title: Booster and anergic effects of the Covishield vaccine among healthcare workers in South India

abstract: Covishield (same as ChAdOx1) vaccine was rolled out in January 2021 against SARS-CoV2 in India. Although studies show good efficacy after two doses, there is limited data on the fate of the elicited antibody responses over time in groups with or without prior exposure to SARS-CoV2. Therefore, in this study we proposed to test naive or previously exposed healthcare workers (HCWs) longitudinally after both doses for anti-SARS-CoV2 spike antibody (ASSA) levels. Serum samples were collected from 205 HCWs at days 14 and 28 after first dose, and at days 14, 28 and 3-months after second dose. ASSA levels were quantitated by ECLIA method. Non-responder rate was 17% (35/205) on day 14 and 2% (5/205) on day 28 after the first dose. After the second dose, the responder rate was 100%. Non-responder rate was significantly higher among males (p<0.00001) and senior citizens (p=0.008). The second dose boosted a 27-fold increase in the COVID-19 naive (CN) group, but caused a 1.5-fold decline in the previously exposed groups. By three months, the antibody levels declined 3-4-folds in all the groups. In spite of high antibody levels (GM-1007 U/ml) after the second dose, 14% developed mild breakthrough infections (BTI). The booster effect was significantly higher when given 10-14 weeks later. The responder rate for Covishield was 98% after first dose and 100% after second dose. The vaccine elicited a prime-boost effect in CN HCWs and a boost-anergy effect in the previously exposed HCWs. ASSA levels began to decline proportionately by three months.


title: Reproducibility of three-dimensional landmarking and Frankfort horizontal plane construction: a comparison of conventional and novel landmarks in presurgical computed tomography scans

abstract:
ObjectivesTo assess manual landmarking repeatability and reproducibility (R&R) of a set of three-dimensional (3D) landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation.

MethodsThirty-three landmarks, divided into "conventional", "foraminal" and "dental", were manually located twice by 3 experienced operators on 20 computed tomography (CT) scans of orthognathic surgery patients. R&R of the landmark localization were computed according to the ISO 5725 standard. These landmarks were then used to construct 2 FH planes: a conventional FH plane (orbitale left, porion right and left) and a newly proposed FH plane (midinternal acoustic foramen, orbitale right and left). R&R of vertical cephalometric measurements were computed using these 2 FH planes as horizontal references for CT reorientation.

ResultsLandmarks showing a 95% confidence interval (CI) of repeatability and/or reproducibility > 2mm were found exclusively in the "conventional" landmarks group. Vertical measurements showed excellent R&R (95% CI < 1mm) with either FH plane as horizontal reference. However, the 2 FH planes were not found to be parallel (absolute angular difference of 2.41{degrees}, SD 1.27{degrees}). The average time needed to landmark one CT scan was 14 {+/-} 3 minutes.

ConclusionsThe "dental" and "foraminal" landmarks tended to be more reliable than the "conventional" landmarks. Despite the poor overall reliability of the landmarks orbitale and porion, the construction of the conventional FH plane using 3 landmarks provided a reliable horizontal reference for 3D craniofacial CT scan reorientation.

category: dentistry and oral medicine


title: Three-dimensional cephalometric landmarking and Frankfort horizontal plane construction: reproducibility of conventional and novel landmarks


title: Sex differences in the risk of cataract associated with type 2 diabetes: a Mendelian randomization study

abstract: Type 2 diabetes (T2D) is a recognized risk factor for developing cataract. However, it is unclear if the shared genetic variance and potential genetic causal relationship between T2D and cataract are different for males and females. We evaluated sex-specific genetic correlation (rg) and putative genetic causality between the two diseases by using linkage disequilibrium score regression (LDSC) and six Mendelian randomization (MR) approaches after leveraging large-scale population-based genome-wide association studies (GWAS) summary of T2D and cataract. Application of LDSC found a significant genetic correlation between T2D and cataract in East Asian males (rg=0.68, 95% confident interval [CI]=0.17 to 1, p-value=8.60x10-3) but a non-significant genetic correlation in East Asian females (rg=0.25, CI= -0.02 to 0.52, p-value=8.38x10-2). MR analyses indicated a consistently stronger (paired t-test |t|=5.87, p-value=2.04x10-3) causal effect of T2D on cataract in East Asian males (liability OR=1.20 to 1.41, p-value=5.86x10-27 to 6.60x10-6) than in females (liability OR=1.12 to 1.21, p-value=2.02x10-14 to 1.82x10-2). In Europeans, the LDSC analysis suggested a close significant genetic correlation between the two diseases in males (rg=0.20, 95% confident interval [CI]=0.08 to 0.32, p-value=7.00x10-4) and females (rg=0.17, CI= 0.05 to 0.29, p-value=4.90x10-3); but the MR analyses provided weak evidences on a causal relationship between the two diseases in both sexes. These results presented the first evidence on sex difference of the casual relationship between cataract and T2D in East Asians, and supported a potential genetic heterogeneity of the shared genetics underlying T2D and cataract between East Asians and Europeans in both sexes.

category: epidemiology


title: Preliminary Analysis of Excess Mortality in India During the Covid-19 Pandemic (Update August 4, 2021).

abstract:
As both testing for SARS Cov-2 and death registrations are incomplete or not yet available in many countries, the full impact of the Covid-19 pandemic is currently unknown in many world regions.

We studied the Covid-19 and all-cause mortality in 19 Indian states (combined population of 1.27 billion) with available all-cause mortality data during the pandemic for the entire state or for large cities. Excess mortality was calculated by comparison with available data from years 2015-2019. The known Covid-19 deaths reported by the Johns Hopkins University Center for Systems Science and Engineering for a state were assumed to be accurate, unless excess mortality data suggested a higher toll during the pandemic. Data from one state were not included in the final model due to anomalies.

In several regions, fewer deaths were reported in 2020 than expected. The excess mortality in Mumbai (in Maharashtra) in 2020 was 137.0 / 100K. Areas in Andhra Pradesh, Delhi, Haryana, Karnataka, Madhya Pradesh, Tamil Nadu, and Kolkata (in West Bengal), saw spikes in mortality in the spring of 2021.

The pandemic-related mortality through August 31, 2021 in 18 Indian states was estimated to be 198.7 per 100,000 population (range 146.1 to 263.8 per 100K). If these rates apply to India as a whole, then 2.69 million people (range 1.98 to 3.57 million) may have perished in India as a result of the Covid-19 pandemic by August 31, 2021.


title: Preliminary Analysis of Excess Mortality in India During the Covid-19 Pandemic (Update September 26, 2021).


title: On the persistence of mental health deterioration during the COVID-19 pandemic by sex and ethnicity in the UK: evidence from Understanding Society

abstract: We use longitudinal data from a representative sample of the UK and compare self-reported mental health, as measured by the GHQ-12 score, at three timepoints (2017-2019, April 2020 and March 2021), for the whole sample and by sex and ethnicity. Out of the 14,382 individuals interviewed in 2017-2019 and April 2020, 10,445 were interviewed again in March 2021. The mean GHQ-12 in April 2020 is 12.37 [95% CI: 12.22, 12.52] and in March 2021 is 12.36 [95% CI: 12.21, 12.51], above that in 2017-2019, 11.13 [95% CI: 10.99, 11.26]. We do not find evidence that the level of mental health goes back to pre-pandemic levels. In terms of inequalities, while the gender gap (mean difference between women and men) in mental health deterioration among White British is closing, there is no clear evidence that the ethnic gap (mean difference between ethnic minorities and White British) among men is changing.

category: psychiatry and clinical psychology


title: Results dissemination from completed clinical trials conducted at German university medical centers remains delayed and incomplete. The 2014-2017 cohort

abstract:
ObjectiveTimely publication of clinical trial results is central for evidence-based medicine. The performance of university medical centers (UMCs) regarding timely results publication informs the local and national decision makers, patients, and the public about the need to improve trial results dissemination.

Study Design and SettingFollowing the same search and tracking methods used in our previous study for the years 2009 - 2013, we identified trials led by German UMCs completed between 2014 and 2017 and tracked results dissemination for the identified trials.

ResultsWe identified 1,658 trials in the 2014-2017 cohort. Of these trials, 43% published results as either journal publication or summary results within 24 months after completion date, which is an improvement of 3.8% percentage points compared to the previous study. At the UMC level, the 24-month publication rates varied from 14% to 71%. Five years after completion, still 30% of the trials remained unpublished.

ConclusionDespite minor improvements compared to the previously investigated cohort, the rate of timely reporting of trials led by German UMCs remains low. German UMCs should take further steps to improve timely reporting rates.

category: public and global health


title: Passive Detection of COVID-19 with Wearable Sensors and Explainable Machine Learning Algorithms

abstract: Individual smartwatch or fitness band sensor data in the setting of COVID-19 has shown promise to identify symptomatic and pre-symptomatic infection or the need for hospitalization, correlations between peripheral temperature and self-reported fever, and an association between changes in heart-rate-variability and infection. In our study, a total of 38,911 individuals (61% female, 15% over 65) have been enrolled between March 25, 2020 and April 3, 2021, with 1,118 reported testing positive and 7,032 negative for COVID-19 by nasopharyngeal PCR swab test. We propose an explainable gradient boosting prediction model based on decision trees for the detection of COVID-19 infection that can adapt to the absence of self-reported symptoms and to the available sensor data, and that can explain the importance of each feature and the post-test-behavior for the individuals. We tested it in a cohort of symptomatic individuals who exhibited an AUC of 0.83 [0.81-0.85], or AUC=0.78 [0.75-0.80] when considering only data before the test date, outperforming state-of-the-art algorithm in these conditions. The analysis of all individuals (including asymptomatic and pre-symptomatic) when self-reported symptoms were excluded provided an AUC of 0.78 [0.76-0.79], or AUC of 0.70 [0.69-0.72] when considering only data before the test date. Extending the use of predictive algorithms for detection of COVID-19 infection based only on passively monitored data from any device, we showed that it is possible to scale up this platform and apply the algorithm in other settings where self-reported symptoms can not be collected.


title: Rapid transmission of coronavirus disease 2019 within a religious sect in South Korea: a mathematical modeling study

abstract:
Rapid transmission of coronavirus disease 2019 (COVID-19) was observed in the Shincheonji Church of Jesus, a religious sect in South Korea. The index case was confirmed on February 18, 2020 in Daegu City, and within two weeks, 3,081 connected cases were identified. Doubling times during these initial stages (i.e., February 18 - March 2) of the outbreak were less than 2 days. A stochastic model fitted to the time series of confirmed cases suggests that the basic reproduction number (R0) of COVID-19 was 8.5 [95% credible interval (CrI): 6.3, 10.9] among the church members, whereas (R0 = 1.9 [95% CrI: 0.4, 4.4]) in the rest of the population of Daegu City. The model also suggests that there were already 4 [95% CrI: 2, 11] undetected cases of COVID-19 on February 7 when the index case reportedly presented symptoms. The Shincheonji Church cluster is likely to be emblematic of other outbreak-prone populations where R0 of COVID-19 is higher. Understanding and subsequently limiting the risk of transmission in such high-risk places is key to effective control.

HighlightsO_LIBasic reproduction number (R0) of COVID-19 in a religious community of Shincheonji Church of Jesus was estimated to be 8.5 [95% credible interval (CrI): 6.3, 10.9], which is more than 4 times larger than the general population (R0 = 1.9 [95% CrI: 0.4, 4.4])
C_LIO_LIThere were estimated 4 [95% CrI: 2, 11] undetected cases when the index case from the religious community reported symptom on February 7.
C_LIO_LIThe Shincheonji Church cluster is likely to be emblematic of other outbreak-prone populations where R0 of COVID-19 is higher. Understanding and subsequently limiting the risk of transmission in such high-risk places is key to effective control.
C_LI

category: infectious diseases


title: Pylorus resection versus pylorus preservation in pancreatoduodenectomy (PyloResPes): study protocol and statistical analysis plan for a German multicentre, single-blind, surgical, registry-based randomised controlled trial

abstract:
IntroductionPartial pancreatoduodenectomy (PD) is the treatment of choice for various benign and malignant tumours of the pancreatic head or the periampullary region. For reconstruction of the gastrointestinal passage, two stomach preserving PD variants exist: pylorus preservation (ppPD), or pylorus resection (prPD) with preservation of the stomach. In pancreatic surgery, delayed gastric emptying (DGE) remains a serious complication after PD with an incidence varying between 4.5% and 45%, potentially delaying hospital discharge or further treatment, e.g. adjuvant chemotherapy. Evidence is lacking to assess which variant of PD entails fewer postoperative DGE.

Methods and analysisThe protocol of a large-scale, multicentre, pragmatic, two-arm parallel-group, registry-based randomised controlled trial (rRCT) using a two-stage group-sequential design is presented. This patient-blind rRCT aims to demonstrate the superiority of prPD over ppPD with respect to the overall incidence of DGE within 30 days after index surgery in a German real-world setting. A total of 984 adults undergoing elective PD for any indication will be randomised in a 1:1 ratio. Patients will be recruited at about 30 hospitals being members of the StuDoQ|Pancreas registry established by the German Society of General and Visceral Surgery (DGAV). The postoperative follow-up for each patient will be 30 days. The primary analysis will follow an intention-to-treat approach and applies a binary logistic random intercepts model. Secondary perioperative outcomes include overall severe morbidity (Clavien-Dindo-classification), blood loss, 30-day all-cause mortality, postoperative hospital stay, and operation time. Complication rates and adverse events will be closely monitored.

Ethics and disseminationThis protocol was approved by the leading ethics committee of the Medical Faculty of the Ludwig-Maximilians-Universitat, Munich (reference no. 19-221). The results will be published in a peer-reviewed journal and presented at international conferences. Study findings will also be disseminated via the website (http://www.dgav.de/studoq/pylorespres/).

Trial registration numberDRKS-ID: DRKS00018842 (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00018842, prospectively registered on 24-Oct-2019)

ARTICLE SUMMARY O_TEXTBOXStrengths and limitations of this study

{blacksquare}This will be the first large-scale, surgical registry-based randomised controlled trial (rRCT) in Germany.
{blacksquare}Patients will be blinded to the allocated and actually performed treatment.
{blacksquare}The active control intervention will be pylorus preserving pancreatoduodenectomy (PD), currently the surgical standard treatment of tumours of the pancreatic head and periampullary region.
{blacksquare}Synthesizing evidences from RCTs for this comparative effectiveness research question (preserving vs. resecting PD) is inconclusive with respect to delayed gastric emptying (DGE), a common post-operative complication.
{blacksquare}The rRCT approach combines the advantages of a prospective (adaptive two-stage) 2-arm parallel-group RCT and the German multicentre StuDoQ|Pancreas registry as platform for patient enrolment, allocation and data collection, with the aim of improving the evidence-based surgical techniques for PD.

C_TEXTBOX

category: surgery


title: MyPlate, Half-Plate, and No Plate: How Visual Plate-related Dietary Benchmarks Influence Meal Composition

abstract: Can visual plate-related dietary guidance systems - such as the MyPlate guideline or the Half-Plate Rule - help people eat better when dining at home or in restaurants? To help explore this, 104 young adults completed a food diary study after having been randomly assigned to follow either 1) USDA MyPlate guidelines, 2) the Half-Plate Rule, or 3) no guidelines (control condition). Both of the visual dietary guidance systems were considered easy to understand, to follow, and left people with fewer questions about what to eat (all p<.01). Moreover, people who rated a system "easy to follow" indicated they had consumed less (meat (r = .268), but this was uncorrelated with fruit and vegetable intake (r =.092) and carbohydrate intake (r = .069). There are three key conclusions to these and other findings: First, the simplest guidance system may be more effective than no system. Second, even the most perfect dietary guidance system will not change behavior if the foods are not available or it is not followed. Third, guidance systems could over-increase the consumption of any food they specifically mention.

category: nutrition


title: COVID-19 & Mental Health: Impact on Working people and Students

abstract: A total of N=618 responses (16-60 years) were recorded to gauge the impact of COVID-19 socially, personally, and psychologically. Comparative results based on employment status, gender, and background were evaluated to identify the impact. While all the groups maintain having information about the pandemic and necessary safety protocols, there is an observable difference in the apprehension levels of financial and mental stability. Due to job security, employed people are less tense and better connected to their family, while unemployed people and students are more concerned with their productivity and quality of work. Students also display higher feelings of uncertainty and helplessness. A considerable number of people feel lonely and deserted during the pandemic. Such thoughts may leave a lasting effect if not tackled at the earliest. While an increase in awareness about mental health is observable, rural and unemployed people are less inclined to approach a professional. The significant difference COVID 19 has created between working people and students and based on gender and background, suggests that the preventive measures to avoid its lasting effects must be devised separately.

category: health informatics


title: COVID-19 mortality prediction model, 3C-M, built for use in resource limited settings - understanding the relevance of neutrophilic leukocytosis in predicting disease severity and mortality

abstract: In this study, a combination of clinical and hematological information, collected on day of presentation to the hospital with pneumonia, was evaluated for its ability to predict severity and mortality outcomes in COVID-19. Ours is a retrospective, observational study of 203 hospitalized COVID-19 patients. All of them were confirmed RT-PCR positive cases. We used simple hematological parameters (total leukocyte count, absolute neutrophil count, absolute lymphocyte count, neutrophil to lymphocyte ration and platelet to lymphocyte ratio); and a severity classification of pneumonia (mild, moderate and severe) based on a single clinical parameter, the percentage saturation of oxygen at room air, to predict the outcome in these cases. The results show that a high absolute neutrophil count on day of onset of pneumonia symptoms correlated strongly with both severity and survival in COVID-19. In addition, it was the primary driver of an initial high neutrophil-to-lymphocyte ratio (NLR) observed in patients with severe disease. The effect of low lymphocyte count was not found to be very significant in our cohort. Multivariate logistic regression was done using Python 3.7 to assess whether these parameters can adequately predict survival. We found that clinical severity and a high neutrophil count on day of presentation of pneumonia symptoms could predict the outcome with 86% precision. This model is undergoing further evaluation at our centre for validation using data collected during the second wave of COVID-19. We present the relevance of an elevated neutrophil count in COVID-19 pneumonia and review the advances in research which focus on neutrophils as an important effector cell of COVID-19 inflammation.


title: Rapid antigen testing for SARS-CoV-2 infection in a university setting in Ireland: learning from a 6-week pilot study.

abstract:
ObjectivesWith the ongoing circulation of SARS-CoV-2 in countries across the world it is essential to identify effective ways to reduce the risk of infection while allowing society to function as close to  normal as possible. Serial testing using rapid lateral flow antigen tests is a possible way to do this by screening populations in a targeted way, identifying infectious (both symptomatic and asymptomatic) people and removing them from circulation while infectious. To make rapid antigen testing effective, high levels of participation are important. This study was designed to evaluate the establishment of a testing programme in a university setting and assess some of the factors that impact participation in such a study among both staff and students.

Study DesignObservational, survey

MethodsA trial period of SARS-CoV-2 rapid testing using the Abbott Panbio rapid antigen test was set up and staff and students based in the University College Dublin Veterinary Hospital were asked to take part voluntarily for 6 weeks. Following the trial period, we used a questionnaire to evaluate satisfaction and to understand some reasons behind participation or lack thereof.

ResultsOverall, almost all respondents to the survey stated that they were happy with having a testing programme present in the workplace and it helped to reduce anxiety associated with COVID-19. Findings indicated that staff and students did not participate equally in the voluntary testing programme. The findings also highlighted that intrinsic motivations and extrinsic motivations for participation differ. For example, participation among staff was much higher than among students, motivational messaging focused on protecting others did not resonate with students as much as staff, convenience was a key factor driving participation in both cohorts and the pressure of being forced to miss class (if positive) close to exam time provided motivation to students to avoid testing.

ConclusionsIntroducing antigen testing into a workplace helped to reduce overall anxiety associated with the potential impact of COVID-19, but achieving good participation was challenging. Participation is key to a successful, campus wide antigen testing programme but reaching high levels of participation is not straightforward and can not be taken for granted. Different motivations drive participation in different cohorts and different messaging/incentivisation is needed to encourage participation in those different cohorts. The findings reported here should inform any SARS-CoV-2 testing programme that will run in these types of settings in the future.


title: The unique evolutionary dynamics of the SARS-CoV-2 Delta variant

abstract: The SARS-Coronavirus-2 (SARS-CoV-2) driven pandemic was first recognized in late 2019, and the first few months of its evolution were relatively clock-like, dominated mostly by neutral substitutions. In contrast, the second year of the pandemic was punctuated by the emergence of several variants that bore evidence of dramatic evolution. Here, we compare and contrast evolutionary patterns of various variants, with a focus on the recent Delta variant. Most variants are characterized by long branches leading to their emergence, with an excess of non-synonymous substitutions occurring particularly in the Spike and Nucleocapsid proteins. In contrast, the Delta variant that is now becoming globally dominant, lacks the signature long branch, and is characterized by a step-wise evolutionary process that is ongoing. Contrary to the "star-like" topologies of other variants, we note the formation of several distinct clades within Delta that we denote as clades A-E. We find that sequences from the Delta D clade are dramatically increasing in frequency across different regions of the globe. Delta D is characterized by an excess of non-synonymous mutations, mostly occurring in ORF1a/b, some of which occurred in parallel in other notable variants. We conclude that the Delta surge these days is composed almost exclusively of Delta D, and discuss whether selection or random genetic drift has driven the emergence of Delta D.


title: Distinct age-specific SARS-CoV-2 IgG decay kinetics following natural infection

abstract:
BackgroundAntibody responses to SARS-CoV-2 can be observed as early as 14 days post-infection, but little is known about the stability of antibody levels over time. Here we evaluate the long-term stability of anti-SARS-CoV-2 IgG antibodies following infection with SARS-CoV-2 in 402 adult donors.

MethodsWe performed a multi-center study carried out at Plasma Donor Centers in the city of Heidelberg (Plasmazentrum Heidelberg, Germany) and Munich (Plasmazentrum Munchen, Germany). We present anti-S/N and anti-N IgG antibody levels in prospective serum samples collected up to 403 days post recovery from SARS-CoV-2 infected individuals.

ResultsThe cohort includes 402 adult donors (185 female, 217 male; 17 - 68 years of age) where anti-SARS-CoV-2 IgG levels were measured in plasma samples collected between 18- and 403-days post SARS-CoV-2 infection. A linear mixed effects model demonstrated IgG decay rates that decrease over time ({chi}2=176.8, p<0.00001) and an interaction of time*age {chi} ({chi}2=10.0, p<0.005)), with those over 60+ years showing the highest baseline IgG levels and the fastest rate of IgG decay. Baseline viral neutralization assays demonstrated that serum IgG levels correlated with in vitro neutralization capacity in 91% of our cohort.

ConclusionLong-term antibody levels and age-specific antibody decay rates suggest the potential need for age-specific vaccine booster guidelines to ensure long term vaccine protection against SARS-CoV-2 infection.


title: Megakaryocytes are a Novel SARS-CoV-2 Infection Target and Risk Factor for Mortality and Multi-Organ Failure

abstract: Discovery of a biomarker for patients at high risk of progression to severe Coronavirus Disease 2019 (COVID-19) is critical for clinical management, particularly in areas of the world where widespread vaccine distribution and herd immunity have yet to be achieved. Herein, we characterize peripheral blood from 218 COVID-19 patients with flow cytometry and provide evidence that megakaryocytes are a target for infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We demonstrate a positive correlation between infected megakaryocytes expressing the protein calprotectin (also called S100A8/A9), a known marker of COVID-19 severity. Additionally, we show that infected, calprotectin expressing megakaryocytes are correlated with COVID-19 severity and are a prognostic indicator of 30-day clinical outcomes including respiratory failure, thrombotic events, acute kidney injury (AKI), ICU admission, and mechanical ventilation. These findings represent a novel SARS-CoV-2 infection target with significant clinical implications as a biomarker for clinical outcomes associated with severe COVID-19.


title: Long COVID in hospitalized and non-hospitalized patients in a large cohort in Northwest Spain, a prospective cohort study

abstract:
BackgroundSurvivors to COVID-19 have described long-term symptoms after acute disease. These signs constitute a heterogeneous group named long COVID or persistent COVID.

ObjectiveThe aim of this study is to describe persisting symptoms six months after COVID-19 diagnosis in a prospective cohort in the Northwest Spain

DesignThis is a prospective cohort study performed in the COVID-19 Cohort of Galicia Sur Health Institute (COHVID-GS).

ParticipantsThis cohort includes patients in clinical follow-up in a health area of 569,534 inhabitants after SARS-CoV-2/COVID-19 diagnosis. Clinical and epidemiological characteristics were collected during the follow up.

Main measures and key resultsA total of 284 patients completed 6 months follow-up, 176 (69.4%) required hospitalization and 29 (10.2%) of them needed critical care. At six months, 119 (48.0%) patients described one or more persisting symptoms. The most prevalent were: extra-thoracic symptoms (39.1%), chest symptoms (27%), dyspnoea (20.6%), and fatigue (16.1%). These symptoms were more common in hospitalized patients (52.3% vs 38.2%) and in women (59.0% vs 40.5%). The multivariate analysis identified Chronic Obstructive Pulmonary Disease (COPD), female gender and tobacco consumption as risk factors for long COVID.

ConclusionsPersisting symptoms are common after COVID-19 especially in hospitalized patients compared to outpatients (52.3% vs. 38.2%). Based on these findings, special attention and clinical follow-up after acute SARS-CoV-2 infection should be provided for hospitalized patients with previous lung diseases, tobacco consumption, and females.


title: Phenotyping of acute and persistent COVID-19 features in the outpatient setting: exploratory analysis of an international cross-sectional online survey

abstract:
BACKGROUNDLong COVID, defined as presence of COVID-19 related symptoms 28 days or more after the onset of acute SARS-CoV-2 infection, is an emerging challenge to healthcare systems. The objective of this study was to phenotype recovery trajectories of non-hospitalized COVID-19 individuals.

METHODSWe performed an international, multi-center, exploratory online survey study on demographics, comorbidities, COVID-19 symptoms and recovery status of non-hospitalized SARS-CoV-2 infected adults (Austria: n=1157), and Italy: n= 893).

RESULTSWorking age subjects (Austria median: 43 yrs (IQR: 31 - 53), Italy: 45 yrs (IQR: 35 - 55)) and females (65.1% and 68.3%) predominated the study cohorts. Course of acute COVID-19 was characterized by a high symptom burden (median 13 (IQR: 9 - 18) and 13 (7 - 18) out of 44 features queried), a 47.6 - 49.3% rate of symptom persistence beyond 28 days and 20.9 - 31.9% relapse rate. By cluster analysis, two acute symptom phenotypes could be discerned: the non-specific infection phenotype and the multi-organ phenotype (MOP), the latter encompassing multiple neurological, cardiopulmonary, gastrointestinal and dermatological features. Clustering of long COVID subjects yielded three distinct subgroups, with a subset of 48.7 - 55 % long COVID individuals particularly affected by post-acute MOP symptoms. The number and presence of specific acute MOP symptoms and pre-existing multi-morbidity was linked to elevated risk of long COVID.

CONCLUSIONThe consistent findings of two independent cohorts further delineate patterns of acute and post-acute COVID-19 and emphasize the importance of symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources.

Key PointsO_ST_ABSQuestionC_ST_ABSWhich acute symptom patterns of acute COVID-19 are associated with prolonged symptom persistence, symptom relapse or physical performance impairment?

FindingsIn this multicenter international comparative survey study on non-hospitalized SARS- CoV-2 infected adults (Austria: n = 1157, Italy: n = 893) we identified distinct and reproducible phenotypes of acute and persistent features. Acute multi-organ symptoms including neurological and cardiopulmonary manifestations are linked to elevated risk of long COVID.

MeaningThese findings suggest to employ symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources.


title: Separating the direct effects of risk factors for atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

abstract:
BackgroundType 2 diabetes and atherosclerotic cardiovascular disease share several risk factors. However, it is unclear whether the effect of these risk factors on liability to atherosclerotic cardiovascular disease is independent of their effect on liability to type 2 diabetes.

MethodsWe performed univariate Mendelian randomization to quantify the effects of continuous risk factors from the IEU OpenGWAS database on liability to three outcomes: type 2 diabetes, coronary artery disease, and peripheral artery disease, as well as the effects of liability to type 2 diabetes on the risk factors. We also performed two-step Mendelian randomization for mediation to estimate the mediating pathways between the risk factors, liability to type 2 diabetes, and liability to the atherosclerotic cardiovascular disease outcomes where possible.

ResultsWe found evidence for 53 risk factors as causes of liability to coronary artery disease, including eight which were causes of liability to type 2 diabetes only and four which were consequences only. Except for fasting insulin and hip circumference, the direct and total effects from the two-step Mendelian randomization were similar. This suggests that the combination of these risk factors with liability to type 2 diabetes was unlikely to alter liability to coronary artery disease beyond their individual effects. We also found 13 risk factors that were causes of liability peripheral artery disease, including six which were causes of liability to type 2 diabetes only and four which were consequences only. Again, the direct and total effects were similar for these ten risk factors apart from fasting insulin.

ConclusionsMost risk factors were likely to affect liability to atherosclerotic cardiovascular disease independently of their relationship with liability to type 2 diabetes. Control of modifiable risk factors therefore remains important for reducing atherosclerotic cardiovascular disease risk regardless of patient liability to type 2 diabetes.

RESEARCH IN CONTEXTO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIType 2 diabetes, coronary artery disease and peripheral artery disease, share several risk factors
C_LIO_LIType 2 diabetes is also one of the strongest independent risk factors for both coronary and peripheral artery disease
C_LI

What is the key question?O_LIWhich risk factors for atherosclerotic cardiovascular disease are mediated by liability to type 2 diabetes and which are independent?
C_LI

What are the new findings?O_LIAmong 108 risk factors in this study, there was evidence to support: 10 risk factors as causes, 23 risk factors as consequences, and 34 risk factors as both causes and consequences of liability to type 2 diabetes
C_LIO_LIIn addition, we found evidence for 53 risk factors as causes of liability to coronary artery disease and 42 risk factors as causes of liability to peripheral artery disease
C_LIO_LIUsing two-step Mendelian randomization for mediation, we found most risk factors for atherosclerotic cardiovascular disease were likely to act independently of liability to type 2 diabetes
C_LI

How might this impact on clinical practice in the foreseeable future?O_LIOur findings support continued control of modifiable risk factors as this is likely to reduce atherosclerotic cardiovascular disease, regardless of patient liability to type 2 diabetes
C_LI


title: Trends in accident-related admissions to pediatric intensive care units during the first COVID-19 lockdown in Germany

abstract:
ObjectiveTo compare the number of accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID-19 lockdown with previous years. To investigate if shifts in types of accidents or injuries occurred, especially regarding non-accidental injuries.

DesignRetrospective observational multicenter study.

Setting37 German PICUs.

Patients1444 children and adolescents < 18 years admitted to German PICUs due to trauma or injuries during the first German lockdown period (16.3.-31.5.2020) and during the same periods of the years 2017-2019.

InterventionsNone.

Measurements and main resultsStandardized morbidity ratios (SMR) and 95% confidence intervals (CI) were calculated for the severity of disease, admission reasons, types of accidents, injury patterns, surgeries and procedures, and outcomes. Disease severity did not differ from previous years. We found an increase in ingestions (SMR 1.41 (CI 0.88 - 2.16)) and a decrease in aspirations (0.77 (0.41 - 1.32)) and burns (0.82 (0.59 - 1.12)). The total number of admissions for trauma remained constant, but traffic accidents (0.76 (0.56 - 1.01) and school/kindergarten accidents (0.25 (0.05 - 0.74) decreased. Household (1.32 (1.05 - 1.64)) and leisure accidents (1.32 (1.05 - 1.65)) increased. Injured structures did not change, but less neurosurgeries (0.69 (0.42 - 1.07)) and more visceral surgeries (2.00 (1.14 - 3.24)) were performed. Non-accidental non-suicidal injuries declined (0.85 (0.50 - 1.37)). Suicide attempts increased in adolescent boys (1.57 (0.58 - 3.42)), while there was a decrease in adolescent girls (0.86 (0.53 - 1.31)).

ConclusionsOur study showed shifts in trauma types and associated surgeries during the lockdown period that are generally in line with current literature. The decreased number of non-accidental non-suicidal injuries we observed does not suggest a fundamental increase in severe child abuse during the lockdown period. The decrease in suicide attempts among adolescent girls confirms previous findings, while the increase among boys has not been described yet and deserves further investigation.

category: pediatrics


title: Mortality and outcomes after decompressive craniectomy in children with severe traumatic brain injury

abstract:
PurposeThe effect of decompressive craniectomy (DC) on mortality and outcomes in children with elevated intracranial pressure after severe head trauma is strongly debated and high-quality evidence is lacking. This study was conducted to determine whether DC in children with severe head trauma is associated with a decrease in mortality or poor outcomes at discharge from the intensive care unit.

MethodsData on patients < 18 years of age treated in Germany, Austria, and Switzerland during a ten-year period were extracted from TraumaRegister DGU(R), forming a retrospective multi-centre cohort study. Descriptive and multivariable analyses were performed to compare mortality and outcomes after decompressive craniectomy and medical management.

Results2507 patients were included, of which 402 underwent decompressive craniectomy. Mortality was 20.6 % in children undergoing DC compared to 13.7 % after medical management. Observed and predicted mortality after DC and medical management matched in all subgroups except in children between six and 17 years of age, where mortality after DC was lower than predicted. Poor outcome was observed in 27.6 % of DC patients vs. 16.1 % receiving medical management. Logistic regression revealed slightly negative effects of DC on mortality (odds ratio 1.20, not significant) and outcomes (odds ratio 1.56 (95% confidence interval 1.01-2.40).

ConclusionDC did not decrease overall mortality or rates of poor outcome. However, children above six years of age may benefit from DC. High quality prospective studies are urgently needed.


title: Altered interpersonal distance regulation in autism spectrum disorder

abstract: Interpersonal distance regulation is an essential element of social communication. Its impairment in autism spectrum disorder (ASD) is widely acknowledged among practitioners, but only a handful of studies reported empirical research in real-life settings focusing mainly on children. Interpersonal distance in adults with ASD and related autonomic functions received less attention. Here, we measured interpersonal distance along with heart rate variability (HRV) in adults with ASD, and tested the modulatory effects of eye-contact and attribution. Twenty-two adults diagnosed with ASD and 21 matched neurotypical controls participated in our study from 2019 October to 2020 February. Our experimental design combined the modified version of the stop distance paradigm with HRV measurement controlling for eye contact between the experimenter and the participant to measure interpersonal distance. Our results showed a greater preferred distance in ASD. These results were altered with eye contact. Moreover, we found lower baseline HRV and reduced HRV reactivity in ASD; however, these autonomic measurements could not predict preferred interpersonal distance. Our study highlights the importance of interpersonal space regulation in ASD and the need for sophisticated experimental designs to grasp the complexity and underlying factors of distance regulation in typical and atypical populations.


title: Recording of 'COVID-19 vaccine declined' among vaccination priority groups: a cohort study on 57.9 million NHS patients' primary care records in situ using OpenSAFELY

abstract:
BackgroundAll patients in England within vaccine priority groups were offered a COVID-19 vaccine by mid-April 2021. Clinical record systems contain codes to denote when such an offer has been declined by a patient (although these can in some cases be entered for a variety of other reasons including vaccination delay, or other administrative issues). We set out to describe the patterns of usage of codes for COVID-19 vaccines being declined.

MethodsWith the approval of NHS England and using the full pseudonymised primary care records for 57.9 million NHS patients, we identified all patients in key vaccine priority groups: aged over 50, or over 16 and at increased risk from COVID-19 (Clinically Extremely Vulnerable [CEV] or otherwise "at risk"). We describe the proportion of patients recorded as declining a COVID-19 vaccination for each priority group, and by other clinical and demographic factors; whether patients recorded as "declined" subsequently went on to receive a vaccination; and the distribution of code usage across GP practices.

ResultsOf 24.5 million patients in priority groups as of May 25th 2021, 89.2% had received a vaccine, 8.8% had neither a vaccination nor a decline recorded, and 663,033 (2.7%) had a decline code recorded. Of patients with a recorded decline, 125,587 (18.9%) were subsequently vaccinated. Subsequent vaccination was slightly more common in the South Asian population than other ethnicities (e.g. 32.3% vs 22.8%, over 65s). The proportion of declining-unvaccinated patients varied strongly with ethnicity (Black 15.3%, South Asian 5.6%, White 1.5% in over 80s); and was higher in patients from more deprived areas. COVID-19 vaccine decline codes were present in almost all practices (98.8%), but with wide variation between practices in rates of usage. Among all priority groups, declining-unvaccinated status was most common in CEV (3.3%).

ConclusionsClinical codes indicative of COVID-19 vaccinations being declined are widely used in English general practice. They are substantially more common among Black and South Asian patients, and patients from more deprived areas. There is a need for more detailed survey and/or qualitative research with patients and clinicians to determine the most common reasons for these recorded declines.


title: Epidemiological characteristics of the B.1.526 SARS-CoV-2 variant

abstract: To characterize the epidemiological properties of the B.1.526 SARS-CoV-2 variant of interest, here we utilized nine epidemiological and population datasets and model-inference methods to reconstruct SARS-CoV-2 transmission dynamics in New York City, where B.1.526 emerged. We estimated that B.1.526 had a moderate increase (15-25%) in transmissibility and could escape immunity in 0-10% of previously infected individuals. In addition, B.1.526 substantially increased the infection-fatality risk (IFR) among adults 65 or older by >60% during Nov 2020 - Apr 2021, compared to baseline risk estimated for preexisting variants. Overall, findings suggest that new variants like B.1.526 likely spread in the population weeks prior to detection and that partial immune escape (e.g., resistance to therapeutic antibodies) could offset prior medical advances and increase IFR. Early preparedness for and close monitoring of SARS-CoV-2 variants, their epidemiological characteristics, and disease severity are thus crucial to COVID-19 response as it remains a global public health threat.


title: IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

abstract:
IntroductionImmunotherapies, such as immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The mechanisms for this are not fully understood, however the composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becomingly increasingly recognised as a driving factor in treatment-refractory disease.

MethodsHere, we employed multiplex IHC (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments of pre-treatment samples from a 2nd line NSCLC ICI-treated cohort (n=41 patients; n=25 responders, n=16 non-responders).

ResultsWe demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p=0.012). Our study revealed that patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p=0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p=0.001) within their stroma, indicative of key conditions for ICI efficacy prior to treatment. IL2 mRNA levels within the stroma positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p=2e-5) and BAD (p=5.5e-4) and negatively correlated with levels of memory T cells (CD45RO) (p=7e-4). Immuno-inhibitory markers CTLA-4 (p=0.021) and IDO-1 (p=0.023) were also supressed in ICI-responsive patients. Of note, tumour CD44 (p=0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of its ligand SPP1 (osteopontin, p=0.008). Analysis of differentially expressed transcripts indicated the potential inhibition of stromal interferon-gamma (IFN{gamma}) activity, as well as estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR=1.61, p=0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR=1.78, p=0.003) and MDSC/M2 macrophage marker ARG1 (HR=2.37, p=0.01) were associated with poorer outcome while levels of apoptotic marker BAD (HR=0.5, p=0.01) appeared protective. Interestingly, stromal mRNA for E-selectin (HR=652, p=0.001), CCL17 (HR=70, p=0.006) and MTOR (HR=1065, p=0.008) were highly associated with poorer outcome, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance.

ConclusionsThrough multi-modal approaches, we have dissected the characteristics of NSCLC and provide evidence for the role of IL2 and stromal activation by osteopontin in the efficacy of current generations of ICI therapy. The enrichment of SPP1 in the stroma of ICI sensitive patients in our data is a novel finding, indicative of stromal activation that may aid immune cell survival and activity despite no clear association with increased levels of immune infiltrate.

category: oncology


title: OtoXNet - Automated Identification of Eardrum Diseases from Otoscope Videos: A Deep Learning Study for Video-representing Images

abstract:
BackgroundThe lack of an objective method to evaluate the eardrum is a critical barrier to an accurate diagnosis. Eardrum images are classified into normal or abnormal categories with machine learning techniques. If the input is an otoscopy video, a traditional approach requires great effort and expertise to manually determine the representative frame(s).

MethodsIn this paper, we propose a novel deep learning-based method, called OtoXNet, which automatically learns features for eardrum classification from otoscope video clips. We utilized multiple composite image generation methods to construct a highly representative version of otoscopy videos to diagnose three major eardrum diseases, i.e., otitis media with effusion, eardrum perforation, and tympanosclerosis versus normal (healthy). We compared the performance of OtoXNet against methods with that either use a single composite image or a keyframe selected by an experienced human. Our dataset consists of 394 otoscopy videos from 312 patients and 765 composite images before augmentation.

ResultsOtoXNet with multiple composite images achieved 84.8% class-weighted accuracy with 3.8% standard deviation, whereas with the human-selected keyframes and single composite images, the accuracies were respectively, 81.8% {+/-} 5.0% and 80.1% {+/-} 4.8% on multi-class eardrum video classification task using an 8-fold cross-validation scheme. A paired t-test shows that there is a statistically significant difference (p-value of 1.3 x 10-2) between the performance values of OtoXNet (multiple composite images) and the human-selected keyframes. Contrarily, the difference in means of keyframe and single composites was not significant (p = 5.49 x 10-1). OtoXNet surpasses the baseline approaches in qualitative results.

ConclusionThe use of multiple composite images in analyzing eardrum abnormalities is advantageous compared to using single composite images or manual keyframe selection.

category: otolaryngology


title: The Impact for Implementing Balanced Scorecard in Health Care Organizations: A Systematic Review

abstract:
AimsThis systematic review aims to assess the impact of Balanced Scorecard (BSC) implementation at Health Care Organizations (HCOs) on Health Care Workers (HCWs) satisfaction, patient satisfaction, and financial performance. Up to now, no previous systematic reviews have performed a comprehensive and rigorous methodological approach to figure out the impact of BSC implementation in HCOs.

MethodsThis systematic review was prepared according to PRISMA guidelines. PubMed, Embase, Cochrane, and Google Scholar databases, as well as Google search engine, were inspected to find all BSC implementations at HCOs until 20 September 2020. Then the resulted articles were screened to find the implementations which measured the impact of BSC on HCWs satisfaction, patient satisfaction, and financial performance. Quality assessment was performed using the Standards for Reporting Implementation Studies: (StaRI) checklist.

ResultsOut of 4031 records, 20 articles were finally included for measuring one or more of the three impact types. 17 measured the impact of BSC on patient satisfaction, 7 on HCWs satisfaction, and 12 on financial performance. Studies with higher quality had a higher positive impact.

ConclusionThis paper offers evidence to HCOs and policymakers on the benefits of implementing BSC. BSC implementations showed a positive impact on patient satisfaction and financial performance in HCOs. However, less impact was found on HCWs satisfaction, which should be given better consideration in future BSC implementations. High and medium-quality BSC studies were associated with higher positive impacts than low ones. BSC can be utilized as an effective tool to improve HCOs performance during the COVID-19 pandemic.

category: health systems and quality improvement


title: Serendipitous COVID-19 Vaccine-Mix in Uttar Pradesh, India: Safety and Immunogenicity Assessment of a Heterologous Regime

abstract: Immunization program against COVID-19 in India started with two vaccines; AstraZenecas ChAdOx1-nCov-19 (termed Covishield in India) and inactivated whole virion BBV152 (Covaxin); homologous prime-boost approach was followed. However, eighteen individuals, under the national program, inadvertently received Covishield as the first jab and Covaxin as the second. We compared the safety and immunogenicity profile of them against that of individuals receiving either Covishield or Covaxin (n=40 in each group). Lower and similar adverse events following immunization in all three groups underlined the safety of the combination vaccine-regime. Immunogenicity profile against Alpha, Beta and Delta variants in heterologous group was superior; IgG antibody and neutralising antibody response of the participants was also significantly higher compared to that in the homologous groups. The findings suggest that immunization with a combination of an adenovirus vector platform-based vaccine followed by an inactivated whole virus vaccine was not only safe but also elicited better immunogenicity.


title: Prevalence and effect of bacterial co-infections on clinical outcomes in hospitalized COVID-19 patients at a tertiary care centre of India

abstract:
BackgroundBacterial co-infections are a leading cause of morbidity and mortality during viral infections including COVID-19. Systematic testing of COVID-19 patients having bacterial co-infections is essential to select the correct antibiotic for treatment in order to reduce mortality and also prevent spread of antimicrobial resistance (AMR). The present study aims to evaluate the prevalence, demographic parameters, antibiotic sensitivity patterns and outcomes in hospitalized COVID-19 patients with bacterial co-infections.

MethodsA total of 1019 COVID-19 patients were selected for the study. We analyzed the prevalence, antibiotic sensitivity pattern and clinical outcomes in COVID-19 patients having bacterial co-infections.

ResultsOut of a total 1019 COVID-19 patients screened, 5.2% of patients demonstrated clinical signs of bacterial co-infection. Bacteremia was found in majority of the patients followed by respiratory and urinary infections. Escherichia coli, Pseudomonas aeruginosa and Klebsiella spp. were most common isolates among the Gram-negative and Coagulase-negative Staphylococci (CONS) and Staphylococcus aureus among the Gram-positive bacterial infections. Antibiotic sensitivity profiling revealed that colistin, imipenem and fosfomycin were the most effective drugs against the Gram-negative isolates while vancomycin, teicoplanin and doxycycline against the Gram-positive isolates. Analysis of clinical outcomes revealed that the mortality rate was higher (39%) among the patients with bacterial co-infections as compared to the group without co-infection (17%).

ConclusionsThis study reveals that the rate of bacterial co-infections is significantly increasing among COVID-19 patients and leading to increase in mortality. Systematic testing of bacterial co-infections is therefore essential in COVID-19 patients for better clinical outcomes and to reduce AMR.


title: The potential impact of delta variant of SARS-CoV-2 in the context of limited vaccination coverage and increasing social mixing in Bogota, Colombia

abstract:
BackgroundIn Bogota by August 1st, more than 27,000 COVID-19 deaths have been reported, while complete and partial vaccination coverage reached 30% and 37%, respectively. Although reported cases are decreasing, the potential impact of new variants is uncertain.

MethodsWe used an agent-based model of COVID-19 calibrated to local data. Variants and vaccination strategies were included. We estimated the impact of vaccination and modelled scenarios of early and delayed introduction of the delta variant, along with changes in mobility, social contact, and vaccine uptake over the next months.

FindingsBy mid-July, vaccination may have prevented 17,800 (95% CrI: 16,000 - 19,000) deaths in Bogota. We found that delta could lead to a fourth wave of magnitude and timing dependent on social mixing, vaccination strategy, and delta dominance. In scenarios of early dominance of delta by mid-July, age prioritization and maintaining the interval between doses were important factors to avert deaths. However, if delta dominance occurred after mid-September, age prioritization would be less relevant, and the magnitude of a four wave would be smaller. In all scenarios, higher social mixing increased the magnitude of the fourth wave. Increasing vaccination rates from 50,000/day to 100,000/day reduced the impact of a fourth wave due to delta.

InterpretationThe magnitude and timing of a potential fourth wave in Bogota caused by delta would depend on social mixing and the timing of dominance. Rapidly increasing vaccination coverage with non-delayed second doses could reduce the burden of a new wave.

FundingNSF RAPID DEB 2027718. HERMES 50419. Medical Research Council. MR/R024855/1

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSThe impact of vaccination strategies in the context of emerging SARS-CoV-2 variants and increasing social mixing in Colombia had not been previously evaluated through mathematical modelling. We searched PubMed for modelling studies using the terms "COVID-19 vaccine AND model AND variant AND Colombia" or "SARS-CoV-2 AND vaccine AND model AND variant AND Colombia" (From 2021/1/1 to 2021/07/31). We did not find studies addressing this question. However, we found a model describing the evolution of the epidemic in the country during the first year, and research on the emergence of alpha, gamma, and B.1.621 variants in Colombia. We extended a previous version of our SARS-CoV-2 agent-based model for Bogota to include the potential effect of vaccination and variants. This model simulates transmission of SARS-CoV-2 based on daily activity patterns of a synthetic population, representing demographic and geographic characteristics of the total population of the city.

Added value of this studyFirst, our study provides a preliminary estimate of the impact of the vaccination program in Bogota in terms of the number of deaths prevented. The second major finding is the indication that due to the introduction of the delta variant in the city, and based on the current knowledge of its biology, there is a risk of a fourth epidemic wave, whose time of occurrence and magnitude would depend mainly on three factors: when delta becomes dominant, the intensity of social contact, and vaccination roll-out strategy and coverage.

Implications of all the available evidenceWe estimate that by mid-July, vaccination may have already prevented 17,800 (95% CrI: 16,000 - 19,000) deaths in Bogota. The delta variant could become dominant and lead to a fourth wave later in the year, but its timing will depend on the date of introduction, social mixing patterns, and vaccination strategy. In all scenarios, higher social mixing is associated with a fourth wave of considerable magnitude. If an early delta introduction occurred (dominance by mid-July), a new wave may occur in August/September and in such case, age prioritization of vaccination and maintaining the 21-day interval between doses of the Pfizer-BioNTech BNT162b2 are more important. However, if introduction occurred one or two months later (with dominance by mid-August/September) a fourth wave would be of smaller magnitude, the age-prioritization is less relevant, but maintaining the dose scheme without postponement is more important. In all scenarios we found that increasing the vaccination rate from the current average of 50,000/day to 100,000/day reduces the impact of a potential fourth wave due to the delta variant. Our study indicates that given the possibility of a fourth wave in the city, it is necessary to continue maintaining adherence to non-pharmacological interventions, such as the use of face masks and physical distancing, to be cautious with the intensification of social activities, and that it is essential to increase the current pace of vaccinations to rapidly reach high vaccination coverage in the population of the city.


title: The impact of vaccination strategies for COVID-19 in the context of emerging variants and increasing social mixing in Bogota, Colombia: a mathematical modelling study


title: Quality of life profile of methadone maintenance treatment patients in Ho Chi Minh City, Vietnam

abstract:
AimTo determine the health-related quality of life (HRQoL) of methadone maintenance treatment patients in Ho Chi Minh City, Vietnam.

Subject and MethodsA cross-sectional study was conducted in 967 patients treating at two methadone clinics in Ho Chi Minh City, in 2018. Patients health-related quality of life was estimated using the EQ-5D-5L and Visual analogue scale (VAS). Tobit regressions were used to identify factors related to patients health-related quality of life.

ResultsOverall, the mean EQ-5D-5L utility and EQ-VAS indexes were 0.96 (SD = 0.12) and 75.8 (SD=15.5), respectively. Factors related with a higher EQ-5D-5L score included peoples who are single, and have a higher monthly income (more than 4 million VND per month), while patients aged under 30 years old, have full-time employment, and have higher education were associated with a higher EQ-VAS score. HIV was associated with lower scores of both EQ-5D-5L and EQ- VAS ({beta} = -0.07 (95%CI: -0.13; -0.01), and {beta} = -7.10 (95%CI: -9.23; -4.98), respectively).

ConclusionHRQoL measurement provides valuable information for the policymaker to adopt suitable decisions on opioid dependence treatment. The finding shows that patients with education, job situation, and socioeconomic status are the related elements with higher HRQoL, which suggested that the policymakers and physicians should pay more attention to these aspects while working on treatment plan for drug users.


title: Methods used to select results to include in meta-analyses of nutrition research: a meta-research study

abstract:
ObjectivesTo investigate the extent of multiplicity of results in study reports of nutrition research, and the methods specified in systematic reviews to select results for inclusion in meta-analyses.

MethodsMEDLINE and Epistemonikos were searched (January 2018 - June 2019) to identify systematic reviews with meta-analysis of the association between food/diet and health-related outcomes. A random sample of these reviews was selected, and for the first presented ( index) meta-analysis, rules used to select effect estimates to include in this meta-analysis were extracted from the reviews and their protocols. All effect estimates from the primary studies that were eligible for inclusion in the index meta-analyses were extracted.

ResultsForty-two systematic reviews were included, 14 of which had a protocol. In 29% of review protocols and 69% of reviews, at least one decision rule to select effect estimates when multiple were available was specified. In 69% (204/325) of studies included in the index meta-analyses, there was at least one type of multiplicity of results.

ConclusionsAuthors of systematic reviews of nutrition research should anticipate encountering multiplicity of results in the included primary studies. Specification of methods to handle multiplicity when designing reviews is therefore recommended.

O_TEXTBOXWhat is new?O_ST_ABSKey FindingsC_ST_ABSO_LIAuthors of systematic reviews of nutrition research should anticipate encountering multiplicity of results in the included primary studies.
C_LIO_LIDecision rules to select results for inclusion in meta-analyses of nutrition research were infrequently pre-specified.
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What this adds to what was known?O_LIPrevious studies have found that multiplicity of results of continuous outcomes in studies included in systematic reviews was common, and methods used to select results to include in meta-analyses were infrequently pre-specified in systematic review protocols. However, none of the studies examined meta-analyses in nutiriton research, inclusion of randomized or non-randomized studies, or where the outcome was non-continuous (e.g. binary, count or time-to-event); circumstances for which different forms of multiplicity might arise. Our study addressed this gap.
C_LI

What is the implication and what should change now?O_LIPre-specification of decision rules to handle multiplicity when designing reviews is recommended. In the systematic review, we recommend reporting any modifications to the specified rules, or any additions that were introduced to cover multiplicity scenarios that had not been anticipated when designing the review.
C_LI

C_TEXTBOX


title: COVID-19 vaccination coverage and hesitancy among groups prioritised in Australia's vaccine rollout

abstract:
BackgroundCOVID-19 vaccination is the cornerstone of managing Australias COVID-19 pandemic and the success of the vaccination program depends on high vaccination coverage. This paper examined differences in COVID-19 vaccination coverage and vaccine hesitancy for people with disability, long-term health conditions, and carers - subgroups that were prioritised in the vaccination program.

MethodsUsing data from 2,400 Australians who participated in two waves of the Taking the Pulse of the Nation survey in April and May 2021, we described vaccination coverage and hesitancy among people with disability, severe mental health conditions, severe long-term health conditions, frequent need for assistance with everyday activities, and carers, disaggregated by age group and gender.

FindingsVaccination coverage was estimated to be 8.2% in the sample overall and was similar for people with disability, those with frequent need for assistance, and carers. It was higher for people with severe long-term health conditions (13.4%) and lower for people with severe mental health conditions (4.3%). Vaccine hesitancy was high overall (35.6%) and was similarly high across the priority groups.

InterpretationThis study highlights the lack of a difference in vaccination coverage and vaccine hesitancy for people with disability, long-term health conditions, and carers compared to the general population. Sub-optimal vaccination coverage for people in the priority population groups leaves many people at significant risk of serious disease or death if exposed to COVID-19, particularly in light of the easing of disease-control restrictions across Australia and the emergence of new COVID-19 variants.

FundingNational Health and Medical Research Council


title: COVID-19 vaccination coverage and hesitancy among Australians with disability and long-term health conditions


title: Preterm birth rates during the COVID-19 lockdown in Queensland Australia

abstract:
BackgroundPreventative strategies for preterm birth are lacking. Recent evidence proposed COVID-19 lockdowns may have contributed to changes in preterm birth. We aimed to determine the prevalence of preterm birth during the COVID-19 lockdown on the Sunshine Coast and in the state of Queensland, Australia.

MethodsRetrospective cohort analysis of all births in Queensland including the Sunshine Coast University Hospital, during two epochs, April 1-May 31, 2020 (lockdown) and June 1-July 31, 2020 (post-lockdown), compared to antecedent calendar-matched periods in 2018-2019. Prevalence of preterm birth, stillbirth, and late terminations were examined.

ResultsThere were 64,989 births in Queensland from April to July 2018-2020. At the Sunshine Coast University Hospital, there was a significantly higher chance of birth at term during both lockdown (OR 1.81, 95% CI 1.17, 2.79; P=0.007) and post-lockdown (OR 2.01, 95% CI 1.27, 3.18; P=0.003). At the same centre, prevalence of preterm birth was 5.5% (30/547) during lockdown, compared to 9.1% (100/1095) in previous years, a 40.0% relative reduction (P=0.016). At this centre during lockdown, emergency caesareans concurrently decreased (P=0.034) and vacuum-assisted births increased (P=0.036). In Queensland overall, there was a nonsignificant decrease in the prevalence of preterm birth during lockdown.

ConclusionsThere is a link between lockdown and a reduction in the prevalence of preterm birth on the Sunshine Coast. The cause is speculative. Further research is needed to determine a causal link and assess if this can be translated into management which provides a sustained reduction in preterm birth and its associated morbidity and mortality.


title: Factorial Structure of the Transactional eHealth Literacy Among Vietnamese Youth: An Instrument Validation Study

abstract: The progression into the Digital Age has brought an array of novel skill requirements. Unlike traditional literacy, there are currently few measures that can reliably measure eHealth literacy. The Transactional Model of eHealth Literacy and subsequent Transactional eHealth Literacy Instrument may provide a feasible option for measuring eHealth literacy. However, this instrument has yet to be validated, which is the aim of this study. We conducted an online cross-sectional study among 236 Vietnamese young people. Using exploratory factor analysis, we ensured that a model consisting of four factors had the best fit (RMSEA = 0.116; CFI = 0.907) and the highest internal consistency (Cronbachs  = 0.96). A confirmatory factor analysis tested measurement invariance at four levels: configural, metric, scalar, and strict invariance. Only metric invariance was partially invariant, while the rest tested fully invariant. Even with partial metric invariance, there is reason to assume that functional, communicative, critical, and translational eHealth literacy (the four levels according to the transactional model) are consistently measured when deploying the Transactional eHealth Literacy Instrument across groups. In other words, this study suggests the instrument can be used for comparisons across groups and has the potential to generate high-quality data usable for informing change agents as to whether a particular population is proficient enough to adopt novel eHealth innovations.


title: Determinants of the COVID-19 Vaccine Hesitancy Spectrum

abstract:
Polls report nearly one-third of the United States population is skeptical or opposed to getting the COVID-19 vaccine. Most of these polls, as well as the scientific research that has been conducted on vaccine hesitancy, was done prior to vaccine eligibility opening to all adults. Now that COVID-19 vaccines are widely available, further research is needed to understand the factors contributing to vaccine intentions across the vaccine hesitancy spectrum. This study conducted an online survey using the Social Science Research Solution (SSRS) Opinion Panel web panelists, representative of U.S. adults age 18 and older who use the internet, with an oversample of rural-dwelling and minority populations between April 8 and April 22, 2021- as vaccine eligibility opened to the country. We examined the relationship between COVID-19 exposure and socio-demographics with vaccine intentions [eager-to-take, wait-and-see, undecided, refuse] among the unvaccinated using multinomial logistic regressions [ref: fully/partially vaccinated]. Results showed vaccine intentions varied by demographic characteristics and risk exposures during the period that eligibility for the vaccine was extended to all adults.

Funding statementFunding for this research was provided by a grant from the National Science Foundation (Grant #2049886). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


title: Prevalence and correlates of SARS-CoV-2 seropositivity among people who inject drugs in the San Diego-Tijuana border region

abstract:
BackgroundPeople who inject drugs may be at elevated SARS-CoV-2 risk due to their living conditions and/or exposures when seeking or using drugs. No study to date has reported upon risk factors for SARS-CoV-2 infection among people who inject drugs or sex workers.

Methods and FindingsBetween October, 2020 and June, 2021, participants aged [≥]18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month underwent interviews and testing for SARS-CoV-2 RNA and antibodies. Binomial regressions identified correlates of SARS-CoV-2 seropositivity. Of 386 participants, SARS-CoV-2 seroprevalence was 36.3% (95% CI: 31.5%-41.1%); 92.1% had detectable IgM antibodies. Only 37.5% had previously been tested. Seroprevalence did not differ by country of residence. None tested RNA-positive. Most (89.5%) reported engaging in [≥]1 protective behavior [e.g., facemasks (73.5%), social distancing (46.5%), or increasing handwashing/sanitizers (22.8%)]. In a multivariate model controlling for sex, older age, and Hispanic/Latinx/Mexican ethnicity were independently associated with SARS-CoV-2 seropositivity, as was engaging in sex work (AdjRR: 1.63; 95% CI: 1.18-2.27) and having been incarcerated in the past six months (AdjRR: 1.49; 95% CI: 0.97-2.27). Presence of comorbidities and substance using behaviors were not associated with SARS-CoV-2 seropositivity.

ConclusionsThis is the first study to show that sex work and incarceration were independently associated with SARS-CoV-2 infection. Despite engaging in protective measures, over one-third had evidence of infection, reinforcing the need for a coordinated binational response. Risk mitigation and vaccination is especially needed among older and Hispanic people who inject drugs and those with less agency to protect themselves, such as those who are sex workers or incarcerated.


title: Accelerated Partner Therapy contact tracing intervention for people with chlamydia: the LUSTRUM process evaluation using programme theory

abstract:
BackgroundUsing programme theory we report a process evaluation of Accelerated Partner Therapy (APT) - a novel contact tracing (partner notification) intervention for people with chlamydia as part of the LUSTRUM trial.

MethodsFollowing the specification and visualisation of initial programme theory, questions of context dependency, fidelity, and functioning of putative intervention mechanisms were addressed using deductive thematic analysis of qualitative data collected through focus groups and individual interviews with purposively sampled health care professionals (n=34 from ten sites), index patients (n=15), and sex partners who received APT (n=17). Analyses were independent of trial results.

ResultsAPT was anticipated to change key interactions and sexual health service organisation to accommodate safe and optimal remote care. APT training and resources transformed key interactions as anticipated. Overall intervention fidelity was good and APT was well-liked by those who delivered and received it. Putative intervention mechanisms worked mostly as expected although those concerned with local implementation sometimes worked counter to expectations. APT and its trial struggled to be implemented at scale across all sites. Considerable pressures drove services to constantly adapt to achieve efficiencies. APT was perceived as time consuming without visible impact on perceived patient numbers in clinic curtailing positive feedback loops driving normalisation.

DiscussionUsing programme theory we show an evidence-based, theoretically informed, overview of how APT worked dynamically within the context of the trial and within UK sexual health services. We find a mixed picture of a well-liked, intuitive, coherent intervention struggling to gain purchase within an already pressured service.

Trial registrationISRCTN15996256

Study protocoldoi.org/10.1136/bmjopen-2019-034806

Ethical approvalThis study received ethical approval from London--Chelsea Research Ethics Committee (18/LO/0773). Findings will be published with open access licences.

FundingThis work presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (reference number RP-PG-0614-20009).

category: sexual and reproductive health


title: Age and smoking predict antibody titres at 3 months after the second dose of the BNT162b2 COVID-19 vaccine

abstract:
ObjectiveWe aimed to determine antibody (Ab) titres 3 months after the second dose of the BNT162b2 coronavirus disease-2019 (COVID-19) vaccine and to explore clinical variables predicting these titres in Japan.

MethodsWe enrolled 378 healthcare workers (255 women, 123 men) whose blood samples were collected 91{+/-}15 days after the second of two inoculations of the BNT162b2 COVID-19 mRNA vaccine (Pfizer/BioNTech) given 3 weeks apart. Medical histories and demographic characteristics were recorded using a structured self-reported questionnaire. The relationships between Ab titres and these factors were analysed.

ResultsMedian age (interquartile range [IQR]) of the participants was 44 (32-54) years. Median Ab titre (IQR) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen was 764 (423-1140) U/mL. Older participants had significantly lower Ab titres; median (IQR) Ab titres were 942 (675-1390) and 1095 (741-1613) U/mL in men and women in their 20s, respectively, but 490 (297-571) and 519 (285-761) U/mL in men and women in their 60s-70s, respectively. In the age-adjusted analysis, the only risk factors for lower Ab titres were male sex and smoking. However, the sex difference may have arisen from the sex difference in smoking rate. Moreover, Ab titres were significantly lower in current smokers than in ex-smokers.

ConclusionThe most important factors associated with low Ab titres were age and smoking habit. In particular, current smoking status caused lower Ab titres, and smoking cessation before vaccination may improve the individual efficacy of the BNT162b2 vaccine.


title: Estimation of Total Immunity to SARS-CoV-2 in Texas

abstract: Given the underestimate of seroprevalence in the US due to insufficient testing, accurate estimates of population immunity to SARS-CoV-2 or vaccinations do not exist. Although model-based estimates have been proposed, they require inputting unknown parameters such as viral reproduction number, longevity of immune response, and other dynamic factors. In contrast to a model-based approach for estimating population immunity, or simplistic summing of natural- and vaccine-induced immunity, the current study presents a data-driven statistical procedure for estimating the total immunity rate in a region using prospectively collected serological data along with state-level vaccination data. We present a detailed procedure so that efforts can be replicated regionally to inform policy-making decisions relevant to SARS-CoV-2. Specifically, we conducted a prospective longitudinal statewide cohort serological survey with 10,482 participants and more than 14,000 blood samples beginning on September 30, 2020. Along with Department of State Health Services vaccination data, as of July 4, 2021, the estimated percentage of those with naturally occurring antibodies to SARS-CoV-2 in Texas is 35.3% (95% CI = (33.7%, 36.9%) and total estimated immunity is 69.1%. We conclude the seroprevalence of SARS-CoV-2 is 4 times higher than the state-confirmed COVID-19 cases (8.8%). This methodology is integral to pandemic preparedness.


title: HIF1alpha cardioprotection in COVID-19 patients

abstract:
ImportanceSARS-CoV-2 infection directly causes severe acute respiratory illness, leading to systemic tissue hypoxia and ischemia including the heart. Myocardial cytopathy associated with hypoxic response has been largely overlooked in COVID-19 patients. Additionally, histology analysis and cardiac function of COVID-19 cases are often reported separately, rendering an incomplete understanding of COVID-19 cardiac symptoms.

ObjectiveTo examine the relationship between myocardial cellular responses to hypoxic stress versus cardiac functional alterations within the same COVID-19 patients.

Design, Setting, and ParticipantsCellular hypoxia Inducible Factor 1 alpha (HIF1) expression was analyzed by immunohistochemistry using post-mortem COVID-19 heart and lung tissues with known cardiac echocardiography records from a total of 8 patients. Clinical echocardiography data were obtained from Mount Sinai Heart between March to December, 2020. All gender and age groups were considered as long as cardiac involvement meets the preserved (EF > 50%) or moderate to severe (EF < 45%) criteria with confirmed SARS-CoV-2 infection. Cell-type specific subcellular localization of HIF1 expression and nuclear stability was examined by immunohistochemistry and transmission electronic microscopy (TEM). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to quantify apoptosis.

Main Outcomes and MeasuresNo planned outcomes of this study as this is a retrospective analysis based on post-mortem specimens exclusively.

ResultsCardiac HIF1 expression was found to be significantly higher in patients with preserved EF levels than it was in the low EF group. In the preserved EF group, HIF1 is protective against apoptosis predominantly in endothelial cells and cardiac fibroblasts. In the low EF group, HIF1 protects cardiomyocyte nuclear integrity as evident by its nuclear accumulation with nuclear envelope preservation.

Conclusions and RelevanceThis study establishes a direct link of cardiac cellular responses to hypoxic stress with matching functional and histological data, serving as one of the first studies to bridge previous stand-alone clinical data and cellular data. The protective role of HIF1 in hearts may help predict cardiac involvement in not only COVID-19 patients, but also decipher the underlying mechanisms in other forms of viral cardiomyopathy.

KEY POINTSO_ST_ABSQuestionC_ST_ABSAre hypoxic signaling pathways associated with cardiac functional alterations in COVID-19 patients?

FindingsCardiac HIF1 expression of COVID-19 patients with EF>50% or EF<45% was analyzed and quantified. Increased cardiac HIF1+ cells were found in patients with higher EF. HIF1+ endothelial cells are resistant to apoptosis, and HIF1+ cardiomyocytes are able to retain nuclear envelope under hypoxic stress.

MeaningHIF1 is cardioprotective in hearts of COVID-19 patients.

category: cardiovascular medicine


title: Surveillance genome sequencing reveal multiple SARS-CoV-2 variants circulating in the central Texas, USA with a predominance of Delta variant and review of vaccine breakthrough cases.

abstract: As surges in the COVID-19 pandemic have continued worldwide, SARS-CoV-2 has mutated, spawning several new variants, and impacting, to various degrees, transmission, disease severity, diagnostics, therapeutics, and natural and vaccine-induced immunity. Baylor Scott & White Health has implemented, along with laboratory diagnosis, SARS-CoV-2 sequencing to identify variants in its geographical service area. We analyzed virus sequencing results of specimens collected across Central Texas and found dramatic changes in variant distribution in the first half of 2021. The alpha variant (B 1.1.7) became predominant at week 13 and continued dominance until week 25. A growth rate of 1.20 (R2 = 0.92) for the first 15 weeks was noted and this growth gradually declined to -0.55 (R2 = 0.99) for the final 13 weeks. Currently, B.1.1.7 is being displaced with B.1.617.2 at 0.58 growth rate (R2 = 0.97). We also investigated vaccine breakthrough cases within our healthcare system and present clinical data on 28 symptomatic patients.


title: Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts

abstract: Quarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.


title: Neutralizing antibody responses to SARS-CoV-2 variants in vaccinated Ontario long-term care home residents and workers

abstract: Prioritizing Ontarios long-term care home (LTCH) residents for vaccination against severe acute respiratory syndrome coronavirus 2 has drastically reduced their disease burden; however, recent LTCH outbreaks of variants of concern (VOCs) have raised questions regarding their immune responses. In 198 residents, mRNA vaccine dose 1 elicited partial spike and receptor binding domain antibody responses, while the second elicited a response at least equivalent to convalescent individuals in most residents. Residents administered mRNA-1273 (Moderna) mounted stronger total and neutralizing antibody responses than those administered BNT162b2 (Pfizer-BioNTech). Two to four weeks after dose 2, residents (n = 119, median age 88) produced 4.8-6.3-fold fewer neutralizing antibodies than staff (n = 78; median age 47) against wild-type (with D614G) pseudotyped lentivirus, and residents administered BNT162b2 produced 3.89-fold fewer neutralizing antibodies than those who received mRNA-1273. These effects were exacerbated upon serum challenge with pseudotyped VOC spike, with up to 7.94-fold reductions in B.1.351 (Beta) neutralization. Cumulatively, weaker vaccine stimulation, age/comorbidities, and the VOC produced an [~]130-fold reduction in apparent neutralization titers in LTCH residents and 37.9% of BNT162b2-vaccinated residents had undetectable neutralizing antibodies to B.1.351. Continued immune response surveillance and additional vaccine doses may be required in this population with known vulnerabilities.


title: Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention deficit hyperactivity disorder

abstract:
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with onset in childhood ("childhood ADHD"), and around two thirds of affected individuals will continue to have ADHD symptoms in adulthood ("persistent ADHD"). Age at first diagnosis can vary, and sometimes ADHD is first diagnosed in adulthood ("late-diagnosed ADHD").

In this study, we analyzed a large Danish population-based case-cohort generated by iPSYCH in order to identify common genetic risk loci and perform in-depth characterization of the polygenic architecture of childhood (N=14,878), persistent (N=1,473) and late-diagnosed ADHD (N=6,961) alongside 38,303 controls. Additionally, the burden of rare protein truncating variants in the three groups were evaluated in whole-exome sequencing data from a subset of the individuals (7,650 ADHD cases and 8,649 controls). We identified genome-wide significant loci associated with childhood ADHD (four loci) and late-diagnosed ADHD (one locus). In analyses of the polygenic architecture, we found higher polygenic score (PGS) of ADHD risk variants in persistent ADHD (mean PGS=0.41) compared to childhood (mean PGS=0.26) and late-diagnosed ADHD (mean PGS=0.27), and we found a significant decreased genetic correlation of late-diagnosed ADHD with inattention (rg=0.57) compared to childhood ADHD (rg=0.86). These results suggest that a higher ADHD polygenic risk burden is associated with persistence of symptoms, and that a later diagnosis of ADHD could be due in part to genetic factors. Additionally, childhood ADHD demonstrated both a significantly increased genetic overlap with autism compared to late-diagnosed ADHD as well as the highest burden of rare protein-truncating variants in highly constrained genes among ADHD subgroups (compared to controls: beta=0.13, P=2.41x10-11). Late-diagnosed ADHD demonstrated significantly larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants (compared to controls: beta=0.06). Overall, our study finds genetic heterogeneity among ADHD subgroups and suggests that genetic factors influence time of first ADHD diagnosis, persistence of ADHD and comorbidity patterns in the sub-groups.


title: Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence

abstract: Although clinical trials and real-world studies have affirmed the effectiveness and safety of the FDA-authorized COVID-19 vaccines, reports of breakthrough infections and persistent emergence of new variants highlight the need to vigilantly monitor the effectiveness of these vaccines. Here we compare the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. We defined cohorts of vaccinated and unvaccinated individuals from Minnesota (n = 25,589 each) matched on age, sex, race, history of prior SARS-CoV-2 PCR testing, and date of full vaccination. Both vaccines were highly effective during this study period against SARS-CoV-2 infection (mRNA-1273: 86%, 95%CI: 81-90.6%; BNT162b2: 76%, 95%CI: 69-81%) and COVID-19 associated hospitalization (mRNA-1273: 91.6%, 95% CI: 81-97%; BNT162b2: 85%, 95% CI: 73-93%). In July, vaccine effectiveness against hospitalization has remained high (mRNA-1273: 81%, 95% CI: 33-96.3%; BNT162b2: 75%, 95% CI: 24-93.9%), but effectiveness against infection was lower for both vaccines (mRNA-1273: 76%, 95% CI: 58-87%; BNT162b2: 42%, 95% CI: 13-62%), with a more pronounced reduction for BNT162b2. Notably, the Delta variant prevalence in Minnesota increased from 0.7% in May to over 70% in July whereas the Alpha variant prevalence decreased from 85% to 13% over the same time period. Comparing rates of infection between matched individuals fully vaccinated with mRNA-1273 versus BNT162b2 across Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa), mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0.39-0.64). In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 was about 60% lower than after full vaccination with BNT162b2 (IRR: 0.39, 95% CI: 0.24-0.62). Our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.


title: MFDNN: Multi-channel feature deep neural network algorithm to identify Covid19 chest X-ray images

abstract: The use of chest X-ray images (CXI) to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) caused by Coronavirus Disease 2019 (COVID-19) is life-saving important for both patients and doctors. This research proposed a multi-channel feature deep neural network algorithm to screen people infected with COVID-19. The algorithm integrates data oversampling technology and a multi-channel feature deep neural network model to carry out the training process in an end-to-end manner. In the experiment, we used a publicly available CXI database with 10,192 Normal, 6012 Lung Opacity (Non-COVID lung infection), and 1345 Viral Pneumonia images. Compared with traditional deep learning models (Densenet201, ResNet50, VGG19, GoogLeNet), the MFDNN model obtains an average test accuracy of 93.19% in all data. Furthermore, in each type of screening, the precision, recall, and F1 Score of the MFDNN model are also better than traditional deep learning networks. Secondly, compared with the latest CoroDet model, the MFDNN algorithm is 1.91% higher than the CoroDet model in the experiment of detecting the four categories of COVID19 infected persons. Finally, our experimental code will be placed at https://github.com/panliangrui/covid19.

category: radiology and imaging


title: Drug-resistant focal epilepsy in children is associated with increased modal controllability of the whole brain and epileptogenic regions

abstract:
Network control theory provides a framework by which neurophysiological dynamics of the brain can be modelled as a function of the structural connectome constructed from diffusion MRI. Average controllability describes the ability of a region to drive the brain to easy-to-reach neurophysiological states whilst modal controllability describes the ability of a region to drive the brain to difficult-to-reach states.

In this study, we identify increases in mean average and modal controllability in children with drug-resistant epilepsy compared to healthy controls. Using simulations, we purport that these changes may be a result of increased thalamocortical connectivity. At the node level, we demonstrate decreased modal controllability in the thalamus and posterior cingulate regions. In those undergoing resective surgery, we also demonstrate increased modal controllability of the resected parcels, a finding specific to patients who were rendered seizure free following surgery.

Changes in controllability are a manifestation of brain network dysfunction in epilepsy and may be a useful construct to understand the pathophysiology of this archetypical network disease. Understanding the mechanisms underlying these controllability changes may also facilitate the design of network-focussed interventions that seek to normalise network structure and function.

category: neurology


title: Probabilistic comparison of gray and white matter coverage between depth and surface intracranial electrodes in epilepsy: a patient-specific modeling and empirical study

abstract:
ObjectiveThe objective of this study is to quantify the coverage of gray and white matter during intracranial electroencephalography in a cohort of epilepsy patients with surface and depth electrodes.

MethodsWe included 65 patients with strip electrodes (n=12), strip and grid electrodes (n=24), strip, grid, and depth electrodes (n=7), or depth electrodes only (n=22) from the University of Utah spanning 2010-2020. Patient-specific imaging was used to generate probabilistic gray and white matter maps and atlas segmentations. The gray and white matter coverage was quantified based on spherical volumes centered on electrode centroids, with radii ranging from 1-15 mm, along with detailed finite element models of local electric fields

ResultsGray matter coverage was highly dependent on the chosen radius of influence (RoI). Using a 2.5 mm RoI, depth electrodes covered more gray matter than surface electrodes; however, surface electrodes covered more gray matter at RoI larger than 4 mm. White matter coverage was greatest for depth electrodes at all RoIs, which is noteworthy for studies involving stimulation mapping. Depth electrodes were able to record significantly more gray matter from the amygdala and hippocampus than subdural electrodes.

SignificanceThis study provides the first probabilistic analysis to quantify gray and white matter coverage for multiple categories of intracranial recording configurations. Depth electrodes may offer increased per contact coverage of gray matter over other recording strategies if the desired signals are local to the contact, while subdural grids and strips can sample more gray matter if the desired signals are more diffuse.


title: Segmentation of vestibular schwannoma from MRI - An open annotated dataset and baseline algorithm

abstract: Automatic segmentation of vestibular schwannomas (VS) from magnetic resonance imaging (MRI) could significantly improve clinical workflow and assist patient management. We have previously developed a novel artificial intelligence framework based on a 2.5D convolutional neural network achieving excellent results equivalent to those achieved by an independent human annotator. Here, we provide the first publicly-available annotated imaging dataset of VS by releasing the data and annotations used in our prior work. This collection contains a labelled dataset of 484 MR images collected on 242 consecutive patients with a VS undergoing Gamma Knife Stereotactic Radiosurgery at a single institution. Data includes all segmentations and contours used in treatment planning and details of the administered dose. Implementation of our automated segmentation algorithm uses MONAI, a freely-available open-source framework for deep learning in healthcare imaging. These data will facilitate the development and validation of automated segmentation frameworks for VS and may also be used to develop other multi-modal algorithmic models.