confirmed cases on 7 May 2021.

MethodsEpidemiological information including date of symptom onset, date of positive-sample detection, and travel and contact history for individual cases from this flight were collected. Whole genome sequencing was performed, and sequences were classified based on the dynamic Pango nomenclature system. Maximum-likelihood phylogenetic analysis compared sequences from this flight alongside other cases imported from India to Hong Kong on 26 flights between June 2020 and April 2021, as well as sequences from India or associated with India-related travel from February to April 2021, and 1,217 reference sequences.

ResultsSequence analysis identified six lineages of SARS-CoV-2 belonging to two variants of concern (Alpha and Delta) and one variant of public health interest (Kappa) involved in this outbreak. Phylogenetic analysis confirmed at least three independent sub-lineages of Alpha with limited onward transmission, a superspreading event comprising 37 cases of Kappa, and transmission of Delta to only one passenger. Additional analysis of another 26 flights from India to Hong Kong confirmed widespread circulation of all three variants in India since early March 2021.

ConclusionsThe broad spectrum of disease severity and long incubation period of SARS-CoV-2 pose a challenge for surveillance and control. As illustrated by this particular outbreak, opportunistic infections of SARS-CoV-2 can occur irrespective of variant lineage, and requiring a nucleic acid test within 72 hours of departure may be insufficient to prevent importation or in-flight transmission.


title: Phase 1 safety and pharmacokinetics studies of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies

abstract:
BackgroundBRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies with modified Fc region that extends half-life and are being developed as cocktail therapy for the treatment of COVID-19. Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in healthy adults.

MethodsSingle ascending doses of BRII-196 and BRII-198 were evaluated in parallel in the first-in-human, placebo-controlled phase 1 studies. A total of 32 healthy adults were randomized and received a single intravenous infusion of 750, 1500, and 3000 mg of BRII-196 (n=12), BRII-198 (n=12), or placebo (n=8) and were followed for 180 days.

ResultsAll infusions were well tolerated at infusion rates between 0.5 mL/min to 4 mL/min with no dose-limiting adverse events, deaths, serious adverse events, or any systemic or local infusion reactions. Most treatment-emergent adverse events were isolated asymptomatic laboratory abnormalities of Grade 1-2 in severity. Each mAb displayed pharmacokinetics expected of Fc-engineered human IgG1 with mean terminal half-lives of approximately 46 days and 76 days, respectively, with no evidence of significant anti-drug antibody development.

ConclusionsBRII-196 and BRII-198 were well-tolerated. Clinical results support further development as therapeutic or prophylactic options for SARS-CoV-2 infection.


title: Fully automatic segmentation of craniomaxillofacial CT scans for computer-assisted orthognathic surgery planning using the nnU-Net framework

abstract:
ObjectivesTo evaluate the performance of the nnU-Net open-source deep learning framework for automatic multi-task segmentation of craniomaxillofacial (CMF) structures in CT scans obtained for computer-assisted orthognathic surgery.

MethodsFour hundred and fifty-three consecutive patients having undergone high-definition CT scans before orthognathic surgery were randomly distributed among a training/validation cohort (n = 300) and a testing cohort (n = 153). The ground truth segmentations were generated by 2 operators following an industry-certified procedure for use in computer-assisted surgical planning and personalized implant manufacturing. Model performance was assessed by comparing model predictions with ground truth segmentations. Examination of 45 CT scans by an industry expert provided additional evaluation. The models generalizability was tested on a publicly available dataset of 10 CT scans with ground truth segmentations of the mandible.

ResultsIn the test cohort, mean volumetric Dice Similarity Coefficient (vDSC) & surface Dice Similarity Coefficient at 1mm (sDSC) were 0.96 & 0.97 for the upper skull, 0.94 & 0.98 for the mandible, 0.95 & 0.99 for the upper teeth, 0.94 & 0.99 for the lower teeth and 0.82 & 0.98 for the mandibular canal. Industry expert segmentation approval rates were 93% for the mandible, 89% for the mandibular canal, 82% for the upper skull, 69% for the upper teeth and 58% for the lower teeth.

ConclusionWhile additional efforts are required for the segmentation of dental apices, our results demonstrated the models reliability in terms of fully automatic segmentation of preoperative orthognathic CT scans.

Key points- The nnU-Net deep learning framework can be used out-of-the-box to provide robust fully automatic multi-task segmentation of CT scans performed for computer-assisted orthognathic surgery planning.
- Commonly used biomedical segmentation evaluation metrics (volumetric and surface Dice Similarity Coefficient) do not always match industry expert evaluation in the case of more demanding clinical applications.

category: dentistry and oral medicine


title: Excess mortality in India from June 2020 to June 2021 during the COVID pandemic: death registration, health facility deaths, and survey data

abstract:
BackgroundIndias official death totals from the COVID pandemic are widely regarded as under-reports.

MethodsWe quantified all-cause excess mortality in India, comparing deaths during the peak of the first and second COVID waves (Jul-Dec 2020 and April-June 2021) with month wise deaths in 2015-19 from three sources: Civil Registration System (CRS) mortality reports from 15 states or cities with 37% of Indias population; deaths in 0.2 million health facilities; and a representative survey of 0.14 million adults about COVID deaths.

ResultsDuring the first viral wave, the median excess mortality compared to CRS baseline was 22% and 41%, respectively, in included states and cities, rising to 46% and 85% during the second wave. In settings with 10 or more months of data across the two waves, the median excess mortality was 32% and 37% for states and cities, respectively. Deaths in health facilities showed a 27% excess mortality from July 2020-May 2021, reaching 120% during April-May 2021. The national survey found 3.5% of adults reported a COVID death in their household in April-June 2021, approximately doubling the 3.2% expected overall deaths. The national survey showed 29-32% excess deaths from June 1, 2020 to June 27, 2021, most of which were likely to be COVID. This translates to 3.1-3.4 million COVID deaths (including 2.5-2.8 million during April-June 2021). National extrapolations from health facility and CRS data suggest 2.7-3.3 million deaths during the year.

ConclusionsIndias COVID death rate may be about 7-8 times higher than the officially reported 290/million population.

category: epidemiology


title: Obesity, Ethnicity, and Covid-19 Mortality: A population-based cohort study of 12.6 Million Adults in England

abstract:
ImportanceObesity and ethnicity are well characterised risk factors for severe COVID-19 outcomes, but the differential effects of obesity on COVID-19 outcomes by race/ethnicity has not been examined robustly in the general population.

ObjectiveTo investigate the association between body mass index (BMI) and COVID-19 mortality across different ethnic groups.

Design, Setting, and ParticipantsThis is a retrospective cohort study using linked national Census, electronic health records and mortality data for English adults aged 40 years or older who were alive at the start of pandemic (24th January 2020).

ExposuresBMI obtained from electronic health records. Self-reported ethnicity (white, black, South Asian, other) was the effect-modifying variable.

Main Outcomes and MeasuresCOVID-19 related death identified by ICD-10 codes U07.1 or U07.2 mentioned on the death certificate from 24th January 2020 until December 28th 2020.

ResultsThe analysis included white (n = 11,074,708; mean age 61.9 [{+/-}13.4] years; 54% women), black (n = 416,542; 56.4 [{+/-}11.7] years; 57% women), South Asian (621,691; 55.7 [{+/-}12.4] years; 51% women) and other (n = 478,196; 55.3 [{+/-}11.6] years; 55% women) ethnicities with linked BMI data. The association between BMI and COVID-19 mortality was stronger in ethnic minority groups. Compared to a BMI of 22.5 kg/m2 in white ethnicities, the adjusted HR for COVID-19 mortality at a BMI of 30 kg/m2 in white, black, South Asian and other ethnicities was 0.95 (95% CI: 0.87-1.03), 1.72 (1.52-1.94), 2.00 (1.78-2.25) and 1.39 (1.21-1.61), respectively. The estimated risk of COVID-19 mortality at a BMI of 40 kg/m2 in white ethnicities (HR = 1.73) was equivalent to the risk observed at a BMI of 30.1 kg/m2, 27.0 kg/m2, and 32.2 kg/m2 in black, South Asian and other ethnic groups, respectively.

ConclusionsThis population-based study using linked Census and electronic health care records demonstrates that the risk of COVID-19 mortality associated with obesity is greater in ethnic minority groups compared to white populations.

QuestionDoes the association between BMI and COVID-19 mortality vary by ethnicity?

FindingsIn this study of 12.6 million adults, BMI was associated with COVID-19 in all ethnicities, but with stronger associations in ethnic minority populations such that the risk of COVID-19 mortality for a BMI of 40 kg/m2 in white ethnicities was observed at a BMI of 30.1 kg/m2, 27.0 kg/m2, and 32.2 kg/m2 in black, South Asian and other ethnicities, respectively.

MeaningBMI is a stronger risk factor for COVID-19 mortality in ethnic minorities. Obesity management is therefore a priority in these populations.


title: Evaluation of a city-wide school-located influenza vaccination program in Oakland, California with respect to race and ethnicity: a matched cohort study

abstract:
ObjectivesTo evaluate the effectiveness of city-wide school-located influenza vaccination by race/ethnicity from 2014-2018.

MethodsWe used multivariate matching to pair schools in the intervention district in Oakland, CA with schools in West Contra Costa County, CA, a comparison district. We estimated difference-in-differences (DIDs) in caregiver-reported influenza vaccination coverage and laboratory-confirmed influenza hospitalization incidence.

ResultsDifferences in influenza vaccination coverage in the intervention vs. comparison site were larger among White and Latino students than Asian/Pacific Islander (API), Black, and multiracial students. Concerns about vaccine effectiveness or safety were more common among Black and multiracial caregivers; logistical barriers to vaccination were more common among White, API, and Latinos. In both sites, hospitalization in 2017-18 was higher in Blacks vs. other races/ethnicities. All-age influenza hospitalization incidence was lower in the intervention site vs. comparison site among White/API individuals in 2016-17 and 2017-18 and Black older adults in 2017-18, but not in other groups.

ConclusionsSLIV was associated with higher vaccination coverage and lower influenza hospitalization, but associations varied by race/ethnicity. SLIV alone may be insufficient to ensure equitable health outcomes for influenza.


title: NO INCREASE IN RELATIVE MORTALITY RATES FOR THOSE WITHOUT A COLLEGE DEGREE DURING COVID-19: AN ANOMALY

abstract: American mortality rates have diverged in recent years between those with and without a four-year college degree, and there are many reasons to expect the education-mortality gradient to have steepened during the pandemic. Those without a BA are more likely to work in frontline occupations, to rely on public transportation, and to live in crowded quarters, all of which are associated with an increase in infection risk, a risk that was zero prior to the pandemic. We use publicly available data from the National Center for Health Statistics on deaths by age, sex, education and race/ethnicity to assess the protective effect of a BA in 2020 compared to 2019. While the BA was strongly protective during 2020, the ratio of mortality rates between those with and without a degree was little changed relative to pre-pandemic years. Among 60 groups (gender by race/ethnicity by age) that are available in the data, the relative risk reduction associated with a BA fell for more than half the groups between 2019 and 2020, and increased by more than 5 percentage points for only five groups. Our main finding is not that the BA was protective against death in 2020, which has long been the case, but that the protective effect was little different than in 2019 and earlier years, in spite of the change in the pattern of risk by occupation and income. The virus maintained the mortality-education gradient that existed pre-pandemic, at least through the end of 2020. Our results suggest that changes in the risk of infection were less important in structuring mortality than changes in the risk of death conditional on infection.


title: Herd immunity induced by COVID-19 vaccination programs to suppress epidemics caused by SARS-CoV-2 wild type and variants in China

abstract:
BackgroundTo allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs.

MethodsWe developed a data-driven model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. The model is calibrated considering COVID-19 natural history and the estimated transmissibility of the Delta variant. Three vaccination programs are tested, including the one currently enacted in China and model-based estimates of the herd immunity level are provided.

ResultsWe found that it is unlike to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021, the exclusion of underage individuals from the targeted population, and the lack of prior natural immunity. We estimate that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 53-58% in case of an epidemic starts to unfold in the fall of 2021.

ConclusionsEfforts should be taken to increase populations confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines for a wider age range.


title: Waiting times, patient flow, and occupancy density in South African primary health care clinics: implications for infection prevention and control

abstract:
BackgroundTransmission of respiratory pathogens, such as Mycobacterium tuberculosis and severe acute respiratory syndrome coronavirus 2, is more likely during close, prolonged contact and when sharing a poorly ventilated space. In clinics in KwaZulu-Natal (KZN) and Western Cape (WC), South Africa, we estimated clinic visit duration, time spent indoors and outdoors, and occupancy density of waiting rooms.

MethodsWe used unique barcodes to track attendees movements in 11 clinics in two provinces, multiple imputation to estimate missing arrival and departure times, and mixed-effects linear regression to examine associations with visit duration.

Results2,903 attendees were included. Median visit duration was 2 hours 36 minutes (interquartile range [IQR] 01:36-3:43). Longer mean visit times were associated with being female (13.5 minutes longer than males; p<0.001) and attending with a baby (18.8 minutes longer than those without; p<0.01), and shorter mean times with later arrival (14.9 minutes shorter per hour after 0700; p<0.001) and attendance for tuberculosis or ante/postnatal care (24.8 and 32.6 minutes shorter, respectively, than HIV/acute care; p<0.01).

Overall, attendees spent more of their time indoors (median 95.6% [IQR 46-100]) than outdoors (2.5% [IQR 0-35]). Attendees at clinics with outdoor waiting areas spent a greater proportion (median 13.7% [IQR 1- 75]) of their time outdoors.

In two clinics in KZN (no appointment system), occupancy densities of [~]2.0 persons/m2 were observed in smaller waiting rooms during busy periods. In one clinic in WC (appointment system), occupancy density did not exceed 1.0 persons/m2 despite higher overall attendance.

ConclusionsLonger waiting times were associated with early arrival, being female, and attending with a young child. Attendees generally waited where they were asked to. Regular estimation of occupancy density (as patient flow proxy) may help staff assess for risk of infection transmission and guide intervention to reduce time spent in risky spaces.

category: public and global health


title: Positive and negative stroke signs revisited: dissociations between synergies, weakness, and impaired reaching dexterity

abstract: Most stroke victims experience motor deficits, usually referred to collectively as hemiparesis. While hemiparesis is one of the most common and clinically recognizable motor abnormalities, it remains under-characterized in terms of its behavioral subcomponents and their interactions. Hemiparesis is comprised of both negative and positive motor signs. Negative signs consist of weakness and loss of motor control (dexterity), whereas positive signs consist of spasticity, abnormal resting posture, and intrusive movement synergies (abnormal muscle co-activations during voluntary movement). How positive and negative signs interact, and whether a common mechanism generates them, remains poorly understood. Here we employed a planar, arm-supported reaching task to assess post-stroke arm dexterity loss, which we compared to the Fugl-Meyer stroke scale; a measure primarily reflecting abnormal synergies. We examined 53 patients with hemiparesis after a first-time ischemic stroke. Reaching kinematics were markedly more impaired in patients with subacute (<3 months) compared to chronic (>6 months) stroke even when matched for Fugl-Meyer score. This suggests a dissociation between abnormal synergies (reflected in the Fugl-Meyer scale) and loss of dexterity, which in turn suggests different underlying mechanisms. Moreover, dynamometry suggested that Fugl-Meyer scores capture weakness as well as abnormal synergies, in line with these two deficits sharing a neural substrate. These findings have two important implications: First, clinical studies that test for efficacy of rehabilitation interventions should specify which component of hemiparesis they are targeting and how they propose to measure it. Second, there may be an opportunity to design rehabilitation interventions to address specific subcomponents of hemiparesis.

category: neurology


title: Change in Plasma Alpha-Tocopherol Associations with Attenuated Pulmonary Function Decline and with CYP4F2 Missense Variation

abstract:
BackgroundGiven its antioxidant activity, vitamin E is hypothesized to attenuate the age-related decline in pulmonary function.

ObjectiveWe investigated the association between change in plasma vitamin E ({Delta}vitE) and pulmonary function decline and examined genetic and non-genetic factors associated with {Delta}vitE.

DesignWe studied 1,144 men randomized to vitE in the Selenium and Vitamin E Cancer Prevention Trial. {Delta}vitE was calculated as the difference between baseline and year 3 vitE concentrations measured with gas chromatography-mass spectrometry. Pulmonary function (forced expiratory volume in the first second [FEV1]) was measured longitudinally with spirometry. We genotyped 555 participants (vitE-only arm) using the Illumina MEGAex array. We examined the association of {Delta}vitE with annual change in FEV1 using mixed-effects linear regression. We also examined the association of previously reported genetic and non-genetic factors with {Delta}vitE.

ResultsGreater {Delta}vitE was associated with attenuated FEV1 decline, with stronger effects in adherent supplement responders: a 1 SD higher {Delta}vitE (+4 {micro}mol/mmol free-cholesterol-adjusted -tocopherol) attenuated FEV1 decline by [~]8.9 mL/year (P=0.014). This effect size is [~]1/4 of the effect of one year of aging, but in the opposite direction. The {Delta}vitE-FEV1 association was positive in never and current smokers (9.7 and 11.0 mL/year attenuated FEV1 decline, respectively), but there was little to no association in former smokers. Greater {Delta}vitE was associated with lower baseline -tocopherol, higher baseline {gamma}-tocopherol, higher baseline free cholesterol, European ancestry (vs. African ancestry) (all P<0.0001), and the minor allele of a missense variant in CYP4F2 (rs2108622-T) (2.4 {micro}mol/L greater {Delta}vitE; P=0.0032).

ConclusionsGreater response to vitE supplementation was associated with attenuated FEV1 decline, and this response was differed by rs2108622 such that individuals with the C allele may need a higher vitE intake dose to reach the same plasma level, compared to the T allele.

category: nutrition


title: Dietary patterns among 13 - 17-years old school adolescents: A national comparison of the three geographical regions in Bolivia

abstract:
IntroductionBolivia is considered one to the most biodiverse countries in the world. It has three ecological floors or geographical regions (highlands, plains and valleys) with very different climatic and cultural characteristics. Traditionally dietary patterns varied in each region. Because two-thirds of premature deaths are associated with behaviors that begin in adolescence, understanding dietary patterns among adolescents is important to improving health. The aim of this study was to identify dietary patterns of adolescents in the different geographical regions of Bolivia.

MethodologyData were obtained from the World Health Organizations Global School-based Student Health Survey 2018 that assesses risky behaviors and protective factors in students aged 13 to 17 years old. It uses an observational cross-sectional method and included 7945 adolescents in schools that were representative of all students in this age group in each of the three geographical regions in Bolivia.

Results3.9% of students in Bolivia are food insecure, with the highest percentage in the highlands (4.6%) and the lowest in the plains (3.1%). Adolescents in the highlands consume vegetables and fruits more frequently than adolescents in the plains and valleys. Water consumption in the valleys was 19.6% students who drink 1-3 glasses/d. Dairy consumption [≥]2 in 7 days is higher in the highlands and lower in the valleys. Consumption of soft drinks at [≥]1 glass per day is 34.3% in the plains and 30.1% in the valleys. Junk food consumption [≥]1 in 7 days was 62.0% with a greater presence on the plains at 65.7%.

ConclusionThe highlands revealed a greater presence of protective factors than the other regions. The valley, despite having greater access to fruits and vegetables, has a greater presence of risky behaviors. Teenagers in the plains have greater exposure to advertising and access to junk food at school.


title: A collaborative maternity dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia

abstract:
BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.

MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random  signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [≤] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.

Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.
 It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.
 The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.
 Data from private maternity hospitals, containing 25% of Melbourne births, are not available.
 This resource will support data-informed hospital pandemic responses through to the end of 2022.

category: obstetrics and gynecology


title: A collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia


title: Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer

abstract: High grade serous ovarian cancer (HGSOC) is a highly heterogeneous disease that often presents at an advanced, metastatic state. The multi-scale complexity of HGSOC is a major obstacle to measuring response to neoadjuvant chemotherapy (NACT) and understanding its determinants. Here we propose a radiogenomic framework integrating clinical, radiomic, and blood-based biomarkers to measure and predict the response of HGSOC patients to NACT, showing how quantitative imaging data can serve as the backbone of multi-scale data integration. We developed and validated our approach in two independent highly-annotated multi-omic multi-lesion data sets. In a discovery cohort (n=72) we found that different tumour sites present distinct response patterns, and identified volumetric response assessment as a better predictor of overall survival (OS) than RECIST 1.1 status. We trained an ensemble machine learning approach to predict tumour volume response to NACT from data obtained prior to treatment, and validated the model in an internal hold-out cohort (n=20) and an independent external patient cohort (n=42). Benchmarking integrated models against models built on single data types highlighted the importance of comprehensive patient characterisation. Our study sets the foundation for developing new clinical trials of NACT in HGSOC.

category: oncology


title: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

abstract: Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we performed a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identified a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 x 10-8; KMT5B). We also identified a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N=1287) at 6p21.32 (rs3916765; P = 1.51 x 10-10; HLA). Our results inform on AML etiology by identifying putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

category: genetic and genomic medicine


title: Association of Sleep-Disordered Breathing With Cardiovascular Events and Death in patients With Ischemic Heart Disease：A systematic review and meta-analysis

abstract:
ObjectivePrevious studies have identified that sleep-disordered breathing is associated with the increased risk of cardiovascular disease. However, CPAP, the preferred treatment of sleep apnea, does not appear to reduce the risk of adverse cardiovascular events and deaths in ischemic heart disease. Our aim was to determine whether OSA can be a prognostic factor for cardiovascular adverse events and deaths in patients with ischemia heart disease.

MethodsWe searched Medline via PubMed, Embase, and the Cochrane Library database for clinical studies reporting the major adverse cardiac outcomes of SDB in patients with myocardial ischemia. Sleep apnea tests is mainly performed with cardiorespiratory polygraphy or portable diagnostic device. Summary hazard ratio(HR) and 95% CIs were conducted using random-effects meta-analysis.

ResultsEighteen literatures were included, with total participants of 9,138. Sixteen studies reported MACCEs, there was significant association of SDB with MACCES (HR, 1.66[95% CI, 1.41 to 1.94]; P< 0.0001), all-cause mortality (HR, 1.39[95% CI 1.12 to 1.73], P=0.0027) and cardiovascular mortality (HR, 2.12[95% CI 1.23 to 3.65], P=0.007). Subgroup analysis showed that one study was the cause of heterogeneity, while no correlation between SDB and outcomes for sleep apnea severity, follow-up time or whether surgery was performed.

ConclusionSDB is associated with adverse cardiac outcomes in patients with ischemic heart disease, suggesting that sleep apnea can be screened for patients with ischemic heart disease, which can be used as a clinically relevant strategy of secondary prevention to reduce the risk of adverse outcomes.

category: geriatric medicine


title: Low CD4/CD8 ratio predicts cancer risk among adults with HIV

abstract:
BackgroundIndependent of CD4 cell count, low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the USA and Canada.

MethodsWe examined all cancer-free PWH with one or more CD4/CD8 values from NA-ACCORD observational cohorts with validated cancer diagnoses between 1998-2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines.

Models were adjusted for age, sex, race/ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.

ResultsAmong 83,893 PWH, there were 5,628 incident cancers, including lung cancer (n=755), Kaposi sarcoma (KS, n=501), non-Hodgkin lymphoma (NHL, n=497), and anal cancer (n=439). Median age at cohort entry was 43 years, 87% were male, and 43% were white. Overall median six-month lagged CD4/CD8 ratio was 0.52 (interquartile range: 0.30-0.82). Compared with six-month lagged CD4/CD8=0.80, CD4/CD8=0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval: 1.14-1.35]). CD4/CD8 ratio was also inversely associated with NHL, KS, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all p<0.05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values.

ConclusionsLow CD4/CD8 ratio up to 24 months prior to cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.

category: hiv aids


title: Sex-specific effects of aging on the humoral immune response to repeat vaccination with the high-dose seasonal influenza vaccine in older adults

abstract: Older adults ([≥]65 years of age) bear a significant burden of severe disease and mortality associated with influenza, despite relatively high annual vaccination coverage and substantial pre-existing immunity to influenza. To test the hypothesis that host factors, including age and sex, play a role in determining the effect of repeat vaccination and levels of pre-existing humoral immunity to influenza, we evaluated pre- and post-vaccination strain-specific hemagglutination inhibition (HAI) titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four out of six influenza seasons (NCT02200276). Neither age, sex, body mass index, frailty, nor repeat vaccination were significantly associated with post-vaccination HAI titer outcomes. Pre-vaccination titers, however, were significantly predictive of post-vaccination outcomes. Pre-vaccination titers to H1N1 remained constant with age, while those to H3N2 and influenza B decreased substantially with age in males but not in females. Our findings highlight the importance of pre-existing immunity in this highly vaccinated older adult population and suggest that older males are particularly vulnerable to reduced pre-existing humoral immunity to influenza from previous annual vaccination.


title: Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in Hospitalized COVID-19 patients - the BISHOP study.

abstract:
BackgroundPatients with severe COVID-19 seem to have a compromised antiviral response and hyperinflammation. Neutrophils are critical players in COVID-19 pathogenesis. IL-17A plays a major role in protection against extracellular pathogens and neutrophil attraction and activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could mitigate the deleterious hyperinflammation in COVID-19.

MethodsBISHOP was an open-label, single-center, phase-II controlled trial. Fifty adults hospitalized Covid-19 patients, confirmed by a positive SARS-CoV-2 RT-PCR, were randomized 1:1 to receive 300mg of secukinumab subcutaneously at day-0 (group A) plus standard of care (SoC: antiviral drugs, antimicrobials, corticosteroids, and/or anticoagulants) or SoC alone (group B). A second dose of 300mg of secukinumab could be administered on day-7, according to staff judgment. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy and safety outcomes were also explored.

FindingsAn intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p=0.62; There was also no difference in hospitalization time, intensive care unit demand, the incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections, and severe adverse events. Pulmonary thromboembolism was less frequent in group A (4.2% vs. 26.2% p=0.04). There was one death in each group. Viral clearance, defined by the viral load fold change (2-{Delta}{Delta}CT) in upper airways, between day-0 and day-7, was also similar: 0.17 (0.05-0.56) in group A vs. 0.24 (0.10-0.57) in group B.

InterpretationThe efficacy of secukinumab in the treatment of Covid19 was not demonstrated. No difference between groups in adverse events and no unexpected events were observed.

FundingNovartis Brazil supported this research providing expert input in the development of the project, drug supply, data management, and monitoring.


title: Patients treated with anti-CD20 therapy can mount robust T cell responses to mRNA-based COVID-19 vaccines

abstract: Patients treated with anti-CD20 therapy are particularly at risk of developing severe COVID-19, however little is known regarding COVID-19 vaccine effectiveness in this population. This study assesses humoral and T-cell responses to mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n=37), compared to immunocompetent individuals (n=22). SARS-CoV-2-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4+ T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8+ T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). Vaccine-specific CD4+ and CD8+ T cells were polyfunctional but expressed more IL-2 in patients than in controls. In summary, our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the prevention of severe COVID-19.

category: allergy and immunology


title: Laboratory study to investigate the sensitivity and specificity of a diagnostic dressing to detect burn wound infection

abstract: Burn Wound Infection (BWI) is difficult to define and detect before it manifests with clear clinical symptoms. In this paper, an ex vivo study of a prototype BWI detecting wound dressing is reported. Consenting patients with burns were recruited from four burns services in the United Kingdom, their burn infection state recorded at time of recruitment and retrospectively following treatment. Their wound dressings were used as a source of inoculating bacteria to create an ex vivo biofilm model in the laboratory with reasonable fidelity to the original microbial state of their wound. The prototype infection detecting wound dressing, which responds to cytolytic toxins secreted by bacteria, was placed on the ex vivo biofilm and the response of the dressing correlated with the clinical decision on the patients wound infection state. The study illustrated a number of broader issues with clinical BWI diagnosis, notably the absence of objective diagnostic criteria: a  reference standard for BWI. The absence of such a reference standard made analysis of the relationship between the dressing response and BWI diagnosis challenging, however a point estimate of 68% sensitivity from the study suggests the potential future utility of using a sensor which detects secreted bacterial virulence factors to assist in BWI diagnosis.

category: emergency medicine


title: The impact of premature extrauterine exposure on infants' stimulus-evoked brain activity across multiple sensory systems

abstract:
Prematurity can result in widespread neurodevelopmental impairment, with the impact of premature extrauterine exposure on brain function detectable in infancy. A range of neurodynamic and haemodynamic functional brain measures have previously been employed to study the neurodevelopmental impact of prematurity, with methodological and analytical heterogeneity across studies obscuring how multiple sensory systems are affected. Here, we outline a standardised template analysis approach to measure the evoked response magnitudes for visual, tactile, and noxious stimulation within individual infants (n=15) using EEG. By studying a cohort of very preterm infants longitudinally (n=10), we observe that the evoked response template magnitudes are significantly associated with age-related maturation. In a subsequent cross-sectional study, we observe significant differences in visual and tactile response template magnitudes between infants born in the very preterm and late preterm periods (n=10 and 8), age-matched at study. These findings demonstrate the significant impact of premature extrauterine exposure on brain function and suggest that prematurity can accelerate maturation of the visual and tactile sensory system in infants born very prematurely. This study highlights the value of using a standardised multi-modal evoked-activity analysis approach to assess premature neurodevelopment, and will likely complement resting-state EEG and behavioural assessments in the study of the functional impact of developmental care interventions.

HighlightsO_LIMulti-modal sensory stimulation is used to assess premature infant brain function
C_LIO_LIA template analysis approach is outlined for multi-modal stimulus-evoked EEG activity
C_LIO_LIStimulus-evoked template magnitudes change with age
C_LIO_LIPrematurity results in accelerated maturation of visual and tactile sensory systems
C_LI

category: pediatrics


title: Australia's worsening mental health - what's next?

abstract:
ObjectivesTo examine trends in psychological distress in Australia between 2001 to 2017-18, including analysis by age, sex, and location.

Design, setting and participantsSecondary analysis of six successive national health surveys of representative samples of the working age population (18-64 years).

Main outcome measuresPrevalence of psychological distress at very-high symptom level (defined by a Kessler Psychological Distress Scale [K10] score of 30 or more) and combined high/very-high level (K10 score of 22 or more).

ResultsThe latest survey showed 5.1% of Australians reporting very-high level distress and 14.8% combined high/very-high level - both the largest rates recorded this century. The greatest increase from 2001 to 2017-18 was in women aged 55-64 with very-high distress significantly increasing from 3.5% (95% CI: 2.5-4.5%) to 7.2% (5.9-8.5%), and; high/very-high distress from 12.4% (10.5-14.2%) to 18.7% (16.7-20.7%). Men aged 25-34 had very-high distress increase from 2.1% (1.4-2.8) to 4.0% (2.9-5.1%); and combined high/very-high distress remained stable at 10.6% (9.1-12.1%) to 11.5% (9.7-13.3%). In 2017-18, greatest distress was in women aged 18-24 years (very-high 8.0% (5.9-10.2%); high/very-high 22.1% (18.8-25.3%)). Overall, distress was significantly more prevalent in inner regional Australia than elsewhere (very-high level 4.8% (4.4-5.1%); high/very-high 14.4% (13.8-15%)).

ConclusionsAustralias annual mental health expenditure over this period has doubled, yet population level psychological distress has increased. A whole of government approach and targeted strategies focusing on groups with the poorest mental health such as older working aged women, younger people, particularly women, and those outside of major cities are indicated.

Box"The known" Previous examinations of national health surveys had suggested that population mental health was stable as measured by psychological distress.

"The new" Examining six consecutive national surveys we provide evidence that mental health has significantly deteriorated between 2001 and 2018. The latest survey showed 5.1% of Australians reporting very-high distress and 14.8% combined high/very-high distress, which are the largest rates reported this century.

"The implications" Whole of government approach and targeted strategies focusing on groups with the poorest mental health such as older working aged women, younger people particularly women, and those outside of major cities are indicated.

category: psychiatry and clinical psychology


title: The COVID-19 pandemic and child malnutrition in sub-Saharan Africa: A scoping review

abstract:
BackgroundAlthough the COVID-19 pandemic has resulted in lower reported number of cases and deaths within the paediatric population, indirect impacts on the health of children in Sub-Saharan Africa such as malnutrition are evident. Data on the socioeconomic factors affecting malnutrition in the under-age population of Sub-Saharan Africa brought by the COVID-19 pandemic remain limited. This paper assesses socioeconomic factors of malnutrition in relation with COVID-19 and potential mitigating measures.

MethodsA scoping review of PubMed, Embase, and Web of Science from March 11, 2020, to May 1, 2021, was conducted. The included studies focused on COVID-19, children malnutrition, and Sub-Saharan Africa and adhered to the PRISMA guideline.

ResultsAmong 73 total screened articles, 15 studies filled the inclusion criteria. The identified socioeconomic factors leading to malnutrition in children were reduction in average income or increase in unemployment rate, access to healthcare and food supplements, disrupted food supply chains and increased prices of food products, pauses in humanitarian responses, and reduced access to school-based meals. Potential mitigation measures were food subsidies, food price control measures, the identification of new vulnerable groups and the implementation of financial interventions.

ConclusionMalnutrition amongst Sub-Saharan African children due to COVID-19 is a result of a combination of multiple socioeconomic factors. To stabilize household purchasing power and eventually malnutrition in children in SSA, a combined strategy of initial detection of newly developing vulnerable groups and efficient, rapid financial assistance through mobile phone transfers was suggested. These strategies were proposed in combination with other economical models.


title: Time trends and factors related to COVID-19 vaccine hesitancy from January-May 2021 among US adults: Findings from a large-scale national survey

abstract:
ImportanceCOVID-19 vaccine hesitancy has become a leading barrier to increasing the US vaccination rate.

ObjectiveTo evaluate time trends in COVID-19 vaccine intent during the US vaccine rollout, and identify key factors related to and self-reported reasons for COVID-19 vaccine hesitancy in May 2021.

Design, participants and settingA COVID-19 survey was offered to US adult Facebook users in several languages yielding 5,088,772 qualifying responses from January 6 to May 31, 2021. Data was aggregated by month. Survey weights matched the sample to the age, gender, and state profile of the US population.

ExposureDemographics, geographic factors, political/COVID-19 environment, health status, beliefs, and behaviors.

Main outcome measures"If a vaccine to prevent COVID-19 were offered to you today, would you choose to get vaccinated." Hesitant was defined as responding probably or definitely would not choose to get vaccinated (versus probably or definitely would, or already vaccinated).

ResultsCOVID-19 vaccine hesitancy decreased by one-third from 25.4% (95%CI, 25.3, 25.5) in January to 16.6% (95% CI, 16.4, 16.7) in May, with relatively large decreases among participants with Black, Pacific Islander or Hispanic race/ethnicity and [≤]high school education. Independent risk factors for vaccine hesitancy in May (N=525,644) included younger age, non-Asian race, < 4 year college degree, living in a more rural county, living in a county with higher Trump vote share in the 2020 election, lack of worry about COVID-19, working outside the home, never intentionally avoiding contact with others, and no past-year flu vaccine. Differences in hesitancy by race/ethnicity varied by age (e.g., Black adults more hesitant than White adults <35 years old, but less hesitant among adults [≥]45 years old). Differences in hesitancy by age varied by race/ethnicity. Almost half of vaccine hesitant respondents reported fear of side effects (49.2% [95%CI, 48.7, 49.7]) and not trusting the COVID-19 vaccine (48.4% [95%CI, 48.0, 48.9]); over one-third reported not trusting the government, not needing the vaccine, and waiting to see if safe. Reasons differed by degree of vaccine intent and by race/ethnicity.

ConclusionCOVID-19 vaccine hesitancy varied by demographics, geography, beliefs, and behaviors, indicating a need for a range of messaging and policy options to target high-hesitancy groups.


title: Time trends, factors associated with, and reasons for COVID-19 vaccine hesitancy in US adults: January-May 2021


title: Time trends, factors associated with, and reasons for COVID-19 vaccine hesitancy in a massive online survey of US adults: January-May 2021


title: 'Exome first' approach can reduce diagnostic costs and time - retrospective single centre analysis of 111 individuals with rare neurodevelopmental disorders

abstract:
This single center study aims to determine the time, diagnostic procedure and cost saving potential of early exome sequencing in a cohort of 111 individuals with genetically confirmed neurodevelopmental disorders.

We retrospectively collected data regarding diagnostic time points and procedures from the individuals medical histories and developed criteria for classifying diagnostic procedures in terms of requirement, followed by a cost allocation. The genetic variants of all individuals were reevaluated according to ACMG recommendations and considering the individuals phenotype.

Individuals who developed first symptoms of their underlying genetic disorder when Next Generation Sequencing (NGS) diagnostics were already available received a diagnosis significantly faster than individuals with first symptoms before this cutoff. The largest amount of potentially dispensable diagnostics was found in genetic, metabolic, and cranial magnetic resonance imaging examinations. Out of 407 performed genetic examinations, 296 (72.7%) were classified as potentially dispensable. The same applied to 36 (27.9%) of 129 cranial magnetic resonance imaging and 111 (31.8%) of 349 metabolic examinations. Dispensable genetic examinations accounted 302,947.07{euro} (90.2%) of the total 335,837.49{euro} in potentially savable costs in this cohort. The remaining 32,890.42{euro} (9.8%) are related to non-required metabolic and cranial magnetic resonance imaging diagnostics. On average, the total potentially savable costs in our study amount to {euro}3,025.56 per individual.

Cost savings by first tier exome sequencing lie primarily in genetic, metabolic, and cMRI testing in this German cohort, underscoring the utility of performing exome sequencing at the beginning of the diagnostic pathway and the potential for saving diagnostic costs and time.


title: Controlled human malaria infection with PvW1: a new clone of Plasmodium vivax with high quality genome assembly

abstract: Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naive UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors ("PvW1") was thawed and used to inoculate six healthy malaria-naive UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.


title: Severity of SARS-CoV-2 reinfections in second wave determines likelihood of mild endemicity

abstract: Immunity to SARS-CoV-2 is building up globally, but will this be sufficient to prevent future COVID-19 epidemics in the face of variants and waning immunity? Manaus, Brazil offers a concerning glimpse of what may come: six months after the majority of the citys population experienced primary infection, a second wave with a new strain resulted in more deaths than the first wave. Current hypotheses for this surge rely on prior immunity waning due to time and antigenic distance. Here we show this hypothesis predicts a severe endemic state. We propose an alternative hypothesis in which individuals infected in the first wave lose protection against transmission but retain immunity against severe disease and show this hypothesis is equally compatible with existing data. In this scenario, the increased number of deaths is due to an increased infection fatality ratio (IFR) for primary infections with the new variant. This alternative predicts a mild endemic state will be reached within decades. Collecting data on the severity of reinfections and infections post-vaccination as a function of time and antigenic distance from the original exposure is crucial for optimizing control strategies.


title: Off-season RSV epidemics in Australia after easing of COVID-19 restrictions

abstract: Human respiratory syncytial virus (RSV) is an important cause of acute respiratory infection (ARI) with the most severe disease in the young and elderly1,2. Non-pharmaceutical interventions (NPIs) and travel restrictions for controlling COVID-19 have impacted the circulation of most respiratory viruses including RSV globally, particularly in Australia, where during 2020 the normal winter epidemics were notably absent3-6. However, in late 2020, unprecedented widespread RSV outbreaks occurred, beginning in spring, and extending into summer across two widely separated states of Australia, Western Australia (WA) and New South Wales (NSW) including the Australian Capital Territory (ACT). Genome sequencing revealed a significant reduction in RSV genetic diversity following COVID-19 emergence except for two genetically distinct RSV-A clades. These clades circulated cryptically, likely localized for several months prior to an epidemic surge in cases upon relaxation of COVID-19 control measures. The NSW/ACT clade subsequently spread to the neighbouring state of Victoria (VIC) and caused extensive outbreaks and hospitalisations in early 2021. These findings highlight the need for continued surveillance and sequencing of RSV and other respiratory viruses during and after the COVID-19 pandemic as mitigation measures introduced may result in unusual seasonality, along with larger or more severe outbreaks in the future.


title: Upregulated of TBX1 by genetic variants are associated with human congenital heart disease

abstract: Congenital heart disease (CHD) is the most common human birth defect worldwide and also an important cause of childhood morbidity and mortality. The transcription factor of TBX1 early expressed in embryonic cardiac progenitor cells underlys embryo cardiogenesis in a dosage-dependent manner. Imbalanced TBX1 level has been shown to lead to cardiac defects. To study the association of TBX1 genetic variants with CHD susceptibility, we screened genetic variants in 409 CHD patients and 203 healthy controls. One single nucleotide polymorphism (SNP), rs41260844, in TBX1 promotor region was identified to be associated with CHD. Functional studies showed the minor allele of rs41260844 is associated with higher CHD risk and increases TBX1 promoter activity through attenuating TBX1 promoter binding affinity with nuclear protein(s). In addition, a novel case-specific missense rare mutation of p.P164L in TBX1 T-box domain was identified and predicted as deleterious mutation, which showed a trend of increased protein function. In summary, we concluded that a higher TBX1 expression level or activity is associated with CHD susceptibility, which could affect TBX1 downstream targets and thus disrupt the balance of the complex regulation network during cardiogenesis. This study deepens our current understanding of embryo cardiogenesis and CHD etiology.


title: Auto tuning SIR model parameters using genetic algorithm

abstract: Earlier studies [1] comparing Covid-19 simulations using extended SIR model [2] with observed new cases in New Jersey and United States showed good agreement between simulated results and observational data. The parameters of the SIR model controlling the behavior of the model have to be manually adjusted until the modelled results and observations reach good agreement. The parameter tuning process is tedious and time consuming. In this work, we have developed an approach using genetic algorithm [3] to automatically select the most optimal set of parameters to minimize the residual between simulated result and observational data. The parameter tuning process applying SIR model can now be automated without tedious and time consuming manual intervention.


title: Ethnic disparities in incident SARS-CoV-2 infections became wider during the second wave of SARS-CoV-2 in Amsterdam, the Netherlands: a population-based longitudinal study

abstract:
BackgroundSurveillance data in high-income countries have reported more frequent SARS-CoV-2 diagnoses in ethnic minority groups. We examined the cumulative incidence of SARS-CoV-2 and its determinants in six ethnic groups in Amsterdam, the Netherlands.

MethodsWe analyzed participants enrolled in the population-based HELIUS cohort, who were tested for SARS-CoV-2-specific antibodies and answered COVID-19-related questions between June 24-October 9, 2020 (after the first wave) and November 23, 2020-March 31, 2021 (during the second wave). We modeled SARS-CoV-2 incidence from January 1, 2020-March 31, 2021 using Markov models adjusted for age and sex. We compared incidence between ethnic groups over time and identified determinants of incident infection within ethnic groups.

Findings2,497 participants were tested after the first wave; 2,083 (83{middle dot}4%) were tested during the second wave. Median age at first visit was 54 years (interquartile range=44-61); 56{middle dot}6% were female. Compared to Dutch-origin participants (15{middle dot}9%), cumulative SARS-CoV-2 incidence was higher in participants of South-Asian Surinamese (25{middle dot}0%; adjusted hazard ratio [aHR]=1{middle dot}66;95%CI=1{middle dot}16-2{middle dot}40), African Surinamese (28{middle dot}9%;aHR=1{middle dot}97;95%CI=1{middle dot}37-2{middle dot}83), Turkish (37{middle dot}0%;aHR=2{middle dot}67;95%CI=1{middle dot}89-3{middle dot}78), Moroccan (41{middle dot}9%;aHR=3{middle dot}13;95%CI=2{middle dot}22-4{middle dot}42), and Ghanaian (64{middle dot}6%;aHR=6{middle dot}00;95%CI=4{middle dot}33-8{middle dot}30) origin. Compared to those of Dutch origin, differences in incidence became wider during the second versus first wave for all ethnic minority groups (all p for interaction<0.05), except Ghanaians. Having household members with suspected SARS-CoV-2 infection, larger household size, and low health literacy were common determinants of SARS-CoV-2 incidence across groups.

InterpretationSARS-CoV-2 incidence was higher in the largest ethnic minority groups of Amsterdam, particularly during the second wave. Prevention measures, including vaccination, should be encouraged in these groups.

FundingZonMw, Public Health Service of Amsterdam, Dutch Heart Foundation, European Union, European Fund for the Integration of non-EU immigrants.


title: Proteomic and metabolomic signatures associated with the immune response in healthy individuals immunized with an inactivated SARS-CoV-2 vaccine

abstract: SummeryCoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results suggest that protective immunity against SARS-CoV-2 can be achieved via multiple mechanisms and highlights the utility of a systems biology approach in defining molecular correlates of protection to vaccination.


title: Incidence of Lyme disease in the United Kingdom and association with fatigue: a population-based, historical cohort study

abstract:
ObjectivesTo evaluate incidence rates of Lyme disease in the UK and to investigate a possible association with subsequent fatigue

DesignPopulation-based historical cohort study with a comparator cohort matched by age, sex, and general practice

SettingPatients treated in UK general practices contributing to IQVIA Medical Research Data

Participants2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018, and 8,510 randomly-sampled matched comparators, followed-up for a median time of 3 years and 8 months.

Main outcome measuresTime from Lyme disease diagnosis to consultation for any fatigue-related symptoms or diagnosis and for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models.

ResultsAverage incidence rate for Lyme disease across the UK was 5.18 per 100,000 py between 2000 and 2018, increasing from 2.55 in 2000 to 9.33 in 2018. In total 929 events of any types of fatigue were observed, i.e. an incidence rate of 307.90 per 10,000 py in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season with highest adjusted HRs in autumn [3.14 (95%CI: 1.92 to 5.13)] and winter [2.23 (1.21 to 4.11)]. Incidence rates of ME/CFS were 11.16 per 10,000 py in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17 to 55.60). Effect on any types of fatigue and ME/CFS was attenuated 6 months after diagnosis but still clearly visible.

ConclusionsUK primary care records provided strong evidence that Lyme disease was associated with acute and chronic fatigue. Albeit weaker, these effects persisted beyond 6 months, suggesting that patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.

Key messages boxO_ST_ABSWhat is already known on this topicC_ST_ABSIncidence rates of Lyme disease in the UK are increasing but estimations vary according to data sources used.

Reports investigating the association between Lyme disease and long-term fatigue are contradictory.

What this study addsAverage incidence rate for Lyme disease across the UK was estimated at 5.18 per 100,000 py between 2000 and 2018, and followed an increasing trend.

In patients with Lyme disease, a 2- and 3-fold increase in any subsequent fatigue was observed in winter and autumn, respectively, and a 16-fold increase in ME/CFS (all seasons combined), compared to a non-Lyme cohort matched by sex, age, and general practice.


title: Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After SARS-Cov-2 Vaccination

abstract: As more people are vaccinated against SARS-CoV-2, many of those already infected are still suffering from Post-Acute Sequelae (PASC). Although there is no current treatment for PASC, reports from patients that the vaccine itself improves, and in some reports, worsens, PASC symptoms may lead to a deeper understanding of the causes of PASC symptoms and viable treatments. As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.


title: Profiling lockdown adherence and poor coping responses towards the COVID-19 crisis in an international cross-sectional survey

abstract: This study uses international respondents to a COVID-lockdown related questionnaire (n = 1,688) to assess the determinants of adherence and poor coping in response to lockdown measures. A regression analysis was used to compare the relative importance of clusters derived from a K-means cluster analysis as well as various demographics (age, gender, level of education, political affiliation, a factor reflecting social security and a factor reflecting the lockdown harshness). Three distinct clusters ("General Population", "Extreme Responders" and "Sufferers) were identified, corresponding well to a previous study. Clusters appeared to be the best overall predictors of coping and adherence although gender, political affiliation and lockdown harshness were also important predictors. The large proportion of variance that remains unexplained, combined with the relatively weak effects of traditional demographics, suggest that less concrete variables such as personality traits, health and environmental factors may be better predictors of adherence and coping during a pandemic.


title: High-throughput Mutational Surveillance of the SARS-CoV-2 Spike Gene

abstract: SARS-CoV-2 has evolved rapidly towards higher infectivity and partial immune escape over the course of the pandemic. This evolution is driven by the enormous virus population, that has infected close to 200 million people by now. Therefore, cost effective and scalable methods are needed to monitor viral evolution globally. Mutation-specific PCR approaches have become inadequate to distinguish the variety of circulating SARS-CoV-2 variants and are unable to detect novel ones. Conversely, whole genome sequencing protocols remain too labor- and cost-intensive to monitor SARS-CoV-2 at the required density. By adapting SARSeq we present a simple, fast, and scalable S-gene tiling pipeline for focused sequencing of the S-gene encoding for the spike protein. This method reports on all sequence positions with known importance for infectivity and immunity, yet scales to >20K samples per run. S-gene tiling is used for nationwide surveillance of SARS-CoV-2 at a density of 10% to 50% of all cases of infection in Austria. SARSeq S-tiling uncovered several infection clusters with variants of concern such as the biggest known cluster of Beta/B.1.351 outside Africa and successfully informed public health measures in a timely manner, allowing their successful implementation. Our close monitoring of mutations further highlighted evolutionary constraints and freedom of the spike protein ectodomain and sheds light on foreseeable evolutionary trajectories.


title: Association of lipid-lowering drugs with COVID-19 outcomes: A Mendelian Randomization study

abstract:
BackgroundLipid metabolism plays an important role in viral infections. Large cohort study suggested a protective potential of lipid-lowering drugs in COVID-19 outcomes, but the nature of observational study precludes it to draw a causal inference.

ObjectivesTo assess the causal effect of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors and NPC1L1 inhibitors) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study.

MethodsWe used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci (eQTLs) of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL) cholesterol from genome-wide association study (GWAS). GWASs of COVID-19 outcomes (susceptibility, hospitalization and very severe disease) were obtained from the COVID-19 Host Genetics Initiative. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates.

ResultsSMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81; P=0.019). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74; P=0.049). No consistent evidence from both SMR and IVW-MR analyses was found for the association of HMGCR inhibitors with COVID-19 susceptibility or very severe disease, or for the association of PCSK9 inhibitors and NPC1L1 inhibitor with COVID-19 outcomes.

ConclusionsIn this 2-sample MR study, we found potential causal evidence that HMGCR inhibitors could reduce the risk of COVID-19 hospitalization. Further research is needed to explore the therapeutic role of statins for COVID-19.


title: Hospitalization Data Supports Correlation of Lower Covid-19 Severity vs. Universal BCG Immunization in the Early Phase of the Pandemic

abstract: The possibility of a correlation between universal administration of the bacillus Calmette-Guerin (BCG) tuberculosis vaccine and lower severity of Covid-19 by national jurisdiction has been pointed out previously. In this work we examined hospitalization data attributed to Covid-19 cause reported by European national jurisdictions with the conclusion of a clear negative correlation between current or recent BCG vaccination program and reduced impact of the epidemics on the population measured in hospital admissions per capita in the early phase of the pandemic, before variants and vaccines. While there is no evidence that BCG vaccination provides strong individual level protection, the results of this work in combination with the results of other studies appear to support the hypothesis of a certain population-wide protection effect that is correlated with BCG immunization.


title: The mystery of COVID-19 reinfections: A global systematic review and meta-analysis of 577 cases

abstract:
BackgroundAs the COVID-19 pandemic rages on, reports on disparities in vaccine roll out alongside reinfection and reactivation from previously recovered cases have been emerging. With newer waves and variants of COVID-19, we conducted a systematic review to assess the determinants and disease spectrum of COVID-19 reinfection.

MethodsA comprehensive search covering relevant databases was conducted for observational studies reporting Polymerase Chain Reaction (PCR) confirmed infection and reinfection cases. Quality assessment tool developed by the National Institute of Health (NIH) for assessment of case series was used. Meta-analyses were performed using RevMan 5.3 for pooled proportions of findings in first infection and reinfection with 95% confidence interval (CI).

ResultsEighty-one studies reporting 577 cases were included from 22 countries. The mean age of patients was 46.2{+/-}18.9 years with males accounting for 45.8% of the study population while 179 (31.0%) cases of comorbidities were reported. The average time duration between first infection and reinfection was 63.6{+/-}48.9 days. During first infection and reinfection, fever was the most common symptom (41.4% and 36.4%, respectively) whilst anti-viral therapy was the most common treatment regimen administered (44.5% and 43.0%, respectively). Overall, comparable odds of symptomatic presentation and management were reported in the two infections. However, a higher Intensive Care Unit (ICU) admission rate was observed in reinfection compared to first infection (10 vs 3). Ten deaths were reported with 565 patients fully recovering. Respiratory failure was the most common cause of death (7/10 deaths). Seventy-two studies were determined to be of good quality whilst nine studies were of fair quality.

ConclusionAs the first global-scale systematic review of its kind, our findings support immunization practices given increased ICU admissions and mortality in reinfections. Our cohort serves as a guide for clinicians and authorities for devising an optimal strategy for controlling the pandemic.


title: Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxia: an international, randomized, blinded trial

abstract:
IMPORTANCEDexamethasone 6 mg daily is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease.

OBJECTIVETo assess the effects of dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxia.

DESIGN, SETTING, PARTICIPANTSWe conducted a parallel-grouped, stratified, blinded randomized trial including 1000 adults with confirmed COVID-19 receiving at least 10 l/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India from August 2020 to May 2021.

INTERVENTIONSPatients were randomized 1:1 to masked intravenous dexamethasone 12 mg or dexamethasone 6 mg daily for up to 10 days.

MAIN OUTCOME MEASURESThe primary outcome was the number of days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) at 28 days. The primary analysis was adjusted for stratification variables (site, age below 70 years and invasive mechanical ventilation).

RESULTSAfter exclusion of 18 patients who withdrew consent, there were 982 patients (613 in Europe, 369 in India) in the intention-to-treat population. We had primary outcome data for 971 patients; 491 assigned to dexamethasone 12 mg and 480 assigned to dexamethasone 6 mg. The median number of days alive without life support was 22.0 days (interquartile range 6.0-28.0) in the 12 mg group and 20.5 days (4.0-28.0) in the 6 mg group (adjusted mean difference 1.3 days, 95% confidence interval (CI), 0.0-2.6; P=0.066). Mortality at 28 days was 27.1% and 32.3% in patients assigned to 12 mg and 6 mg, respectively (adjusted relative risk 0.86, 99% CI, 0.68-1.08). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% versus 13.2% of patients in the 12 mg group and 6 mg group, respectively (adjusted relative risk 0.85, 99% CI, 0.55-1.32).

CONCLUSIONS AND RELEVANCEAmong patients with COVID-19 and severe hypoxia, dexamethasone 12 mg did not result in statistically significantly more days alive without life support at 28 days than dexamethasone 6 mg. However, the confidence interval around the point estimate should be considered when interpreting the results of this trial.

TRIAL REGISTRATIONClinicalTrials.gov (NCT04509973) and Clinical Trial Registry India (2020/10/028731).

category: intensive care and critical care medicine


title: Variant-driven multi-wave pattern of COVID-19 via Machine Learning clustering of spike protein mutations

abstract:
Never before such a vast amount of data, including genome sequencing, has been collected for any viral pandemic than for the current case of COVID-19. This offers the possibility to trace the virus evolution and to assess the role mutations play in its spread within the population, in real time. To this end, we focused on the Spike protein for its central role in mediating viral outbreak and replication in host cells. Employing the Levenshtein distance on the Spike protein sequences, we designed a machine learning algorithm yielding a temporal clustering of the available dataset. From this, we were able to identify and define emerging persistent variants that are in agreement with known evidences. Our novel algorithm allowed us to define persistent variants as chains that remain stable over time and to highlight emerging variants of epidemiological interest as branching events that occur over time. Hence, we determined the relationship and temporal connection between variants of interest and the ensuing passage to dominance of the current variants of concern. Remarkably, the analysis and the relevant tools introduced in our work serve as an early warning for the emergence of new persistent variants once the associated cluster reaches 1% of the time-binned sequence data. We validated our approach and its effectiveness on the onset of the Alpha variant of concern. We further predict that the recently identified lineage AY.4.2 ( Delta plus) is causing a new emerging variant. Comparing our findings with the epidemiological data we demonstrated that each new wave is dominated by a new emerging variant, thus confirming the hypothesis of the existence of a strong correlation between the birth of variants and the pandemic multi-wave temporal pattern. The above allows us to introduce the epidemiology of variants that we described via the Mutation epidemiological Renormalisation Group (MeRG) framework.

HighlightsO_LIObjectives To study the relation among Spike protein mutations, the emergence of relevant variants and the multi-wave pattern of the COVID-19 pandemic.
C_LIO_LISetting Genomic sequencing of the SARS-CoV-2 Spike proteins in the UK nations (England, Scotland, Wales). Epi-demiological data for the number of infections in the UK nations, South Africa, California and India.
C_LIO_LIMethodology We design a machine learning algorithm, based on the Levenshtein distance on the Spike protein sequences, that leads to a temporal clustering of the available dataset, from which we define emerging persistent variants. The above allows us to introduce the epidemiology of variants that we described via the Mutation epidemiological Renormalisation Group (MeRG) framework.
C_LIO_LIResults We show that:
O_LIOur approach, based only on the Spike protein sequence, allows to efficiently identify the variants of concern (VoCs) and of interest (VoIs), as well as other emerging variants occurring during the diffusion of the virus.
C_LIO_LIWithin our time-ordered chain analysis, a branching relation emerges, thus permitting to reconstruct the evolutionary diversification of Spike variants and the establishment of the epidemiologically relevant ones.
C_LIO_LIOur analysis provides an early warning for the emergence of new persistent variants once its associated dominant Spike sequence reaches 1% of the time-binned sequence data. Validation on the onset of the Alpha VoC shows that our early warning is triggered 6 weeks before the WHO classification decision.
C_LIO_LIComparison with the epidemiological data demonstrates that each new wave is dominated by a new emerging variant, thus confirming the hypothesis that there is a strong correlation between the emergence of variants and the multi-wave temporal pattern depicting the viral spread.
C_LIO_LIA theory of variant epidemiology is established, which describes the temporal evolution of the number of infected by different emerging variants via the MeRG approach. This is corroborated by empirical data.
C_LI
C_LI

O_LIConclusions Applying a ML approach to the temporal variability of the Spike protein sequence enables us to identify, classify and track emerging virus variants. Our analysis is unbiased, in the sense that it does not require any prior knowledge of the variant characteristics, and our results are validated by other informed methods that define variants based on the complete genome. Furthermore, correlating persistent variants of our approach to epidemiological data, we discover that each new wave of the COVID-19 pandemic is driven and dominated by a new emerging variant. Our results are therefore indispensable for further studies on the evolution of SARS-CoV-2 and the prediction of evolutionary patterns that determine current and future mutations of the Spike proteins, as well as their diversification and persistence during the viral spread. Moreover, our ML algorithm works as an efficient early warning system for the emergence of new persistent variants that may pose a threat of triggering a new wave of COVID-19. Capable of a timely identification of potential new epidemiological threats when the variant only represents 1% of the new sequences, our ML strategy is a crucial tool for decision makers to define short and long term strategies to curb future outbreaks. The same methodology can be applied to other viral diseases, influenza included, if sufficient sequencing data is available.
C_LI


title: Variant-driven multi-wave pattern of COVID-19 via a Machine Learning analysis of spike protein mutations


title: Blood bacterial DNA, intestinal adenoma and colorectal cancer

abstract:
ObjectiveWe aimed to investigate the relation of blood bacterial DNA load and profiling with intestinal adenoma (IA) and colorectal cancer (CRC) patients.

DesignWe performed 16S rRNA gene analysis of blood from 100 incident histologically confirmed CRC cases, 100 IA and 100 healthy subjects, matched to cases by centre, sex and age. Bacterial load was analysed using multiple conditional logistic regression. Differences in terms of abundance of bacteria between groups were estimated through analysis based on negative binomial distribution normalization. Random Forest was applied to predict the group assignment.

ResultsWe found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls (IA and healthy subjects). The odds ratio of colon cancer for the highest versus the lowest three quintiles of gene copies was 2.62. (95% confidence interval=1.22-5.65). No difference was found for rectal cancer and IA. For high 16S rRNA, community diversity was higher in colon cancers than controls. CRC cases had an enrichment of Peptostreptococcaceae and Acetobacteriaceae and a reduced abundance of Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae. Identified variables predicted CRC from control and IA patients with an accuracy of 0.70.

ConclusionColon cancer patients had a higher DNA bacterial load and a different bacterial profiling as compared to healthy subjects, IA and rectal cancers, indicating a higher passage of bacteria from gastrointestinal tract to bloodstream. Further studies are needed to confirm this result and exploit it to conceive new non-invasive techniques for an early diagnosis of CRC.


title: Natural Language Word-Embeddings as a glimpse into healthcare at the End Of Life

abstract:
IntroductionPlanning in advance and personalised discussions on limitation of life sustaining treatment (LST) is an indicator of good care. However, there are many linguistic nuances and misunderstandings around dying in hospital as well as inaccuracy in individual-level prognostication.

MethodsUsing unsupervised natural language processing (NLP), we explored real-world terminology using phrase clusters with most similar sematic embeddings to "Ceiling of Treatment" and their prognostication value in the electronic health record of an urban teaching hospital.

ResultsWord embeddings with most similar to "Ceiling of Treatment" clustered around phrases describing end-of-life care, ceiling of care and resuscitation discussions. The phrases have differing prognostic profile with the highest 7-day mortality in the phrases most implicitly referring to end of life -"terminal care", "end of life care" (57.5%) and "unsurvivable" (57.6%).

ConclusionNLP can quantify and analyse real-world end of life discussions around prognosis and appropriate LST.

Patient-friendly Summary(by expert patients: Sherry Charing, Alan Quarterman, Harold Parkes)

Discussions between doctors, patients and family in deciding what is the appropriate maximum treatment a specific patient should have based on their clinical condition is complex. Discussions, often involving expressions regarding "End Of Life" care are used to describe the maximum invasive treatments a patient should have or would want. There are a range of expressions used, many with overlapping meanings which can be confusing, not only for the patient and family, but also for doctors reading the patients clinical notes. In this study, a computational approach using Artificial Intelligence to read clinical patient notes was carried out by looking at thousands of patient records from a large urban hospital. Expressions that doctors use to describe these discussions were analysed to show the associations of particular words and phrases in relation to mortality. Using a computer analysis for this study it was possible to quantify the use of these expressions and their relation to the "End Of Life". Through this AI-based approach, real-world use of phrases and language relating "End Of Life" can be analysed to understand how doctors and patients are communicating, and about any possible misunderstandings of language.

category: palliative medicine


title: The human vestibular cortex: functional anatomy, connectivity and the effect of vestibular disease

abstract:
Area OP2 in the posterior peri-sylvian cortex has been proposed to be the core human vestibular cortex. We defined the functional anatomy of OP2 using spatially constrained independent component analysis of functional MRI data from the Human Connectome Project. Ten distinct subregions were identified. Most subregions showed significant connectivity to other areas with vestibular function: the parietal opercula, the primary somatosensory cortex, the supracalcarine cortex, the left inferior parietal lobule and the anterior cingulate cortex. OP2 responses to vestibular and visual-motion were analysed in 17 controls and 17 right-sided unilateral vestibular lesion patients (vestibular neuritis) who had previously undergone caloric and optokinetic stimulation during functional MRI. In controls, a posterior part of right OP2 showed: (a) direction-selective responses to visual motion; and (b) activation during caloric stimulation that correlated positively with perceived self-motion, and negatively with visual dependence. Patients showed abnormal OP2 activity, with an absence of visual or caloric activation of the healthy ear and no correlations with dizziness or visual dependence - despite normal brainstem responses to caloric stimulation (slow-phase nystagmus velocity). A lateral part of right OP2 showed activity that correlated with chronic dizziness (situational vertigo) in patients. Our results define the functional anatomy of OP2 in health and disease. A posterior subregion of right OP2 shows strong functional connectivity to other vestibular regions and a visuo-vestibular profile that becomes profoundly disrupted after vestibular disease. In vestibular patients, a lateral subregion of right OP2 shows responses linked to the challenging long-term symptoms which define poorer clinical outcomes.

Significance statementThe human cortical vestibular network is critical to higher vestibular functions such as the perception of self-motion, judgements about verticality ( which way is up), and adaptation following peripheral vestibular disease (e.g. vestibular neuritis). The functional organisation of this network has remained poorly understood. In this study, we define the functional anatomy of area OP2 - a core region within the human cortical vestibular network. We identify subregions of OP2 with strong connectivity to other cortical vestibular areas. We show specific subregions of right OP2 process vestibular and visual motion information in health and that such processing is disrupted following peripheral vestibular disease. Abnormal signal processing within OP2 may underpin chronic dizziness following peripheral vestibular disease.


title: Disrupted PGR-B and ESR1 signaling underlies preconceptional defective decidualization linked to severe preeclampsia

abstract: Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlaying the in vivo defect linking decidualization to sPE is unknown. Here, we discover the footprint encoding this decidualization defect comprising of 166 genes using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. Estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B) were found highly interconnected with the dynamic network of defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that may be leverage for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments.


title: Patient stratification reveals the molecular basis of disease comorbidities

abstract:
Epidemiological evidence shows that some diseases tend to co-occur; more exactly, certain groups of patients with a given disease are at a higher risk of developing a specific secondary condition. Despite the considerable interest, only a small number of connections between comorbidities and molecular processes have been identified.

Here we develop a new approach to generate a disease network that uses the accumulating RNA-seq data on human diseases to significantly match a large number of known comorbidities, providing plausible biological models for such co-occurrences. Furthermore, 64% of the known disease pairs can be explained by analysing groups of patients with similar expression profiles, highlighting the importance of patient stratification in the study of comorbidities.

These results solidly support the existence of molecular mechanisms behind many of the known comorbidities. All the information can be explored on a large scale and in detail at http://disease-perception.bsc.es/rgenexcom/.


title: Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

abstract:
Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard "2 doses" scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.

One sentence summaryThe generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.

category: transplantation


title: Hypocalcemia and Acute Pulmonary Embolism Hospitalizations in the United States: Highlights from the propensity matched 2017 Nationwide Inpatient Sample

abstract: Acute pulmonary embolism (PE) is a common cause for hospitalization associated with significant mortality and morbidity. Disorders of calcium metabolism are a frequently encountered medical problem. The effect of hypocalcemia is not well defined on the outcomes of patients with PE. We aimed to identify the prognostic value of hypocalcemia in hospitalized PE patients utilizing the 2017 Nationwide Inpatient Sample (NIS). In this retrospective study, we selected patients with a primary diagnosis of Acute PE using ICD 10 codes. They were further stratified based on the presence of hypocalcemia. We primarily aimed to compare in-hospital mortality for PE patients with and without hypocalcemia. In the 2017 NIS, 187,989 patients had a principal diagnosis of acute PE. Among the above study group, 1565(0.8%)had an additional diagnosis of hypocalcemia. 12.4% of PE patients with hypocalcemia died in the hospital in comparison to 2.95% without hypocalcemia. On multivariate regression analysis, PE and hypocalcemia patients had 4 times higher odds (aOR-4.03, 95% CI 2.78-5.84, p<0.001) of in-hospital mortality compared to those with only PE. We observed a similarly high odds of mortality(aOR=4.4) on 1:1 propensity-matched analysis. The incidence of acute kidney injury (aOR=2.62, CI 1.95-3.52, p<0.001), acute respiratory failure (a0R=1.84, CI 1.42-2.38, p<0.001), sepsis (aOR=4.99, CI 3.08-8.11, p<0.001) and arrhythmias (aOR=2.63, CI 1.99-3.48, p<0.001) were also higher for PE patients with hypocalcemia. Thus, PE patients with hypocalcemia have higher in-hospital complications and mortality than those without hypocalcemia.

category: cardiovascular medicine


title: A Wastewater-Based Epidemic Model for SARS-CoV-2 with Application to Three Canadian Cities

abstract:
1The COVID-19 pandemic has stimulated wastewater-based surveillance, allowing public health to track the epidemic by monitoring the concentration of the genetic fingerprints of SARS-CoV-2 shed in wastewater by infected individuals. Wastewater-based surveillance for COVID-19 is still in its infancy. In particular, the quantitative link between clinical cases observed through traditional surveillance and the signals from viral concentrations in wastewater is still developing and hampers interpretation of the data and actionable public-health decisions.

We present a modelling framework that includes both SARS-CoV-2 transmission at the population level and the fate of SARS-CoV-2 RNA particles in the sewage system after faecal shedding by infected persons in the population.

Using our mechanistic representation of the combined clinical/wastewater system, we perform exploratory simulations to quantify the effect of surveillance effectiveness, public-health interventions and vaccination on the discordance between clinical and wastewater signals. We also apply our model to surveillance data from three Canadian cities to provide wastewater-informed estimates for the actual prevalence, the effective reproduction number and incidence forecasts. We find that wastewater-based surveillance, paired with this model, can complement clinical surveillance by supporting the estimation of key epidemiological metrics and hence better triangulate the state of an epidemic using this alternative data source.

category: epidemiology