title: Prevalence, characteristics, and predictors of Long COVID among diagnosed cases of COVID-19

abstract:
BackgroundLong COVID or long-term complication after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe cases. We did this study to estimate the prevalence and identify the characteristics and predictors of Long COVID among our patients.

MethodologyWe recruited adult ([≥]18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID.

ResultsWe have analyzed 487 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47). Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) participants. Prevalence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n=72). The most common Long COVID symptom was fatigue (64.8%) followed by cough (32.4%). Statistically significant predictors of Long COVID were - Pre-existing medical conditions (Adjusted Odds ratio (aOR)=2.00, 95% CI: 1.16,3.44), having a more significant number of symptoms during acute phase of COVID-19 disease (aOR=11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR=2.32, 95% CI: 1.17,4.58), the severity of illness (aOR=5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR)=3.89, 95% CI: 2.49,6.08).

ConclusionA considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.


title: A method for variant agnostic detection of SARS-CoV-2, rapid monitoring of circulating variants, detection of mutations of biological significance, and early detection of emergent variants such as Omicron

abstract:
The rapid emergence of new SARS-CoV-2 variants raises a number of public health questions including the capability of diagnostic tests to detect new strains, the efficacy of vaccines, and how to map the geographical distribution of variants to better understand patterns of transmission and possible load on healthcare resources. Next-Generation Sequencing (NGS) is the primary method for detecting and tracing the emergence of new variants, but it is expensive, and it can take weeks before sequence data is available in public repositories. Here, we describe a Polymerase Chain Reaction (PCR)-based genotyping approach that is significantly less expensive, accelerates reporting on SARS-CoV-2 variants, and can be implemented in any testing lab performing PCR.

Specific Single Nucleotide Polymorphisms (SNPs) and indels are identified that have high positive percent agreement (PPA) and negative percent agreement (NPA) compared to NGS for the major genotypes that circulated in 2021. Using a 48-marker panel, testing on 1,128 retrospective samples yielded a PPA and NPA in the 96.3 to 100% and 99.2 to 100% range, respectively, for the top 10 most prevalent lineages. The effect on PPA and NPA of reducing the number of panel markers was also explored.

In addition, with the emergence of Omicron, we also developed an Omicron genotyping panel that distinguishes the Delta and Omicron variants using four (4) highly specific SNPs. Data from testing demonstrates the capability to use the panel to rapidly track the growing prevalence of the Omicron variant in the United States in December 2021.

category: infectious diseases


title: Granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies treatment for COVID-19 patients: a meta-analysis

abstract:
ObjectiveWe performed a meta-analysis in order to determine safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies on COVID-19.

MethodsWe searched from the Cochrane Library, PubMed, Embase, biorxiv and medrxiv databases beginning in the COVID-19 outbreak on December 1, 2019 until August 29, 2021. The primary outcomes included death, the incidence of invasive mechanical ventilation (IMV), ventilation requirement, and secondary infection.

Results6 eligible literature involving 1501 COVID-19 patients were recruited, and they were divided into experimental group (n = 736) and control group (n = 765). Using a random-effect model, we found that the GM-CSF antibodies treatment was associated with a 3.8-26.9% decline of the risk of mortality[odds ratio (OR) = 0.06, 95% confidence interval (CI): -0.11, -0.01, p =0.02], a 5.3-28.7% reduction of incidence of IMV [OR = 0.51, 95% CI: 0.28, 0.95, p =0.03], and a 23.3-50.0% enhancement of ventilation improvement [OR = 11.70, 95% CI: 1.99, 68.68, p=0.006]. There were no statistically significant differences in the association between two groups in second infection.

ConclusionSevere COVID-19 patients may benefit from GM-CSF antibodies.


title: Safety and immunogenicity of the BBIBP-CorV vaccine in adolescents aged 12-17 years in Thai population, prospective cohort study.

abstract:
IntroductionCOVID-19 pandemic affects all populations worldwide, including adolescents. Adolescents can develop a severe form of COVID-19, especially with comorbidity underlying. The prior studies of the mRNA COVID-19 vaccine showed excellent effectiveness in adolescents. Therefore, this study aimed to evaluate the safety and effectiveness of the BBIBP-CorV vaccine with the immunobridging approach in Thai adolescents.

MethodsThis single-center, prospective cohort study compared the immunogenicity after 2 doses of the BBIBO-CorV vaccine with 21 days interval of participants aged 12-17 years with 18-30 years at Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand. The key eligible criteria were healthy or had stable pre-existing comorbidity participants, aged 12-17 years. The primary endpoint was the anti-receptor binding domain antibody concentration at 4 weeks after dose 2 of the vaccine. In addition, safety profiles were solicited adverse events within 7 days after each dose of vaccine and any adverse events through 1 month after dose 2 of the vaccine.

ResultsFour weeks after the second vaccination, the GMC of anti-RBD antibody in the adolescent cohort was 102.9 BAU/mL (95%CI; 91.0-116.4) and 36.9 BAU/mL (95%CI; 30.9-44.0) in the adult cohort. The GMR of the adolescent cohort was 2.79 (95%CI; 2.25-3.46, p-value; <0.0001) compared with the adult cohort which met non-inferiority criteria. The reactogenicity was slightly less reported in the adolescent cohort compared with the adult cohort. No serious adverse events were reported in both cohorts.

ConclusionVaccination with the BBIBP-CorV vaccine in the adolescent participants was safe and effective.


title: Maternal smoking during pregnancy and type 1 diabetes in the offspring: A nationwide register-based study with family-based designs

abstract:
ObjectivesMaternal smoking during pregnancy is associated with a reduced risk of type 1 diabetes (T1D) in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs.

DesignA nationwide, prospective cohort study and a nested case-control study (quasi-experiment) comparing children with T1D to their age-matched siblings (or cousins).

SettingSwedish national registers.

ParticipantsWe included 2,995,321 children born in Sweden between 1983 and 2014.

ExposureInformation on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register.

Main outcome measuresChildren were followed for a diagnosis of T1D until 2020 through the National Patient, Diabetes and Prescribed Drug Registers.

ResultsA total of 18,617 children developed T1D, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7,988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring T1D in the full cohort (hazard ratio: 0.78, 95% confidence interval [CI]: 0.75 to 0.82) in the multivariable-adjusted model. The corresponding odds ratio was 0.78 (95% CI: 0.69 to 0.88) in the sibling and 0.72 (95% CI: 0.66 to 0.79) in the cousin comparison analysis.

ConclusionsThis nationwide, family-based study provides support for a protective effect of maternal smoking on offspring T1D. Mechanistic studies are needed to elucidate the underlying pathways behind this link.

category: epidemiology


title: Clinical Performance of the cobas Liat SARS-CoV-2 & Influenza AB for the Detection of SARS-CoV-2 in Nasal Samples

abstract:
Background and ObjectivePoint-of-care type molecular diagnostic tests have been used for detecting SARS-CoV-2, although their clinical utility with nasal samples has yet to be established. This study evaluated the clinical performance of the cobas Liat SARS-CoV-2 & Influenza AB (Liat) in nasal samples.

MethodsNasal and nasopharyngeal samples were collected and were tested using the Liat, the cobas 6800 system and the cobas SARS-CoV-2 & Influenza AB (cobas), and a method developed by National Institute of Infectious Diseases, Japan (NIID).

ResultsA total of 814 nasal samples were collected. The Liat assay was positive for SARS-CoV-2 in 113 (13.9%). The total, positive, and negative concordance rate between the Liat and cobas/NIID assays were 99.3%/98.4%, 99.1%/100%, and 99.3%/98.2%, respectively. Five samples were positive only using the Liat assay. Their Ct values ranged from 31.9 to 37.2. The Ct values of the Liat assay were significantly lower (p < 0.001) but were correlated (p < 0.001) with those of other molecular assays. In the participants who tested positive for SARS-CoV-2 on the Liat assay using nasopharyngeal samples, 88.2% of their nasal samples also tested positive using the Liat assay.

ConclusionThe Liat assay showed high concordance with other molecular assays in nasal samples. Some discordance occurred in samples with Ct values > 30 on the Liat assay.

Key PointsO_LIThe cobas Liat SARS-CoV-2 & Influenza AB assay showed high concordance with other molecular assays in nasal and nasopharyngeal samples, providing results within 20 minutes.
C_LIO_LISome discordance occurred in samples with Ct values > 30 on the Liat assay.
C_LIO_LIThe Liat assay may be suitable for use in a variety of clinical situations, primarily where accurate detection of SARS-CoV-2 is necessary.
C_LI


title: The Dynamics of SARS-CoV-2 Infectivity with Changes in Aerosol Microenvironment

abstract:
Understanding the factors that influence the airborne survival of viruses such as SARS-CoV-2 in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets ([~]5-10{micro}m equilibrated radius) over timescales spanning from 5 seconds to 20 minutes using a novel instrument to probe survival in a small population of droplets (typically 5-10) containing [~]1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to [~]10 % of the starting value was observable for SARS-CoV-2 over 20 minutes, with a large proportion of the loss occurring within the first 5 minutes after aerosolisation. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallise at RHs below 50% leading to a near instant loss of infectivity in 50-60% of the virus. However, at 90% RH the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 minutes, beyond which it decays to only 10% remaining infectious after 10 minutes. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilisation of CO2 from bicarbonate buffer within the droplet. Three different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.

SignificanceThe aerosol microenvironment is highly dynamic exposing pathogens, such as the SARS-CoV-2 virus when exhaled in respiratory aerosol, to extreme conditions of solute concentration, pH and evaporative cooling. Yet surviving this environment is a key step in the transmission of such pathogens. Understanding the impact that airborne transport has on pathogens and the influence of environmental conditions on pathogen survival can inform the implementation of strategies to mitigate the spread of diseases such as COVID-19. We report changes in the infectivity of the airborne virus over timescales spanning from 5 s to 20 minutes and demonstrate the role of two microphysical processes in this infectivity loss: particle crystallisation and aerosol droplet pH change.


title: Anti-PEG antibodies boosted in humans by SARS-CoV-2 lipid nanoparticle mRNA vaccine

abstract:
Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle mRNA vaccines for SARS-CoV-2 contain small amounts of PEG but it is not known if PEG antibodies are enhanced by vaccination and if there are any consequences. We studied plasma from 55 people receiving the Comirnaty (Pfizer-BioNTech) mRNA vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was boosted a mean of 1.78-fold (range 0.68 to 16.6) by vaccination. Anti-PEG IgM increased 2.64-fold (0.76 to 12.84) following vaccination. PEG antibodies did not impact the neutralizing antibody response to vaccination. Pre-existing levels of anti-PEG IgM correlated with increased reactogenicity. A rise in PEG antibodies following vaccination was associated with an increase in the association of PEG-based nanoparticles to blood immune cells ex vivo. We conclude that low level PEG-specific antibodies can be modestly boosted by a lipid nanoparticle mRNA-vaccine and that PEG-specific antibodies are associated with higher reactogenicity. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA-vaccines should be monitored.

One-Sentence SummaryA rise in PEG antibodies following mRNA lipid nanoparticle vaccination was associated with higher reactogenicity and PEG particle-leukocyte interactions.

category: allergy and immunology


title: Autoantibodies in COVID-19 correlate with anti-viral humoral responses and distinct immune signatures

abstract:
BackgroundSeveral autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19.

MethodsWe performed highly sensitive indirect immunofluorescence assays to detect anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed-up to one year after infection, eleven vaccinated individuals, and 41 unexposed controls.

ResultsCompared to healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA- negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B cell compartment after recovery.

ConclusionHighly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased anti-viral humoral immune responses and inflammatory immune signatures.


title: Computer adaptive testing to assess impairing behavioral health problems in emergency department patients

abstract:
Study ObjectiveTo assess the prevalence of several impairing behavioral health domains in stable patients presenting to the emergency department (ED) through the use of computer adaptive testing and the association among the domains, standard assessments, and ED utilization.

MethodsThis was a single-center observational study of 828 randomly selected adult patients presenting to the ED from May 2019 to March 2020. The main outcomes of interest were the self-administered, validated computer adaptive assessments of suicidality, depression, anxiety, PTSD, and substance abuse using computer adaptive testing, the CAT-MH. We estimated the association among the CAT-MH subscales, standard assessments, and the number of ED visits in the year prior and 30 days after enrollment.

ResultsThe proportion of those who scored above the threshold of low/mild risk were: 24.1% (suicidality), 8.3% (depression), 16.5% (anxiety), 12.3% (PTSD), and 20.4% (substance use). While the CAT-MH subscales were highly correlated with other self-report assessments, they were not highly associated with standard ED assessments of suicidality. When examining associations with ED use, for example, individuals who had two or more ED visits in the prior year had 51% increased odds of being in the intermediate-high suicide risk category (95% Confidence Interval [CI], 1.03-2.23) compared to those with zero prior ED visits.

ConclusionThe CAT-MH can document the high prevalence of mental health conditions in the ED, which were missed by standard ED practices. Mental health problems are associated with ED utilization in a population of patients presenting largely for somatic complaints.

category: emergency medicine


title: Identifying SARS-CoV-2 regional introductions and transmission clusters in real time

abstract: The unprecedented SARS-CoV-2 global sequencing effort has suffered from an analytical bottleneck. Many existing methods for phylogenetic analysis are designed for sparse, static datasets and are too computationally expensive to apply to densely sampled, rapidly expanding datasets when results are needed immediately to inform public health action. For example, public health is often concerned with identifying clusters of closely related samples, but the sheer scale of the data prevents manual inspection and the current computational models are often too expensive in time and resources. Even when results are available, intuitive data exploration tools are of critical importance to effective public health interpretation and action. To help address this need, we present a phylogenetic summary statistic which quickly and efficiently identifies newly introduced strains in a region, resulting clusters of infected individuals, and their putative geographic origins. We show that this approach performs well on simulated data and is congruent with a more sophisticated analysis performed during the pandemic. We also introduce Cluster Tracker (https://clustertracker.gi.ucsc.edu/), a novel interactive web-based tool to facilitate effective and intuitive SARS-CoV-2 geographic data exploration and visualization. Cluster-Tracker is updated daily and automatically identifies and highlights groups of closely related SARS-CoV-2 infections resulting from inter-regional transmission across the United States, streamlining public health tracking of local viral diversity and emerging infection clusters. The combination of these open-source tools will empower detailed investigations of the geographic origins and spread of SARS-CoV-2 and other densely-sampled pathogens.


title: The skin we live in: pigmentation traits and tanning behaviour in British young adults, an observational and genetically-informed study.

abstract:
BackgroundSkin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet radiation (UVR) devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to reduce skin cancer rates, there is insufficient evidence on the motivations for tanning preferences and their relationship with pigmentation phenotypes. The present observational and genetically- informed study investigates motives for tanning and the role that pigmentation phenotypes play on outdoor and indoor tanning behaviour in British young adults.

MethodsThis study included 3722 participants from the Avon Longitudinal Study of Parents and Children in South West England. Skin, hair and eye colour features, and tanning ability and preferences were collected using a questionnaire applied when participants were [~]25 years of age. Genotypes for 41 single nucleotide polymorphisms (SNPs) associated with pigmentation were obtained from a subset of participants who provided a biological sample, and used to estimate the probability of having particular pigmentation traits with the HIrisPlex-S system.

ResultsLiking to tan and outdoor tanning were strongly influenced by skin, hair and eye pigmentation, and tanning ability. However, the association of these traits with UV indoor tanning was weaker. Conversely, females, participants of lower socioeconomic position, individuals who were unhappy with their pigmentation phenotype during adolescence, and participants who believed that tanning helps prevent sunburn were more likely to have used UVR-based tanning devices.

ConclusionOur results provide evidence to support the implementation of skin cancer preventative interventions that consider individual biological characteristics and motives for undergoing outdoor and indoor tanning.


title: Two schizophrenia imaging signatures and their associations with cognition, psychopathology, and genetics in the general population

abstract: The prevalence and significance of schizophrenia-related phenotypes at the population-level are debated in the literature. Here we assess whether two recently reported neuroanatomical signatures of schizophrenia, signature 1 with widespread reduction of gray matter volume, and signature 2 with increased striatal volume, could be replicated in an independent schizophrenia sample, and investigate whether expression of these signatures can be detected at the population-level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk. This cross-sectional study used an independent schizophrenia-control sample (n=347; age 16-57 years) for replication of imaging signatures, and then examined two independent population-level datasets: Philadelphia Neurodevelopmental Cohort [PNC; n=359 typically developing (TD) and psychosis-spectrum symptoms (PS) youth] and UK Biobank (UKBB; n=836; age 44-50 years) adults. We quantified signature expression using support-vector machine learning, and compared cognition, psychopathology, and polygenic risk between signatures. Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youth with PS than TD youth, whereas signature 2 frequency was similar. In both youth and adults, signature 1 had worse cognitive performance than signature 2. Compared to adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2. We successfully replicate two neuroanatomical signatures of schizophrenia, and describe their prevalence in population-based samples of youth and adults. We further demonstrate distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

category: radiology and imaging


title: Population-split-based risk assessment model of venous thromboembolism in Chinese medical inpatients

abstract:
AbstractsO_ST_ABSObjectiveC_ST_ABSInpatients with high risk of venous thromboembolism (VTE) usually face serious threats to their health and economic conditions. Many studies using machine learning (ML) models to predict VTE risk neglected an important statistical phenomenon,  fuzzy feature, and achieved inferior results. Considering the effect of  fuzzy feature, our study aims to develop a VTE risk assessment model suitable for Chinese medical inpatients.

Materials and MethodsInpatients in the medical department of Peking Union Medical College Hospital (PUMCH) from January 2014 to June 2016 were collected. A new ML VTE risk assessment model was built through population splitting. First patients were classified into different groups based on values of VTE risk factors, then trustless groups were filtered out, and finally ML models were built on training data in unit of groups. Predictive performances of our method, five traditional ML models, and the Padua model were compared.

ResultsThe  fuzzy feature was verified on the whole dataset. Compared with the Padua model, the proposed model showed higher sensitivities and specificities on training data, and higher specificities and similar sensitivities on test data. Standard deviations of predictive validity of five ML models were larger than the proposed model.

DiscussionThe proposed model was the only one which showed advantages on both sensitivity and specificity over Padua model. Its robustness was better than traditional ML models.

ConclusionThis study built a population-split-based ML model of VTE for Chinese medical inpatients and it may help clinicians stratify VTE risk and guide prevention more efficiently.

category: respiratory medicine


title: Payments to key opinion leader physicians and drug sales of top pharmaceutical companies during the COVID-19 pandemic

abstract:
BackgroundThe unprecedented context of the COVID-19 pandemic poses the opportunity to study several questions in circumstances that would probably not otherwise occur. We sought to determine the dynamics of pharmaceutical company drug sales revenue, market capitalization and payments to physicians during the pandemic, focusing on payments to so-called key opinion leaders (KOLs).

MethodsWe analyzed the CMS Open Payments data of 15 top pharmaceutical company general payments to US physicians. We calculated total payments per year for all physicians, KOLs and 2018 KOLs in subsequent years. Drug-related fold changes in payments, drug revenues and company market capitation were calculated using Q1-2018 as reference. Yearly differences in payments, drug sales revenue and market capitalization were tested using generalized estimation equations (GEE). A double-sided p<0.05 was considered significant.

ResultsThe analyzed dataset comprised 8,563,872 payments to 382,779 physicians. In 2020, we observed a reduction in payments to physicians and KOLs compared to prior years. The total amount per KOL physician per company also decreased for each year for KOLs and the 2018 KOLs in the subsequent years. Payments per drug, but neither drug revenues nor pharmaceutical company market capitalization, followed a downward trend in 2020 compared to prior years. GEE analysis confirmed that, compared to 2018, the decrease in payments to KOLs overall and for the top drugs of each company was statistically significant. Yet, no significant differences in drug sales revenue and market capitalization was observed.

ConclusionsA substantial and significant reduction in payments to KOLs during the first fiscal year of the COVID-19 pandemic was not associated with a reduction in drug sales revenue of blockbuster drug products and the market capitalization of 15 top pharmaceutical companies. Overall, these findings suggest that a substantial part of pharmaceutical payments to KOLs do not appear to impact top drug sales revenues.

category: medical ethics


title: Chronic kidney disease is associated with attenuated plasma metabolome response to oral glucose tolerance testing

abstract: Chronic kidney disease (CKD), a major public health problem, is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of the response to oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. Using targeted metabolic profiling, we examined plasma metabolome in 41 moderate-to-severe non-diabetic CKD patients with estimated glomerular filtration rate (eGFR)<60ml/min per 1.73m2 (38.9{+/-}12.7) and 20 healthy controls with normal eGFR (87.2{+/-}17.7) before and after 2h of 75g oral glucose load. Compared to controls, CKD participants had higher lactate: pyruvate (L:P) ratio both at fasting and after oral glucose challenge. Total energy production estimated through GTP:GDP ratio was impaired during OGTT despite similar fasting GTP:GDP ratio. CKD group had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into insulin sensitizers in patients with non-diabetic CKD and their impact on energy metabolism.

category: nephrology


title: The Challenges for Screening and Diagnosing Gestational Diabetes Mellitus in Brazil: a cross-sectional study in a low-risk obstetric hospital.

abstract:
BackgroundGestational Diabetes Mellitus (GDM) is a very prevalent disease and can cause several morbidities for women and their offspring. The literature demonstrates the necessity for a better approach during prenatal assistance to detect and treat the disease. We aimed to evaluate the model and efficacy of GDM screening and diagnosis in a referenced low-risk obstetrical center of the municipality of Assis, Sao Paulo state, Brazil. Moreover, the specific objective was to evaluate the prevalence of GDM.

MethodsWe conducted a retrospective cross-sectional study of pregnant women, in which 257 prenatal cards and the clinical approaches used for GDM diagnosis and their results. We observed the consecutive patients admitted to the low-risk referenced obstetrical service of the "Santa Casa de Assis-SP" for childbirth from January to August 2021.

ResultsThere were 257 pregnant women, 227 prenatal cards obtained. Of these, 24.6% of the cards were considered incomplete, 25 (9.72%) did not contain the initial fasting plasma glucose information, and 93 (36.18%) did not describe this information in the second to the third trimester. The prevalence of GDM in the population was 14.78%.

ConclusionWe observed many pregnant women not screened according to the recommended guidelines and many prenatal cards with incomplete information. According to the screening and diagnosis guidelines, GDM prevalence was underestimated. The lack of prenatal card information and inadequacy of screening and diagnoses were observed in this population.

category: obstetrics and gynecology


title: Neoantigen Landscape Supports Feasibility of Personalized Cancer Vaccine for Follicular Lymphoma

abstract: Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that  polyvalent vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole exome sequencing (WES) and RNA sequencing (RNA-Seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-Seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by alignment of B-cell receptor (BCR) CDR3 regions from RNA-Seq data, grouping at the protein level, and comparison to the BCR repertoire of RNA-Seq data from healthy individuals. An average of 52 somatic mutations per patient (range: 2-172) were identified, and two or more (median: 15) high-quality neoantigens were predicted for 56 of 58 samples. The predicted neoantigen peptides were composed of missense mutations (76%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide (SLP) vaccines were successfully synthesized for and administered to all four patients enrolled to date. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field.

category: genetic and genomic medicine


title: The Presence of Non-organ-specific Autoantibodies in Chronic Hepatitis C Treatment-naive Patients

abstract:
BackgroundIn the patients with hepatitis C virus (HCV) various immune-mediated phenomena are described, and non-organ-specific autoantibodies (NOSAs) in particular are common. The aim of the present study was to investigate the NOSAs prevalence in chronic hepatitis c treatment-naive patients.

Patients and MethodsSera of 76 consecutive HCV treatment-naive patients were considered to be eligible for this study for evaluation of Anti-nuclear, anti-smooth muscle, anti-mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal antibodies. Criteria of eligibility were serum anti-HCV antibody and HCV RNA positivity, chronic inflammation revealed by histological analysis of the liver, genotyping, treatment-naive patients, and no have the diagnosis of probable or definite autoimmune hepatitis.

ResultsMean chronological age for the 76 patients (44 females and 32 males) was 51.3 {+/-} 13,9 years (range: 20-67 years). Nineteen patients (25.0%) infected with HCV had detectable levels of NOSAs at before combined antiviral treatment. SMA was present in 16 (21.0%) of 76 patients, ANA in 2 patients (2.6%), and pANCA (perinuclear ANCA) in 1 patients (1.3%). No patient had specimens reactive to AMA, LMK, or cANCA (cytoplasmic ANCA).

ConclusionsIn this study, we show the NOSAs positivity in chronic hepatitis c treatment-naive patients. Assigned to high prevalence of SMA positivity is associated with high METAVIR score, and HCV-genotype 1 and 1b, may reflect a release of intracellular antigens at the time of hepatocellular injury triggering immune responses in the form of autoantibody production or a direct infection of immunocytes by the HCV.


title: Egg-derived anti-SARS-CoV-2 immunoglobulin Y (IgY) with broad variant activity as intranasal prophylaxis against COVID-19: preclinical studies and randomized controlled phase 1 clinical trial

abstract: COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019- nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is distinct for sera from immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo- controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. (ClinicalTrials.gov: NCT04567810, https://www.clinicaltrials.gov/ct2/show/NCT04567810)


title: Egg-derived anti-SARS-CoV-2 immunoglobulin Y (IgY) with broad variant activity as intranasal prophylaxis against COVID-19


title: SARS-CoV-2-positive patients display considerable differences in proteome diversity in urine, nasopharyngeal, gargle solution and bronchoalveolar lavage fluid samples

abstract:
BackgroundProteome profile changes post-severe acute respiratory syndrome coronavirus 2 (post-SARS-CoV-2) infection in different body sites of humans remains an active scientific investigation whose solutions stand a chance of providing more information on what constitutes SARS-CoV-2 pathogenesis. While proteomics has been used to understand SARS-CoV-2 pathogenesis, there are limited data about the status of proteome profile in different human body sites infected by the sarscov2 virus. To bridge the gap, our study aims to profile the proteins secreted in urine, bronchoalveolar lavage fluid (BALF), gargle solution, and nasopharyngeal samples and assess the proteome differences in these body samples collected from SARS-CoV-2-positive patients.

Materials and methodsWe downloaded publicly available proteomic data from (https://www.ebi.ac.uk/pride/). The data we downloaded had the following identifiers: i) PXD019423, n=3 from Charles Tanford Protein Center in Germany. ii) PXD018970, n=15 from Beijing Proteome Research Centre, China. iii)PXD022085, n=5 from Huazhong University of Science and Technology, China, and iv) PXD022889, n=18 from Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA. MaxQuant was used for the peptide spectral matching using humans, and SARS-CoV-2 was downloaded from the UniProt database (access date 13th October 2021).

ResultsThe individuals infected with SARS-CoV-2 viruses displayed a different proteome diversity from the different body sites we investigated. Overall, we identified 1809 proteins across the four different sample types we compared. Urine and BALF samples had significantly more abundant SARS-CoV-2 proteins than the other body sites we compared. Urine samples had 257(33.7%) unique proteins, followed by nasopharyngeal with 250(32.8%) unique proteins. Garage solution and BALF had 38(5%) and 73(9.6%) unique proteins.

ConclusionsUrine, gargle solution, nasopharyngeal, and bronchoalveolar lavage fluid samples have different protein diversity in individuals infected with SARS-CoV-2. Moreover, our data demonstrated that a given body site is characterized by a unique set of proteins in SARS-CoV-2 seropositive individuals.


title: Direct Comparison of SARS Co-V-2 Nasal RT- PCR and Rapid Antigen Test (BinaxNOWTM) at a Community Testing Site During an Omicron Surge

abstract: In 731 persons seeking COVID-19 testing at a walk-up San Francisco community site in January 2022, simultaneous nasal rapid antigen testing (BinaxNOW) and RT-PCR testing was performed. There were 296 (40.5%) positive tests by RT-PCR; 98.5% of a random sample (N=67) were the omicron variant. Sensitivity of a single antigen test was 95.2% (95% CI 92-98%); 82.1% (95% CI 77-87%) and 65.2% (95% CI 60-71%) for Ct threshold of < 30, < 35 and no threshold, respectively. We also compared BinaxNOW to RT-PCR from oral cheek swabs to nasal swabs (N=75); oral cheek specimen was significantly less sensitive than nasal swab. A single BinaxNOW oral cheek rapid antigen test failed to detect 91% (20 of 22) of specimens that were BinaxNOW positive from the standard nasal sampling. In a separate direct comparison of BinaxNOW between specimens collected from nasal or throat (tonsillar) swab (N=115), sensitivity was 97.7% for nasal and 48.8% for throat swabs that were PCR-positive on nasal swab with a Ct threshold < 30. Among persons with either a nasal or throat RT-PCR positive swab with Ct<30, BinaxNOW sensitivity was 85.7% for nasal and 89.8% for nasal plus throat swabs. BinaxNOW continues to be a very useful diagnostic during the omicron surge; oral (throat or cheek swab) should not replace nasal swabs due to significantly reduced sensitivity compared to nasal. As currently recommended, repeat testing should be done for high-risk persons with an initial negative antigen test result.


title: Direct Comparison of SARS Co-V-2 Nasal RT- PCR and Rapid Antigen Test (BinaxNOW(TM)) at a Community Testing Site During an Omicron Surge


title: Direct Comparison of SARS CoV-2 Nasal RT- PCR and Rapid Antigen Test (BinaxNOW(TM)) at a Community Testing Site During an Omicron Surge


title: Direct Comparison of SARS-CoV-2 Nasal RT- PCR and Rapid Antigen Test (BinaxNOW(TM)) at a Community Testing Site During an Omicron Surge


title: Time-Specific Associations of Wearable, Sensor-Based Cardiovascular and Behavioral Readouts with Disease Phenotypes in the Outpatient Setting of the Chronic Renal Insufficiency Cohort (CRIC)

abstract: Patients with chronic kidney disease (CKD) are at risk of developing cardiovascular disease. To facilitate out-of-clinic evaluation, we piloted wearable device-based analysis of heart rate variability and behavioral readouts in patients with CKD participating in the Chronic Renal Insufficiency Cohort and (n=49) controls. Time-specific partitioning of HRV readouts indicate higher parasympathetic nervous activity during the night (mean RR at night 14.4{+/-}1.9 ms versus 12.8{+/-}2.1 ms during active hours; n=47, ANOVA q=0.001). The 2 long-term fluctuations in the detrended fluctuation analysis, a parameter predictive of cardiovascular mortality, significantly differentiated between diabetic and non-diabetic patients (prominent at night with 0.58{+/-}0.2 versus 0.45{+/-}0.12, respectively, adj. p=0.004). Both diabetic and nondiabetic CKD patients showed loss of rhythmic organization compared to controls, with diabetic CKD patients exhibiting deconsolidation of peak phases between their activity and SDNN (standard deviation of interbeat intervals) rhythms (mean phase difference CKD 8.3h, CKD/T2DM 4h, controls 6.8h). This work provides a roadmap toward deriving actionable clinical insights from the data collected by wearable devices outside of highly controlled clinical environments.

category: cardiovascular medicine


title: Estimation of the test to test distribution as a proxy for generation interval distribution for the Omicron variant in England

abstract:
BackgroundEarly estimates from South Africa indicated that the Omicron COVID-19 variant may be both more transmissible and have greater immune escape than the previously dominant Delta variant. The rapid turnover of the latest epidemic wave in South Africa as well as initial evidence from contact tracing and household infection studies has prompted speculation that the generation time of the Omicron variant may be shorter in comparable settings than the generation time of the Delta variant.

MethodsWe estimated daily growth rates for the Omicron and Delta variants in each UKHSA region from the 23rd of November to the 23rd of December 2021 using surveillance case counts by date of specimen and S-gene target failure status with an autoregressive model that allowed for time-varying differences in the transmission advantage of the Delta variant where the evidence supported this. By assuming a gamma distributed generation distribution we then estimated the generation time distribution and transmission advantage of the Omicron variant that would be required to explain this time varying advantage. We repeated this estimation process using two different prior estimates for the generation time of the Delta variant first based on household transmission and then based on its intrinsic generation time.

ResultsVisualising our growth rate estimates provided initial evidence for a difference in generation time distributions. Assuming a generation time distribution for Delta with a mean of 2.5-4 days (90% credible interval) and a standard deviation of 1.9-3 days we estimated a shorter generation time distribution for Omicron with a mean of 1.5-3.2 days and a standard deviation of 1.3-4.6 days. This implied a transmission advantage for Omicron in this setting of 160%-210% compared to Delta. We found similar relative results using an estimate of the intrinsic generation time for Delta though all estimates increased in magnitude due to the longer assumed generation time.

ConclusionsWe found that a reduction in the generation time of Omicron compared to Delta was able to explain the observed variation over time in the transmission advantage of the Omicron variant. However, this analysis cannot rule out the role of other factors such as differences in the populations the variants were mixing in, differences in immune escape between variants or bias due to using the test to test distribution as a proxy for the generation time distribution.


title: Modelling COVID-19 Vaccine Breakthrough Infections in Highly Vaccinated Israel - the effects of waning immunity and third vaccination dose

abstract: In August 2021, a major wave of the SARS-CoV-2 Delta variant erupted in the highly vaccinated population of Israel. The Delta variant has a transmission advantage over the Alpha variant, and thus replaced it in approximately two months. The outbreak led to an unexpectedly large proportion of breakthrough infections (BTI)-- a phenomenon that received worldwide attention. The BTI proportion amongst cases in the age group of 60+ years reached levels as high as [~]85% in August 2021. Most of the Israeli population, especially those 60+ age, received their second dose of the vaccination, four months before the invasion of the Delta variant. Hence, either the vaccine induced immunity dropped significantly or the Delta variant possesses immunity escaping abilities. In this work, we analyzed and model age-structured cases, vaccination coverage, and vaccine BTI data obtained from the Israeli Ministry of Health, to help understand the epidemiological factors involved in the outbreak. We propose a mathematical model which captures a multitude of factors, including age structure, the time varying vaccine efficacy, time varying transmission rate, BTIs, reduced susceptibility and infectivity of vaccinated individuals, protection duration of the vaccine induced immunity, and the vaccine distribution. We fitted our model to the cases among vaccinated and unvaccinated, for <60 and 60+ age groups, to address the aforementioned factors. We found that the transmission rate was driven by multiple factors including the invasion of Delta variant and the mitigation measures. Through a model reconstruction of the reproductive number R0(t), it was found that the peak transmission rate of the Delta variant was 1.96 times larger than the previous Alpha variant. The model estimated that the vaccine efficacy dropped significantly from >90% to [~]40% over 6 months, and that the immunity protection duration has a peaked Gamma distribution (rather than exponential). We further performed model simulations quantifying the important role of the third vaccination booster dose in reducing the levels of breakthrough infections. This allowed us to explore "what if" scenarios should the booster not have been rolled out. Application of this framework upon invasion of new pathogens, or variants of concern, can help elucidate important factors in the outbreak dynamics and highlight potential routes of action to mitigate their spread.

category: public and global health


title: Adaptation and validation of a scale to evaluate the quality of virtual courses developed for medical students in Peru during the COVID-19 pandemic

abstract:
BackgroundDuring the COVID-19 pandemic, medical education migrated to digital environments, without clear guidelines for virtual courses or evaluations of how these courses have been developed.

ObjectiveTo adapt and validate a scale to evaluate the quality of virtual courses developed for human medicine students in Peru.

MethodsCross-sectional study that adapted a scale to assess the quality of virtual courses to the context of Peruvian medical students during the COVID-19 pandemic, using the Delphi methodology and pilot tests for a rigorous evaluation of the items, resulting in a scale of 30 items that were described with summary statistics. In addition to the exploratory factor analysis (EFA) with Oblimin rotation, together with the adequacy and sample fit with Bartlett test and Kaiser-Meyer-Olkin (KMO), while the internal consistency was estimated with the alpha coefficient.

ResultsA total of 297 medical students in Peru were surveyed. The descriptive statistics for the items showed a normal distribution, while the Bartlett test showed no inadequacy (X2=6134.34, p<0.01) and with the KMO test an overall value greater than 0.92 was found, therefore an AFE was performed where five factors were identified (General Quality and Didactic Methodology, Design and Navigation of the Virtual Platform, Multimedia Resources, Academic Materials) with 30 items. In the internal consistency, an alpha coefficient greater than 0.85 was estimated for the factors evaluated.

ConclusionsThe adapted scale of 30 items grouped into five factors or domains, show adequate evidence of validity and reliability to be used in the evaluation of the quality of virtual courses developed for Peruvian human medicine students during the context of the COVID-19 pandemic.

category: medical education


title: Paramagnetic rim lesions are associated with pathogenic CSF profiles and worse clinical outcomes in multiple sclerosis: a retrospective cross-sectional study

abstract:
Background and ObjectiveParamagnetic rims have been observed as a feature of some MS lesions on susceptibility-sensitive MRI and indicate ongoing inflammation, principally consisting of compartmentalized activated microglia/macrophages. We investigated clinical, MRI, and intrathecal (cerebrospinal fluid, CSF) associations of paramagnetic rim lesions (PRL) using 3T MRI in MS.

MethodsThis is a retrospective, cross-sectional analysis of patients at a single neuroimmunology clinic. All patients had standardized 3T MRI using a multiecho T2*-weighted sequence with susceptibility postprocessing (SWAN protocol, GE) as part of the inclusion criteria. SWAN-derived filtered phase maps and corresponding T2-FLAIR images were manually reviewed by one expert rater blinded to clinical data, and PRL were determined based on qualitative assessment of hypointense paramagnetic edges on corresponding T2-hyperintense lesions. Descriptive statistics, t-tests, ANOVA, and linear regression determined demographic, clinical, MRI, and intrathecal profile associations with the presence of one or more PRL.

ResultsOne hundred and forty-seven (147) MS patients were included in this analysis (2 clinically isolated syndrome, 118 relapsing-remitting, 14 secondary progressive, 13 primary progressive). Baseline mean age was 48.8 years, disease duration 12.8 years, and median EDSS 2, with 79% women. Seventy-five percent of patients were receiving a disease-modifying therapy, and 79 patients (54%) had available cerebrospinal fluid (CSF) analysis. Sixty-three patients (43%) had at least 1 PRL. PRL status (presence or absence) did not vary by sex or EDSS but was associated with younger age (51 vs 46 years; p=0.01) and shorter disease duration (14.5 vs 10.5 years; p=0.01). PRL status was also associated with worse disease (MS severity score: 2.8 vs 3.7; p=0.05) and blood-brain barrier disruption as determined by higher protein and pathologically elevated albumin quotient, as well as the presence of CSF oligoclonal bands (all p[≤]0.05); there was no association with immunoglobulin index or synthesis rate. PRL status was additionally associated with higher burden of T2-hyperintense cerebral lesion volume (T2LV), higher age-adjusted cerebral brain volume loss (especially of gray matter), and poorer performance on multiple clinical measures, including the 9-hole peg test and symbol digit modalities test (but not timed 25-foot walk speed). Clinical and intrathecal profiles remained associated with PRL after adjustment for age and in many cases T2LV as well. Sensitivity analyses limited to subgroups of patients without disease activity at the time of CSF sampling remained supportive of results. Patients with PRL were being treated with higher-efficacy disease-modifying therapies at the time of the data query.

ConclusionsPRL, an emerging noninvasive biomarker of chronic cerebral neuroinflammation in MS, are confirmed to be associated with greater disease severity and newly shown to be associated with intrathecal inflammation and blood-brain-barrier disruption.

category: neurology


title: Angle-angle diagrams in the assessment of locomotion in persons with multiple sclerosis: A preliminary study

abstract: Gait analysis is clinically relevant in persons with multiple sclerosis (PwMS) and consists of several joint angular displacement-time relationships and spatiotemporal parameters. However, it lacks representation by means of diagrams in which knee angle-hip angle and knee angle-ankle angle variations are plotted against each other at the same instants of time. Three-dimensional kinematic analysis was performed on 20 subjects (10 PwMS/10 healthy controls, HCs), and the knee-angle/hip-angle and knee-angle/ankle-angle diagrams of both lower limbs were determined in the sagittal plane while walking on a motorized treadmill. The area (a quantifier of conjoint range of motion) and the perimeter (a quantifier of coordination) of angle-angle diagram loops were calculated. PwMS showed reduced knee-angle/ankle-angle loops compared to HCs (P<0.05, ES = 0.80), whereas the hip-angle/ankle-angle loops between the PwMS and HCs was not significant (P> 0.05). Similarly, the activation of leg muscles showed significant differences between PwMS and HCs (p ranged from 0.05-to 0.001; ES ranged from 1.30 to 1.89). The results indicate that the proposed knee-angle/hip-angle diagram is feasible and could be applied as a reliable tool in future studies aimed at assessing the acute and longterm effects of specific exercise programmes and/or pharmacological treatment in PwMS.


title: Clinical and Genetic Associations of Deep Learning-Derived Cardiac Magnetic Resonance-Based Left Ventricular Mass

abstract:
Increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH) are risk markers for adverse cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance (CMR) is the gold standard for LVM estimation, but is challenging to obtain at scale, which has limited the power of prior genetic analyses. In the current study, we performed a genome-wide association study (GWAS) of CMR-derived LVM indexed to body surface area (LVMI) estimated using a deep learning algorithm within nearly 50,000 participants from the UK Biobank. We identified 12 independent associations (1 known at TTN and 11 novel) meeting genome-wide significance, implicating several candidate genes previously associated with cardiac contractility and cardiomyopathy. Greater CMR-derived LVMI was associated with higher risk of incident dilated (hazard ratio [HR] 2.58 per 1-SD increase, 95% CI 2.10-3.17) and hypertrophic (HR 2.62, 95% CI 2.09-3.30) cardiomyopathies. A polygenic risk score (PRS) for LVMI was also associated with incident hypertrophic cardiomyopathy within a separate set of UK Biobank participants (HR 1.12, 95% CI 1.01-1.12) and among individuals in an external Mass General Brigham dataset (HR 1.18, 95% CI 1.01-1.37). In summary, using CMR-derived LVM available at scale, we have identified 12 common variants associated with LVMI (11 novel) and demonstrated that both CMR-derived and genetically determined LVMI are associated with risk of incident cardiomyopathy.

Journal Subject Termsmachine learning, left ventricular hypertrophy, genetics


title: Prevalence of Salivary IgA Reacting with SARS-CoV-2 among Japanese People Unexposed to the Virus

abstract:
While the COVID-19 pandemic caused by SARS-CoV-2 has posed a threat to public health as the number of cases and COVID-19-related deaths are increasing worldwide, the incidence of the virus infection are extremely low in Japan compared with many other countries. To explore the reason for this strange phenomenon, we hypothesized the high prevalence of "natural" secretory IgA in saliva as mucosal IgA reacting with SARS-CoV-2, and thus surveyed the positivity for, as well as levels of, such reactive salivary IgA in a cohort of Japanese people of a wide range of age. The major findings were that 95/180 (52.78 %) of overall individuals who had not been exposed to SARS-CoV-2 were positive for salivary IgA with the levels ranging from 0.002 to 3.272 ng/ml, and that there may be a negative trend in positivity for salivary IgA according to age. These results suggest a role of mucosal IgA in host defense against SARS-CoV-2 infection.

One Sentence Summary"Natural" secretory immunoglobulin A autoantibodies may play a role in mucosal defense against SARS-CoV-2.

category: dentistry and oral medicine


title: Protective effect of a first SARS-CoV-2 infection from reinfection: a matched retrospective cohort study using PCR testing data in England

abstract:
The duration of immunity after first SARS-CoV-2 infection and the extent to which prior immunity prevents reinfection is uncertain and remains an important question within the context of new variants.

Using a retrospective population-based matched observational study approach, we identified cases with a first PCR positive test between 01 March 2020 and 30 September 2020 and cases were matched by age, sex, upper tier local authority of residence and testing route to individuals testing negative in the same week (controls) by PCR. After a 90-day pre-follow up period for cases and controls, any subsequent positive tests up to 31 December 2020 and deaths within 28 days of testing positive were identified, this encompassed an essentially vaccine-free period.

There were 517,870 individuals in the matched cohort with 2,815 reinfection cases and 12,098 first infections. The protective effect of a prior SARS-CoV-2 PCR-positive episode was 78% (OR 0.22, 0.21-0.23). Protection rose to 82% (OR 0.18, 0.17-0.19) after a sensitivity analysis excluded 934 individuals with a first test between March and May and a subsequent positive test between June and September 2020.

Amongst individuals testing positive by PCR during follow-up, reinfection cases had 77% lower odds of symptoms at the second episode (adjusted OR 0.23, 0.20-0.26) and 45% lower odds of dying in the 28 days after reinfection (adjusted OR 0.55, 0.42-0.71).

Prior SARS-CoV-2 infection offered protection against reinfection in this population. There was some evidence that reinfections increased with the Alpha variant compared to the wild-type SARS-CoV-2 variant highlighting the importance of continued monitoring as new variants emerge.


title: Experimental Methods of Investigating Airborne Indoor Virus-Transmissions Adapted to Several Ventilation Measures

abstract: This study introduces a principle, which unifies two experimental methods for airborne indoor virus-transmissions adapted to several ventilation measures. A first-time comparison of mechanical/natural ventilation and air purifiers with regard to infection risks is achieved. Effortful computational fluid dynamics demand detailed boundary conditions for accurate calculations of indoor airflows, which are often unknown. Hence a suitable, simple and generalized experimental set up for identifying the spatial and temporal infection risk for different ventilation measures is required. A trace gas method is suitable for mechanical and natural ventilation with outdoor air exchange. For an accurate assessment of air purifiers based on filtration a surrogate particle method is appropriate. The release of a controlled rate of either trace gas or particles simulates an infectious person releasing virus material. Surrounding substance concentration measurements identify the neighborhood exposure. One key aspect of the study is to prove that the requirement of concordant results of both methods is fulfilled. This is the only way to ensure that the comparison of different ventilation measures described above is reliable. Two examples (a two person office, several classrooms) show how practical both methods are and how the principle is applicable for different types and sizes of rooms.


title: Connectome-wide mega-analysis reveals robust patterns of atypical functional connectivity in autism

abstract:
Neuroimaging studies on functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age- and/or sex-dependent. The study included resting-state fMRI and clinical data from the LEAP and the ABIDE I and II initiatives, of 1824 (796 with autism) participants with age range 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis.

Autism was associated with a brain-wide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior (RRB), and sensory processing. Hyperconnectivity was observed primarily between the default mode network (DMN) and the rest of the brain, and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant.

The FC alterations observed in this study, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the DMN and subcortex with the rest of the brain, do not appear to be age or sex-dependent and correlate with clinical dimensions of social difficulties, RRBs, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the three main symptom domains.

category: psychiatry and clinical psychology


title: Mutual relationships between head injury and conduct problems in children aged 9 months to 14 years in the UK Millennium Cohort Study

abstract:
BackgroundResearch suggests a link between acquired head injury and signs of conduct disorder, with a majority of findings based on retrospective reports and comparison samples. The relationship between head injuries and conduct problems and how they may influence one another during development is currently unclear. This study aimed to investigate direct and indirect associations between head injury and conduct problems through to early adolescence.

MethodsData from the UK Millennium Cohort Study was used to investigate the relationship between conduct problems as assessed by the Strengths and Difficulties Questionnaire and parent reported head injury over time, at ages 9 months, 3, 5, 7, 11 and 14 years, using a cross-lagged path analysis. This is data from 18,552 children, participating in a UK cohort study that is representative of the UK population. We included 7,041 (3,308 male) children, who had full information about head injuries and conduct problems at age 14.

ResultsWe found a mutual association between childhood head injuries and conduct problems but with distinct timings: Head injury between 5-7 years predicted greater chance of conduct problems at age 11 and 14 years, while greater conduct problems at 5 years predicted a significantly greater chance of a head injury at age 7-11 years.

ConclusionsThese findings have important implications for the timing of preventive and ameliorative interventions. Prior to school entry, interventions aiming to reduce conduct problems would appear most effective at reducing likelihood of head injuries in future years. However, equivalent interventions targeting head injuries would be better timed either as children are entering formal primary education, or soon after they have entered.


title: Efficacy of conservative physiotherapeutic approaches in hormonal-related headaches: a scoping review protocol.

abstract:
IntroductionHeadache is one of the most common and disabling conditions worldwide, as described by the World Health Organization report. The risk of suffering from headache has been described to increase from twofold to threefold in adult women compared to men, depending on the studies. These gender differences have been linked to environmental, genetic, epigenetic, and hormonal aspects. Sex hormones can enhance headaches mainly through sensitization of the trigemino-vascular system and modulation of the blood vessel factors, with significant clinical consequences. International guidelines suggest several pharmacological and non-pharmacological treatments in the management of headache disorders as acute or preventive therapies. Few studies have been conducted on the efficacy and effectiveness of therapies in managing hormonal-related headaches to date. Therefore, this scoping review (ScR) aims to summarize the evidence regarding the efficacy of conservative physiotherapeutic approaches on this topic in the domain of gender medicine, which studies sex influences on pathophysiology, clinical signs, prevention, and therapy of diseases.

Methods and analysisThe ScR will be performed following the 6-stage methodology suggested by Arksey and OMalley and the extensions to the original framework recommended by the Joanna Briggs Institute. MEDLINE, Cochrane Central, Scopus, CINHAL, Embase and PEDro databases will be searched. Additional records will be identified through searching in grey literature and the reference lists of all relevant studies. No study design, publication type, language nor date restrictions will be applied. Two reviewers will independently screen all abstracts and full-text studies for inclusion. The research team will develop a data collection form to extract the studies characteristics. A tabular and accompanying narrative summary of the information will be provided. This protocol received input from all authors who have expertise in research methodology and specific knowledge in the field.

Ethics and disseminationThis study does not require ethical approval as we will not collect personal data. It will summarize information from publicly available studies in line with the nature of the studys methodology. Regarding dissemination activities, the results of this review will be submitted for publication in a peer-reviewed journal, presented at relevant conferences in the field and disseminated through working groups, webinars and partners.

Strengths and limitations of this studyO_LIThis will be the first ScR to provide a comprehensive overview of all studies dealing with conservative physiotherapeutic approaches in hormonal-related headaches.
C_LIO_LIResults from this study will provide gender-specific and age-specific evidence of efficacy
C_LIO_LIThe results will add meaningful information for clinicians for the management of this condition and researchers to direct future research.
C_LIO_LIA robust clinical recommendation will be possibly prevented due to limitations of the available literature.
C_LI

category: rehabilitation medicine and physical therapy


title: Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma

abstract:
PurposeLymphopenia is frequently observed and is associated with poor prognosis in glioblastoma (GBM) patients. Restoring lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to amplify the total lymphocyte count (TLC), IL-7 therapy has been tried for various cancers, although the results are inconclusive. Here, we describe the clinical results of recurrent GBM treated with long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc).

MethodsThis prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Patients with recurrent GBM were enrolled to Seoul St. Marys Hospital. Primary outcomes were the safety profile and elevated total lymphocyte count (TLC). Secondary outcomes were overall survival (OS) and progression-free survival (PFS). The duration of median follow-up was 372.6 days (range 98-864 days).

ResultsAmong 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. The mean TLC of enrolled patients after the first treatment with rhIL-7-hyFc was significantly increased from 1,131 cells/mm3 (range 330-2,989) at baseline to 4,356 cells/mm3 (range 661-22,661). Similar increase was observed in 16 of 18 patients (88.8%), only after the first treatment of rhIL-7-hyFc. TLCs of these patients were maintained higher while rhIL-7-hyFc was repeatedly administered. Most common adverse events were injection sites reactions (64.7%) including urticaria and itching sensation, however, there were no serious adverse events more than grade III. Median OS and PFS were 378 days (range 107-864 days) and 231 days (55-726 days), respectively.

ConclusionOur study first reports that IL-7 immunotherapy can restore lymphopenia and maintain TLC with various salvageable chemotherapies in recurrent GBM patients without serious adverse toxicities. This outcome warrants further larger and randomized clinical trials to validate the clinical benefits of rhIL-7-hyFc for GBM patients.


title: Identifying healthy individuals with Alzheimer neuroimaging phenotypes in the UK Biobank

abstract: Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimers disease (AD) in particular, to identify populations suitable for preventive and early disease modifying trials. Evidence from genetic studies suggest the neurodegeneration of Alzheimers disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be detected in sporadic disease. To address this challenge we train a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD-score representing the probability of AD using structural MRI data in the Alzheimers Disease Neuroimaging Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real world dataset of the National Alzheimers Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80), and demonstrate correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimers disease. This cohort have a cognitive profile in keeping with Alzheimers disease, with strong evidence for poorer fluid intelligence, and with some evidence of poorer performance on tests of numeric memory, reaction time, working memory and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimers disease.


title: Genetic background of grey matter brain networks related to attention-deficit/hyperactivity disorder

abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder and is associated with structural grey matter differences in the brain. We investigated the genetic background of some of these brain differences in a sample of 899 adults and adolescents consisting of individuals with ADHD and healthy controls. Previous work in an overlapping sample identified three ADHD-related grey matter brain networks located in areas of the superior, middle, and inferior frontal gyrus as well as the cerebellar tonsil and culmen. We associated these brain networks with protein coding genes using a statistical stability selection approach. We identified ten genes, the most promising of which were NR3C2, TRHDE, SCFD1, GNAO1, and UNC5D. These genes are expressed in brain and linked to neuropsychiatric disorders including ADHD. With our results we aid in the growing understanding of the aetiology of ADHD from genes to brain to behaviour.


title: Potential uses of AI for perioperative nursing handoffs: a qualitative study.

abstract:
ObjectiveSituational awareness and anticipatory guidance for nurses receiving a patient after surgery are key to patient safety. Little work has defined the role of artificial intelligence (AI) to support these functions during nursing handoff communication or patient assessment. We used interviews and direct observations to better understand how AI could work in this context.

Materials and Methods58 handoffs were observed of patients entering and leaving the post- anesthesia care unit at a single center. 11 nurses participated in semi-structured interviews. Mixed inductive-deductive thematic analysis extracted major themes and subthemes around roles for AI supporting postoperative nursing.

ResultsFour themes emerged from the interviews: (1) Nurse understanding of patient condition guides care decisions, (2) Handoffs are important to nurse situational awareness; problem focus and information transfer may be improved by AI, (3) AI may augment nurse care decision making and team communication, (4) User experience and information overload are likely barriers to using AI. Key subthemes included that AI-identified problems would be discussed at handoff and team communications, that AI-estimated elevated risks would trigger patient re- evaluation, and that AI-identified important data may be a valuable addition to nursing assessment.

Discussion and ConclusionMost research on postoperative handoff communication relies on structured checklists. Our results suggest that properly designed AI tools might facilitate postoperative handoff communication for nurses by identifying elevated risks faced by a specific patient, triggering discussion on those topics.

LAY SUMMARYNurses caring for patients after surgery make many decisions about what complications to look for and how to treat issues that arise. They rely on handoffs from prior providers to understand the patients background, events, and plans so far. We observed nurse handoffs after surgery where operating room nurses transfer information and their care responsibility to postoperative unit nurses to ensure care continuity. We also interviewed nurses to ask if and how artificial intelligence (AI) might help them focus their handoff communication on likely problems and generally understand the patient. Our participants stated that if AI identified likely issues, they would discuss those topics in handoff, communicate about those problems with physicians, and modify their monitoring and treatment to the level of risk faced by the patient. This finding runs against most research on improving communication, which focuses on checklists of topics to discuss. Most uses of AI for nurses focus on making specific to-do recommendations and documentation reminders and search, but we find that nurses would benefit from AI which focuses more on their understanding of the patients condition. These findings have major implications for the application of AI support for nurses.

category: health informatics


title: Molecular surveillance reveals widespread colonisation by carbapenemase and extended spectrum beta-lactamase producing organisms in neonatal units in Kenya and Nigeria

abstract:
ObjectivesNeonatal sepsis, a major cause of death amongst infants in sub-Saharan Africa, is often gut derived. Impairments in immunity and the gut barrier in sick neonates allow colonisation by opportunistic pathogens such as Enterobacteriaceae to progress to blood stream infection. Colonisation by Enterobacteriaceae producing extended spectrum beta-lactamase (ESBL) or carbapenemase enzymes is particularly problematic and can lead to antimicrobial-resistant (AMR) or untreatable infections. We sought to explore the rates of colonisation by ESBL or carbapenemase producers and their genotypes in two neonatal units (NNUs) in West and East Africa.

MethodsStool and rectal swab samples were taken at multiple timepoints from newborns admitted to the NNUs at the University College Hospital, Ibadan, Nigeria and the Jaramogi Oginga Odinga Teaching and Referral Hospital, Kisumu, western Kenya. Samples were tested for ESBL and carbapenemase genes using a previously validated qPCR assay with high resolution melt analysis. Kaplan-Meier survival analysis was used to examine colonisation rates at both sites.

ResultsA total of 119 stool and rectal swab samples were taken from 42 infants admitted to the two NNUs. Six (14.3%) infants were extremely preterm (gestation <28 weeks), 19 (45.2%) were born by Caesarean section and 3 (8.6%) mothers were HIV positive. Median (IQR) duration of admission was 12.5 (5-26) days and 12 (28.6%) infants died. Overall, colonisation with ESBL (37 infants, 89%) was more common than with carbapenemase producers (26, 62.4%; P = 0.093). Median survival time before colonisation with ESBL organisms was 7 days and with carbapenemase producers 16 days (P=0.035). The majority of ESBL genes detected belonged to the CTX-M-1 (36/38; 95%), and CTX-M-9 (2/36; 5%) groups. The most prevalent carbapenemase was blaNDM (27/29, 93%). Single blaVIM (1/32, 3%) and blaOXA-48 genes (1/32, 3%) were also detected.

ConclusionsGut colonisation of neonates by AMR organisms was common and occurred rapidly in NNUs in Kenya and Nigeria. Active surveillance of colonisation will improve the understanding of AMR in these settings and guide infection control and antibiotic prescribing practice to improve clinical outcomes.

HighlightsO_LIColonisation with extended spectrum beta-lactamase (ESBL) or carbapenemase producing bacteria was common in two neonatal units in Kenya and Nigeria
C_LIO_LIESBL colonisation occurred in 89% of neonates, with a median colonisation time of 7 days
C_LIO_LIColonisation with carbapenemase producers occurred in 62% of neonates, with a median time to colonisation of 16 days
C_LIO_LIThe most common ESBL genes detected were of the CTX-M-1 family, whilst the most common carbapenemase detected was blaNDM
C_LI

category: infectious diseases


title: Durability and cross-reactivity of SARS-CoV-2 mRNA vaccine in adolescent children

abstract: Emergent SARS-CoV-2 variants and waning humoral immunity in vaccinated individuals have resulted in increased infections and hospitalizations. Children are not spared from infection nor complications of COVID-19, and the recent recommendation for boosters in individuals ages 12 years or older calls for broader understanding of the adolescent immune profile after mRNA vaccination. We tested the durability and cross-reactivity of anti-SARS-CoV-2 serologic responses over a six-month time course in vaccinated adolescents against the SARS-CoV-2 wild type and Omicron antigens. Serum from 77 adolescents showed that anti-Spike antibodies wane significantly over 6 months. After completion of a two-vaccine series, cross-reactivity against Omicron-specific receptor-binding domain (RBD) was seen. Evidence of waning mRNA-induced vaccine immunity underscores vulnerabilities in long-term pediatric protection against SARS-CoV-2 infection, while cross-reactivity highlights the additional benefits of vaccination. Characterization of adolescent immune signatures post-vaccination will inform guidance on vaccine platforms and timelines, and ultimately optimize immunoprotection of children.


title: Reconstructing transmission chains of SARS-CoV-2 amid multiple outbreaks in a geriatric acute-care hospital

abstract:
BackgroundThere is ongoing uncertainty regarding transmission chains and the respective roles of healthcare workers (HCWs) and elderly patients in nosocomial outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in geriatric settings.

MethodsWe performed a retrospective cohort study including patients with nosocomial coronavirus disease 2019 (COVID-19) in four outbreak-affected wards, and all SARS-CoV-2 RT-PCR positive HCWs from a Swiss university-affiliated geriatric acute-care hospital that admitted both Covid-19 and non-Covid-19 patients during the first pandemic wave in Spring 2020. We combined epidemiological and genetic sequencing data using a Bayesian modelling framework, and reconstructed transmission dynamics of SARS-CoV-2 involving patients and HCWs, in order to determine who infected whom. We evaluated general transmission patterns according to type of case (HCWs working in dedicated Covid-19 cohorting wards: HCWcovid; HCWs working in non-Covid-19 wards where outbreaks occurred: HCWoutbreak; patients with nosocomial Covid-19: patientnoso) by deriving the proportion of infections attributed to each type of case across all posterior trees and comparing them to random expectations.

ResultsDuring the study period (March 1 to May 7, 2020) we included 180 SARS-CoV-2 positive cases: 127 HCWs (91 HCWcovid, 36 HCWoutbreak) and 53 patients. The attack rates ranged from 10-19% for patients, and 21% for HCWs. We estimated that there were 16 importation events (3 patients, 13 HCWs) that jointly led to 16 secondary cases. Most patient-to-patient transmission events involved patients having shared a ward (97.6%, 95% credible interval [CrI] 90.4-100%), in contrast to those having shared a room (44.4%, 95%CrI 27.8-62.5%). Transmission events tended to cluster by type of case: patientnoso were almost twice as likely to be infected by other patientnoso than expected (observed:expected ratio 1.91, 95%CrI 1.08 - 4.00, p = 0.02); similarly, HCWoutbreak were more than twice as likely to be infected by other HCWoutbreak than expected (2.25, 95%CrI 1.00-8.00, p = 0.04). The proportion of infectors of HCWcovid were as expected as random. The proportions of high transmitters ([≥]2 secondary cases) were significantly higher among HCWoutbreak than patientnoso in the late phases (26.2% vs. 13.4%, p<2.2e-16) of the outbreak.

ConclusionsMost importation events were linked to HCW. Unexpectedly, transmission between HCWcovid was more limited than transmission between patients and HCWoutbreak. This highlights gaps in infection control and suggests possible areas of improvements to limit the extent of nosocomial transmission.


title: Towards definitions of critical illness and critical care using concept analysis

abstract:
ObjectiveAs "critical illness" and "critical care" lack consensus definitions, this study aims to explore how the concepts are used, describe their defining attributes and propose potential definitions.

DesignWe used the Walker and Avant stepwise approach to concept analysis. The uses and definitions of the concepts were identified through a scoping review of the literature and an online survey of 114 global clinical experts. Through content analysis of the data we extracted codes, categories and themes to determine the concepts defining attributes and we proposed potential definitions. To assist understanding, we present model, related and contrary cases concerning the concepts, we identified antecedents and consequences to the concepts, and defined empirical referents.

ResultsThe defining attributes of critical illness were a high risk of imminent death; vital organ dysfunction; requirement for care to avoid death; and potential reversibility. The defining attributes of critical care were the identification, monitoring and treatment of critical illness; vital organ support; initial and sustained care; any care of critical illness; and specialized human and physical resources. Our proposed definition of critical illness is, "a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and the potential for reversibility". Our proposed definition of critical care is, "the identification, monitoring and treatment of patients with critical illness through the initial and sustained support of vital organ functions."

ConclusionThe concepts critical illness and critical care lack consensus definitions and have varied uses. Through concept analysis of uses and definitions in the literature and among experts we have identified the defining attributes of the concepts and propose definitions that could aid clinical practice, research, and policy making.

Strengths and Limitations of the StudyO_LIThis concept analysis is the first study to systematically describe the uses and definitions of the concepts critical illness and critical care
C_LIO_LIThe study uses a scoping review of the literature and input from over one hundred clinical experts from diverse settings globally to identify the defining attributes and provide proposed definitions of the concepts
C_LIO_LISome uses and definitions of the concepts in languages other than English, in unpublished grey literature and from clinical experts not included in the study may have been missed
C_LIO_LIAs current usage of the concepts is diverse, the proposed definitions may not be universally accepted and are aimed to stimulate further discussion
C_LI

category: intensive care and critical care medicine


title: Subtypes of early childhood caries predict future caries experience

abstract:
ObjectivesTo test whether postulated subtypes of early childhood caries (ECC) are predictive of subsequent caries experience in a population-based cohort of Swedish children.

MethodsThe study included children aged between 3 and 5 years at study entry with dental records available for at least 5 years of follow-up. Dental record data were retrieved from the Swedish Quality Registry for Caries and Periodontal disease (SKaPa) for the initial and follow-up visits. Participants who had ECC at study entry were assigned to one of five ECC subtypes (termed classes 1 to 5) using latent class modelling of tooth surface-level caries experience. Subsequent experience of caries was assessed using the decayed, missing, and filled surfaces indices (dmfs/DMFS) at follow-up visits, and compared between ECC subtypes using logistic and negative binomial regression modelling.

ResultsThe study included 128,355 children who had 3 or more dental visits spanning at least 5 years post baseline. Of these children, 31,919 had caries at the initial visit. Baseline ECC subtype was associated with differences in subsequent disease experience. As an example, 83% of children who had a severe form of ECC at age 5 went on to have caries in the permanent dentition by the end of the study, compared to 51% of children who were caries-free at age 5 (adjusted odds ratio of 4.9 for new disease at their third follow-up).

ConclusionsECC subtypes assigned at a baseline visit are associated with differences in subsequent caries experience in both primary and permanent teeth. This suggests that the development and future validation of an ECC classification can be used in addition to current prediction tools to help identify children at high risk of developing new caries lesions throughout childhood and adolescence.


title: Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response

abstract: Although insulin resistance often leads to Type 2 Diabetes Mellitus (T2D), its early stages remain often unrecognized thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual patient. To identify potential candidate genes for the prediction of diabetes risk and intervention response we linked genetic expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose (FG) and glucose infusion rate (GIR). We found that genes with a strong association to these measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied strongly between muscle and IMAT. Moreover, we discovered that individual genetic expression based classifications may differ from those classifications based predominantly on clinical parameters indicating a potential incomplete patient stratification. Out of the 15 top hit candidate genes, we identified ST3GAL2, AASS, ARF1 and the transcription factor SIN3A as novel candidates for a refined diabetes risk and intervention response prediction. Our results confirm that disease progression and a successful intervention depend on individual genetics. We anticipate that our findings may lead to a better understanding and prediction of the individual diabetes risk and may help to develop individualized intervention strategies.

category: endocrinology


title: Omicron Impact in India: An Early Analysis of the Ongoing COVID-19 Third Wave

abstract: The Omicron variant of coronavirus has caused major disruptions world-wide with countries struggling to manage the overwhelming number of infections. Omicron is found to be significantly more transmissible compared to its predecessors and therefore almost every impacted country is exhibiting new infection peaks than seen earlier. In this work, we analyze the global statistics of Omicron-impacted countries including South Africa, the United Kingdom, the United States, France, and Italy to quantitatively estimate the intensity and severity of recent waves. Next, these statistics are used to estimate the impact of Omicron in India, which is experiencing an intense third wave of COVID-19 since 28 Dec., 2021. The rapid surge in the daily number of infections, comparable to the global trends, strongly suggests the dominance of the Omicron variant in infections in India. The logarithmic regression suggests the early growth rate of infections in this wave is nearly four times that in the second wave. Another notable difference in this wave is the relatively concurrent arrival of outbreaks all across the country; the effective reproduction number (Rt) although has significant variations among different regions. The test positivity rate (TPR) also displays a rapid growth in the last 10 days in several states. Preliminary estimates with the Susceptible-Infected-Removed (SIR) model suggest that the peak in India to occur in late January 2022 with a caseload exceeding that in the second wave. Although global Omicron trends, as analyzed in this work, suggest a decline in case fatality rate and hospitalizations compared to Delta, a sudden accumulation of active infections can potentially choke the already stressed healthcare infrastructure for the next few weeks.

category: epidemiology


title: Omicron Impact in India: Analysis of the Ongoing COVID-19 Third Wave Based on Global Data


title: Epidemiology of SARS-CoV-2 infection in Italy using real-world data: methodology and cohort description of the second phase of web-based EPICOVID19 study.

abstract: Digital technologies have been extensively employed in response to the SARS-CoV-2 pandemic worldwide. This study describes the methodology of the two-phase internet-based EPICOVID19 survey, and the characteristics of the adult volunteers respondents who lived in Italy during the first (April - May 2020) and the second wave (January - February 2021) of the epidemic. Validated scales and ad-hoc questionnaires were used to collect socio-demographic, medical and behavioural characteristics, as well as information on COVID-19. Among those who provided email addresses during phase I (105,355), 41,473 participated in phase II (mean age 50.7 years {+/-} 13.5 SD, 60.6% females). After a median follow-up of ten months, 52.8% had undergone naso-pharyngeal swab (NPS) testing and 13.2% had positive result. More than 40% had undergone serological test (ST) and 11.9% were positive. Out of the 2,073 participants with at least one positive ST, 72.8% had only negative results from NPS or never performed it. These results indicate that a large fraction of individuals remained undiagnosed, possibly contributing to the spread of the virus in the community. Participatory online surveys offer a unique opportunity to collect relevant data at individual level from large samples during confinement.


title: COVID-19-related school disruptions and well-being of children and adolescents in Geneva

abstract:
BackgroundVarious studies showed the negative impact of COVID-19-related lockdowns and school closures on the well-being of children and adolescents. However, the prevalence and consequences of occasional short-term school disruptions due to COVID-19-related quarantine or isolation remain unknown. This study evaluated their impact on the well-being and stress level of children and adolescents.

MethodsIn June/July 2021, we conducted a survey selecting a representative sample of children and adolescents of a Swiss canton population. Parents of school-aged children reported information about them missing school because of COVID-19, from August 2020 to June 2021, as well as about their health-related quality of life (HRQoL) measured with the KINDL(R) scale and their stress level.

ResultsAmong the 538 participants, 216/538 (40.1%) pupils missed school at least once for COVID-19-related causes, with a total of 272 absences. We observed no relationship between the frequency of COVID-19-related absences and the HRQoL or stress level, even when stratifying by the type of absence or socio-demographic factors.

DiscussionOverall, these findings are reassuring in that quarantines and related school disruptions, which we know are a common and effective way of controlling SARS-CoV-2 transmission, did not seem to meaningfully impact children and adolescents wellbeing and stress. Finding the right balance between SARS-CoV-2 control and young populations well-being is challenging, and the current results provide additional information for decision makers.


title: Sun, Sleep, and Satisfaction: Mediating Role of Depression and Source of Endogeneity among Middle-aged and Older Adults in China

abstract:
PurposeTo examine: (i) depression as a mediator in effects of sleep duration and quality on life satisfaction (LS), (ii) source of endogeneity in self-reported data on sleep, and (iii) predictive power of sleep duration and quality on LS.

MethodsPanel data of 22,674 observations from the China Health and Retirement Longitudinal Survey (2015 & 2018) was used. Sleep was assessed with self-reported duration and quality. Depression was measured by the 10-question version of the Center for Epidemiological Survey - Depression. LS was rated by five scales. Fixed-effects ordered logit models were used to determine the effect of sleep duration and quality on life satisfaction and the mediating role of depression. We used instrumental variable strategy to explore the source of endogeneity. Information value and random forest model were used to examine the predictive power of sleep measures duration and quality.

ResultsSleep duration and quality were found to improve life satisfaction via lower depression score. Non-agricultural employed population with urban hukou (household registration) accounted for the endogeneity, but the instrument variable sunset failed the weak instrument test. Sleep measures were found to predict life satisfaction, especially for the lower life satisfaction groups.

ConclusionOur findings suggest the importance of sleep and the study of the associations between solar cues, social schedules, and sleep. Policy makers of social care of older adults might consider sleep intervention among this population.