title: Single Injection Nerve Blocks Plus IV Lidocaine Infusions as an Alternative to Continuous Nerve Blocks for Perioperative Pain Management: A retrospective review.

abstract:
PurposeContinuous nerve blocks (CNBs) and intravenous lidocaine infusions (IV Lido) represent an effective approach to perioperative pain management. We hypothesized that a single injection nerve block (SNB) plus intravenous lidocaine infusion (IV Lido) would be as effective as CNBs. Furthermore, since recently, the use of facial plane blocks are increasingly advocated, we compared CNBs vs SNBs plus IV Lido in patients undergoing erector spinae plane (ESP) and quadratus lumborum (QL) blocks for video assisted thoracic surgery (VATS) and abdominal/retroperitoneal surgeries, respectively.

Patients and MethodUsing our IRB approved registry (PRO10120146), we retrospectively reviewed the electronic record of 105 patients, including 51 patients who underwent VATS and received either single injection erector plane block (SESPB) plus IV lido or continuous erector spinae plane block (CESPB), and 54 patients who underwent major abdominal surgery and received either single injection quadratus lumborum block (SQLB) plus IV Lido or continuous quadratus lumborum block (CQLB). Demographics, verbal pain scores (0-10), and opioid consumption (morphine intravenous equivalent; MIVE), all in the context of the same multimodal approach (acetaminophen, ketamine, dexmedetomidine, and ketorolac) were collected at 24, 48, and 72 hours after surgery. Alpha was set to 0.05.

ResultsSNBs plus IV Lido were as effective as CNBs regarding pain control and total MIVE at 24, 48, or 72 hours after surgery. Subgroup analysis indicated similar findings were observed in patients who underwent VATS or major abdominal surgery.

ConclusionsThis analysis suggests that SNBs plus IV Lido are as effective as CNBs for perioperative pain management when ESP or QL blocks are used for VATS or major abdominal surgery, respectively.

category: anesthesia


title: Multi-ancestry Genome-wide Association Study of Varicose Veins Reveals Polygenic Architecture, Genetic Overlap with Arterial and Venous Disease, and Novel Therapeutic Opportunities

abstract: BackgroundVaricose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose veins risk factors, the molecular and genetic basis remains uncertain. Here, we analyzed the contribution of common genetic variants to varicose veins using data from the VA Million Veteran Program and other large multi-ancestry biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases, and dozens of anthropometric factors. Using Mendelian randomization, we prioritized novel therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling, and angiogenesis. These findings may facilitate future efforts to develop non-surgical therapies for varicose veins.

category: cardiovascular medicine


title: An Analysis Between Trump's Presidency and Health-Seeking Behaviors of African Americans in the United States

abstract:
BackgroundSlavery legally ended over 150 years ago, yet African Americans are still oppressed. The lingering effects of systemic and institutional racism are still present in all walks of life, especially in healthcare. As a result, Black patients have historically been less likely to seek preventative care and subsequently, reported lower health outcomes compared to their white counterparts. The election of Donald Trump in 2016 forced a shift in that narrative. This study aimed to investigate whether there was any correlation between changing racial preferences fueled by Trumps racist rhetoric and the health-seeking behaviors of Black patients. Through this, we explored if the number of Black patients that reported not having a primary care physician has changed, and how online search history trends researching Black physicians have also changed.

MethodsThis study utilized datasets from the Behavioral Risk Factor Surveillance System (BRFSS) and Google Trends. Pearsons correlation testing was run to establish any correlation between the number of google searches and positive health-seeking behaviors.

ResultsGoogleTrends data does support an increased popularity for the search term "black doctor near me" over the years of 2015-2018, supporting our hypothesis. Multiple logistic regression analysis was performed to determine if race, among other variables, was a significant predictor for our predetermined health indicators. The results showed race was significant in nine out of our eleven health indicators.

DiscussionDespite decades of work to minimize healthcare disparities, this study has demonstrated how much more still needs to be done. It has shown how the intersection of seemingly unrelated issues, such as politics and health, as described in this study, can drastically impact health outcomes. This study highlights the importance of targeted and equitable programming to ensure quality care for all, that can withstand political and social pressures.

category: epidemiology


title: Cell-Mediated Immune Response after COVID 19 Vaccination in Patients with Inflammatory Bowel Disease

abstract:
IntroductionMost patients with IBD mount an antibody response to mRNA COVID-19 vaccines, but few studies have evaluated the cell mediated immune response (CMIR).

MethodsWe performed a prospective study (HERCULES) to evaluate CMIR among patients with IBD and healthy controls (HC) after completion of the primary series of mRNA COVID-19 vaccines.

ResultsOne hundred 158 patients with IBD and 20 HC were enrolled. The majority (89%) of IBD patients developed a CMIR which was not different than HC (94%, p=0.6667). There was no significant difference (p=0.5488) in CMIR response between those not immunosuppressed (median 255 Spike T cells/million PBMC, IQR 146, 958) and immunosuppressed (median 377, IQR 123, 1440). There was also no correlation between antibody responses and CMIR (p=0.5215)

DiscussionMost patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes.

category: gastroenterology


title: Cannabis Smoking and Academic Achievement in Colombian High-School Students

abstract: A cross-sectional study was designed with high-school students. The studys objective was to establish the relationship between cannabis smoking and academic achievement, adjusted for clinically important depressive symptoms and family dysfunction. The authors quantified lifetime cannabis smoking, perception of academic achievement, clinically important depressive symptoms, and family dysfunction. It was computed crude association between cannabis smoking and academic achievement and adjusted by clinically important depressive symptoms and family dysfunction. A total of 1,462 students between 13 and 17 years participated in the research; 11.63% reported lifetime cannabis smoking; 30.78%, poor-fair academic achievement; 7.05%, clinically important depressive symptoms; and 76.06%, family dysfunction. The lifetime cannabis smoking was significantly associated with poor-fair academic achievement after adjusting for clinically important depressive symptoms and family dysfunction (OR = 1.61, 95%CI 1.16 - 2.24). In conclusion, lifetime cannabis smoking is related to poor-fair academic achievement among high-school students in Santa Marta, Colombia.

category: public and global health


title: Cerebral Organoids Containing an AUTS2 Missense Variant Model Microcephaly

abstract: Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband COs exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control COs. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-{beta}-Catenin signaling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of COs to uncover molecular mechanisms underlying AUTS2 syndrome.

category: neurology


title: The effect of digital-enabled multidisciplinary therapy conferences on efficiency and quality of the decision making in prostate-cancer care

abstract:
ObjectivesTo investigate the impact on efficiency and quality of pre-prostatectomy multidisciplinary therapy conferences (MDT) at Karolinska University Hospital related to the use of a digital solution compared to standard of care. Further, to explore whether gains in MDT efficiency and quality impact oncological or functional patient outcomes.

MethodsWe conducted a prospective, observational study of preoperative prostate-cancer MDT at Karolinska between February 2017 and March 2021. We compared efficiency and quality of the standard MDT and the MDT using the digital solution IntelliSpace Precision Medicine Multidisciplinary Team Orchestrator (ISPM) based on the previously used MDT-MODe approach. Clinical and patient-reported functional outcomes were derived from the medical records and the Swedish National Prostate Cancer Register (NPCR).

ResultsWhile ISPM was used during the multidisciplinary therapy conference, the time spent per patient was reduced by 24 % (p<0.001) and most of the MDT-MODe items were scored significantly higher. There was a reduction in pelvic lymph-node dissection procedures in the ISPM cohort (p=0.001) and an increased proportion of unilateral nerve-sparing procedures (p=0.005), while all other outcome-related measures were not significantly different between the two patient groups.

Discussion & ConclusionTo increase the value of the MDT, all data relevant for treatment decision need to be purposefully presented and compiled, which also enables secondary use of the data.

The use of a digital solution during preoperative MDTs for prostate-cancer decision-making at Karolinska University Hospital improved the efficiency and quality of this multidisciplinary team meeting without impacting patient outcomes.

What is already known?O_LIMultidisciplinary therapy conferences are widely used in modern cancer care.
C_LIO_LIPatients discussed in a multidisciplinary therapy conference are more likely to receive appropriate staging and treatment.
C_LIO_LIThe multidisciplinary therapy conference is time consuming and rarely digitalized or adequately structured.
C_LI

What does this paper add?O_LIThe use of a digital clinical decision support system during preoperative prostate-cancer multidisciplinary therapy conferences improved the efficiency and quality of the meetings.
C_LIO_LIThe introduction of this digital clinical decision support system was not associated with changes in oncological and functional outcomes after surgery.
C_LI

category: health systems and quality improvement


title: Immunological pathways underlying autism: Findings from Mendelian randomization and genetic colocalisation analyses.

abstract: Emerging evidence implicates the role of inflammation and immunity in autism. However, little is known about the involvement of specific immunological pathways and their causal role. In 18,381 autism cases and 27,969 controls from the PGC and the iPSYCH consortia, we investigated whether 15 cytokines implicated in the differentiation and function of CD4+ T cell subsets (TH1, TH2, TH9, TFH, TH17, TReg) could be causally linked to autism. Within a Mendelian randomization framework, we used protein quantitative trait loci (pQTLs; N=1,000-3,394) to assess the effects of genetically proxied levels of plasma cytokines on autism. We additionally used brain cortex expression quantitative trait loci (eQTLs; N= 6,601) to investigate whether genetically predicted expression of the genes encoding the cytokines of interest influence autism. We performed colocalisation to assess the possibility that the identified effects were confounded due to Linkage Disequilibrium (LD). We also assessed the possibility of reverse causation. We report consistent evidence for causal effects of genetically predicted levels of IFN-{gamma}R1, IL-12R{beta}1 (TH1), and IL-4RA, IL-5RA, IL-13RA1 (TH2) on autism. We identified brain-specific effects of genetically predicted expression of IFNGR1, IL12RB1, IL23A, which in the case of IFNGR1 and IL23A were additionally supported by evidence suggestive of colocalisation. Findings appeared unlikely to be influenced by reverse causation. Our findings are consistent with a potentially causal effect of TH1 and TH2 pathway cytokines in autism, and further research is required to elucidate the pathways via which TH1 and TH2 influence its phenotypic presentation.


title: Feasibility of a novel non-invasive swab technique for serial whole-exome sequencing of cervical tumors during chemoradiation therapy

abstract:
BackgroundClinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to develop a novel noninvasive cervical swab technique to collect tumor DNA with adequate throughput to perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT).

MethodsCervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were analyzed with whole-exome sequencing (WES) with mutation calling using a custom pipeline optimized for shallow whole-exome sequencing with low tumor purity. Tumor mutation changes over the course of treatment were profiled.

Results217 samples were collected and successfully sequenced for 70 patients. A total of 33 patients had a complete set of samples at all four time points. The mean mapping rate was 98% for all samples, and the mean target coverage was 180. Overall mutation frequency decreased during CRT with disease response but mapping rate and mean target coverage remained at >98% and >180 reads at week 5.

ConclusionThis study demonstrates the feasibility and application of a noninvasive swab-based technique for WES analysis to investigate dynamic tumor mutational changes during treatment and may be a valuable approach to identify novel genes which confer radiation resistance.

category: oncology


title: Polygenic scores in disease prediction: evaluation using the relevant performance metrics

abstract: We examine the performance of polygenic scores in screening and disease prediction using metrics which are firmly established for non-genetic tests but rarely reported in evaluations of polygenic scores. Using performance metrics in the Polygenic Score Catalog (odds and hazard ratios, area under the receiver operating characteristic curve or C-index), we calculate the sensitivity or detection rate (DR5) for polygenic score cut-offs that define a 5% false positive rate (FPR). To examine clinical and public health relevance, we use information on disease incidence to calculate the odds of being affected given a positive result (OAPR; the ratio of true to false positives) both for an individual and a population. Polygenic scores typically detect 7.6 - 16.4% (and therefore miss 83.6 - 92.4%) of affected individuals with a 5% FPR. For a polygenic score for coronary artery disease (CAD) with a DR5 of 12% (88% of cases missed), the OAPR is 1: 3.75 if used in a population with an average 10-year CAD risk of 10%, and 1: 41 in a population with an average 10-year CAD risk of 1%. For a polygenic score for breast cancer also with a DR5 of 12% and a population average 10-year risk of 1 in 65 (odds =1: 64), odds are reduced to 1: 91 for a woman with a polygenic score at the 25th centile and increased to 1: 53 for a woman with a result at the 75th centile. Analysis using the relevant metrics reveals the weak predictive performance of polygenic risk scores, which limits their effectiveness in screening and disease prevention.

category: genetic and genomic medicine


title: Longitudinal Trend Monitoring of Multiple Sclerosis Ambulation using Smartphones

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSGoalC_ST_ABSSmartphone and wearable devices may act as powerful tools to remotely monitor physical function in people with neurodegenerative and autoimmune diseases from out-of-clinic environments. Detection of progression onset or worsening of symptoms is especially important in people living with multiple sclerosis (PwMS) in order to enable optimally adapted therapeutic strategies. MS is a disease whose symptoms typically follow subtle and fluctuating disease courses, patient-to-patient, and over time. Current in-clinic assessments are often too infrequently administered to reflect longitudinal changes in MS impairment that impact daily life. This work, therefore, explores how smartphones can administer daily two-minute walking assessments to monitor PwMS physical function at home.

MethodsRemotely collected smartphone inertial sensor data was transformed through state-of-the-art Deep Convolutional Neural Networks, to estimate a participants daily ambulatory-related disease severity, longitudinally over a 24-week study.

ResultsThis study demonstrated that smartphone-based ambulatory severity outcomes could accurately estimate MS level of disability, as measured by the EDSS score (r2: 0.56,p <0.001). Furthermore, longitudinal severity outcomes were shown to accurately reflect individual participants level of disability over the study duration.

ConclusionSmartphone-based assessments, that can be performed by patients from their home environments, could greatly augment standard in-clinic outcomes for neurodegenerative diseases. The ability to understand the impact of disease on daily-life between clinical visits, through objective digital outcomes, paves the way forward to better measure and identify signs of disease progression that may be occurring out-of-clinic, to monitor how different patients respond to various treatments, and to ultimately enable the development of better, and more personalised care.

category: health informatics


title: Association of Workload and Practice of Respectful Maternity Care Among the Healthcare Providers, Before and During the COVID-19 Pandemic in South Western Nepal: A Cross-Sectional Study

abstract:
IntroductionRespectful maternity care is an approach that involves respecting womens belief, choices, emotions, and dignity during the childbirth process. As the workload among maternity care workforce affects intrapartum quality care, respectful maternity care might have also been affected, particularly during the pandemic. Thus, this study was conducted to examine the association between workload among healthcare providers and their practice of respectful maternity care, before and during the pandemic.

MethodsA cross-sectional study was conducted in South Western Nepal. A total of 267 healthcare providers from 78 birthing centers were included. Data collection was done through telephone interviews. The exposure variable was workload among the healthcare providers, and the outcome variable was respectful maternity care practice before and during the COVID-19 pandemic. Multilevel mixed-effect linear regression was used to examine the association.

ResultsThe median client-provider ratio before and during the pandemic was 21.7 and 13.0, respectively. The mean score of respectful maternity care practice was 44.5 (SD 3.8) before the pandemic, which was decreased to 43.6 (SD 4.5) during the pandemic. Client-provider ratio was negatively associated with respectful maternity care practice for both times; before (Coef. -5.16; 95% CI -8.41 to -1.91) and during (Coef. -7.47; 95% CI -12.72 to -2.23) the pandemic.

ConclusionsWhile a higher client-provider was associated with a lower respectful maternity care practice score both before and during the COVID-19 pandemic, the coefficient was larger during the pandemic. Therefore, workload among the healthcare providers should be considered before the implementation of respectful maternity care, and more attention should be given during the pandemic.


title: Abdominal Imaging Associates Body Composition with COVID-19 Severity

abstract: The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n=967) and matched controls (n=913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.

category: infectious diseases


title: Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection

abstract:
BackgroundCommunity-directed treatment with 150 {micro}g/kg ivermectin (CDTI), the current control strategy, is insufficient for eliminating Onchocerca volvulus transmission across sub-Saharan Africa. Our study in CDTI-naive areas in Nord Kivu and Ituri (Democratic Republic of the Congo (DRC), Lofa County (Liberia) and Nkwanta district (Ghana) showed that a single 8 mg moxidectin dose reduced skin microfilariae density (microfilariae/mg skin, SmfD) better and for longer than a single 150{micro}g/kg ivermectin dose.

Methodology/Principal FindingsWe analysed drug efficacy by study area and pre-treatment SmfD (intensity of infection, IoI). Four and three IoI categories were defined for across-study and by-study area analyses, respectively. We used a general linear model to analyse SmfD 1, 6, 12 and 18 months post-treatment, a logistic model to determine the odds of undetectable SmfD from month 1 to month 6 (UD1-6), month 12 (UD1-12) and month 18 (UD1-18), and descriptive statistics to quantitate inter-interindividual response differences. Twelve months post-treatment, treatment differences were 92.9%, 90.1%, 86.8% and 84.5% in Nord Kivu, Ituri, Lofa and Nkwanta, and 74.1%, 84.2%, 90.0% and 95.4% for participants with SmfD 10-20, [≥]20-<50, [≥]50-<80, [≥]80, respectively. Ivermectins efficacy was lower in Ituri and Nkwanta than Nord Kivu and Lofa (p[≤]0.002) and moxidectins efficacy lower in Nkwanta than Nord Kivu, Ituri and Lofa (p<0.006). Odds ratios for UD1-6, UD1-12 or UD1-18 after moxidectin versus ivermectin treatment exceeded 7.0. Suboptimal response (SmfD 12 months post-treatment >40% of pre-treatment SmfD) occurred in 0%, 0.3%, 1.6% and 3.9% of moxidectin and 12.1%, 23.7%, 10.8% and 28.0% of ivermectin treated participants in Nord Kivu, Ituri, Lofa and Nkwanta, respectively.

Conclusions/significanceThe benefit of moxidectin vs ivermectin treatment increased with pre-treatment IoI. The possibility that parasite populations in different areas have different drug susceptibility without prior ivermectin selection pressure needs to be considered and further investigated.

Author SummaryOnchocerciasis or river blindness is a parasitic disease primarily in sub-Saharan Africa and Yemen. It can cause debilitating morbidity including severe itching, skin changes, visual impairment and even blindness. Many years of control efforts, today primarily based on mass administration of ivermectin (MDA) in endemic communities, have reduced morbidity and the percentage of infected individuals so that elimination of parasite transmission is now planned. WHO estimated that in 2020 more than 239 million people required MDA. Ivermectin may not be sufficiently efficacious to achieve elimination everywhere. Our study in areas in Liberia, Ghana and the Democratic Republic of the Congo where MDA had not been implemented yet showed that moxidectin reduced parasite levels in the skin better and for longer than ivermectin. Here we show that people with higher numbers of parasites in the skin benefit more from moxidectin treatment than those with lower numbers and that the efficacy of ivermectin and moxidectin differs between study areas. Provided WHO and countries include moxidectin in guidelines and policies, this information could help decisions on when and where to use moxidectin.


title: Avoiding false positive SARS-CoV-2 rapid antigen test results with point-of-care molecular testing on residual test buffer

abstract:
ObjectivesAntigen-based rapid diagnostic tests (Ag-RDTs) have been widely used for the detection of SARS-CoV-2 during the Covid-19 pandemic. In settings of low disease prevalence, such as asymptomatic community testing, national guidelines recommend molecular confirmation of positive Ag-RDT results. This often requires patients to be recalled for repeat specimen recollection and subsequent testing in reference laboratories. This project assessed the use of a point-of-care molecular method for SARS-CoV-2 detection on-site at a volunteer-led asymptomatic community testing site, using the residual test buffer (RTB) from positive Ag-RDTs.

MethodsThe Abbott COVID-19 ID NOW assay was performed on RTB from two Ag-RDTs: the Abbott Panbio COVID-19 Ag Rapid Test Device and the BTNX Rapid Response COVID-19 Antigen Rapid Test Device. All RTBs were tested using real-time RT-PCR at a reference laboratory using the ThermoFisher TaqPath COVID-19 Combo kit which was used to assign positive Ag-RDTs results as true or false positives. Analytical specificity of the ID NOW was assessed with a panel of various respiratory organisms.

ResultsOf 419 positive Ag-RDTs from 5148 tests performed, ID NOW testing of the RTB was positive in 100% of the samples characterized as true positives by RT-PCR. No SARS-CoV-2 detections by ID NOW were observed from 10 specimens characterized as false positive Ag-RDTs, or from contrived specimens with various respiratory organisms.

ConclusionsThe use of on-site molecular testing on RTB provides a suitable option for rapid confirmatory testing of positive Ag-RDTs, thereby obviating the need for specimen recollection for molecular testing at local reference laboratories.


title: SARS-CoV-2 seroprevalence, vaccination, and hesitancy in agricultural workers in Guatemala

abstract:
BackgroundDuring the COVID-19 pandemic, serological tests to screen populations have provided better estimates of the cumulative incidence of infection. This study evaluated the seroprevalence of SARS-CoV-2 in agricultural workers in rural Guatemala, their COVID-19 vaccine uptake and vaccination attitudes.

MethodsA cross-sectional study was undertaken from August to November of 2021, in agricultural workers at a sugar plantation in Guatemala. A questionnaire was used to collect demographic, previous COVID-19 infection, vaccination, and attitudes toward vaccination. Serological testing was performed to detect SARS-CoV-2 IgM and IgG.

ResultsOf the 4,343 study participants, 1,279 (29.4%) were seropositive for SARS-CoV-2 compared to 2.3% who reported previous COVID-19 infection. COVID-19 vaccine coverage was 85% for the first dose and 21.9% for second dose. Vaccine refusal was 0.6%, and 13.9% expressed some degree of vaccine hesitancy. Vaccine hesitant workers or those refusing were less likely to have had the COVID-19 vaccine. Main reasons to get the vaccine were to protect family, coworkers, and community.

ConclusionAgricultural workers in countries like Guatemala have suffered a high incidence of asymptomatic and undetected SARS-CoV-2 infection. Most have received the COVID-19 vaccine, but there are moderate degrees of vaccine hesitancy that require better public health information to overcome it.


title: SARS-CoV-2 Infection Breakthrough among the non-vaccinated and vaccinated: a Real World Evidence study based on Big Data

abstract:
BackgroundSARS-CoV-2 infection after vaccination can occur because COVID-19 vaccines do not offer 100% protection. The aim of this study was to assess vaccination coverage among people nasopharyngeal swabs, disease symptoms and type of hospitalisation (Intensive Care Unit) between the non-vaccinated and the effective dose vaccinated and to evaluate vaccination trend over time.

MethodsA retrospective cohort study was carried out among people tested positive for COVID-19 in Campania Region using collected information from Health Information System of Campania Region (Sinfonia).

The status of vaccination was assess according to the following timetable: "non-vaccinated"; "Ineffective dose" vaccination; "Effective dose" vaccination.

Univariate and multivariate logistic regression models were conducted to evaluate the association between Intensive Care Unit (ICU) to COVID-19 and gender, age groups and vaccine.

To determine vaccine coverage in subjects who received an effective dose, trend changes over time were investigated using segmented linear regression models and breakpoints estimations.

Vaccination coverage was assessed by analysing the trend in the percentage of covid 19 positive subjects in the 9 months after vaccination with an effective dose stratified by age group and type of vaccine. Statistical analyses were performed using R platform

ResultsA significant association with the risk of hospitalisation in Intensive Care Unit was the vaccination status of the subjects: subjects with ineffective dose (adjusted OR: 3.68) and subjects no-vaccination (adjusted OR: 7.14) were at three- and seven-times higher risk of hospitalisation in Intensive Care Unit, respectively, than subjects with an effective dose.

Regarding subjects with an effective dose of vaccine, the vaccines ability to protect against infection in the months following vaccination decreased.

The first breakpoints is evident five months after vaccination ({beta} =1.441, p<0.001). This increase was most evident after the seventh month after vaccination ({beta} =3.110, p<0.001).

ConclusionsCOVID19 vaccines protect from symptomatic infection by significantly reducing the risk of ICU hospitalization for severe disease. However, it seems they have trend to decrease their fully protection against SARS-COV-2 after five months regardless age, sex or type of vaccine. Therefore it seems clear that those not undergoing vaccine had higher risk to develop clinically significant disease and being at risk of ICU stay. Thus, considering highest percentage of asymptomatic patients and that few data about their capacity to transmit SARS-CoV-2, third dose vaccination should be introduced as soon as possible while awaiting antivirals.Finally, a surveillance approach based on the use of integrated BIG Data system to match all clinical conditions too, offer a precise and real analysis with low incidence of errors in the categorization of subjects.


title: Exploring facilitators for a transition from alternative and complementary therapies to evidence-based treatments in Ugandan first-episode psychosis patients.

abstract:
IntroductionMost patients with psychotic disorders in Africa initially use alternative and complementary therapies leading to delays accessing evidence-based treatments. This delay, known as the duration of untreated psychosis (DUP), is associated with suboptimal response and reduced efficacy in short-term and long-term outcomes. In this study, we explore facilitators for transitioning from alternative and complementary therapies to evidence-based treatments for psychotic disorders, comparing these facilitators between patients and their caregivers.

MethodsThe study was conducted at Butabika hospital in Kampala, Uganda. Participants included patients with first-episode psychosis who had used alternative and complementary therapies and their caregivers. An exploratory qualitative design using in-depth interviews was performed with thematic analysis used to analyze the data.

ResultsWe interviewed eight patients and eight caregivers. The key themes that led to a switch were the high cost of alternative therapies, a desire to know the cause of the illness, seeking better care and the influence of friends and community members. Themes were similar among the participants and their caregivers except for stigma, which was only found among the caregivers.

ConclusionsThe reasons for transitioning from alternative and complementary therapies to evidence-based treatments are similar between patients and caregivers, except for stigma that is a more important factor for transition among caregivers. Since this was an exploratory study, additional research with a larger sample and more diverse population would enable a deeper understanding of these factors and guide the development of interventions to reduce DUP and improve outcomes for psychotic disorders.

category: psychiatry and clinical psychology


title: The immune profile of Major Dysmood Disorder: proof of concept and mechanism using the precision nomothetic psychiatry approach

abstract: Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class namely Major Dysmood Disorder, a new pathway phenotype namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMDs features and IRS, CIRS, M1, T helper (Th)1, Th2, Th17, Tregulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 g/mL of PHA and 25 g/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into one a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS / CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase triggered STAT protein phosphorylation, TLR/NF-{kappa}B, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMDs heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.


title: An atlas of trait associations with resting-state and task-evoked human brain functional architectures in the UK Biobank

abstract: medRxiv has withdrawn this manuscript because it was submitted and made public without the full consent of all the authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.


title: LABELLING HUMAN KINEMATICS DATA USING CLASSIFICATION MODELS

abstract: The goal of this study is to develop a classification model that can accurately and efficiently label human kinematics data. Kinematics data provides information about the movement of individuals by placing sensors on the human body and tracking their velocity, acceleration and position in three dimensions. These data points are available in C3D format that contains numerical data transformed from 3D data captured from the sensors. The data points can be used to analyse movements of injured patients or patients with physical disorders. To get an accurate view of the movements, the datasets generated by the sensors need to be properly labelled. Due to inconsistencies in the data capture process, there are instances where the markers have missing data or missing labels. The missing labels are a hindrance in motion analysis as it introduces noise and produces incomplete datapoints of sensors positioning in 3 dimensional space. Labelling the data manually introduces substantial effort in the analysis process. In this paper, we will describe approaches to pre-process the kinematics data from its raw format and label the data points with missing markers using classification models.

category: rehabilitation medicine and physical therapy


title: Gestational SARS-CoV-2 infection is associated with placental expression of immune and trophoblast genes

abstract:
IntroductionMaternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy.

MethodsWe performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fishers exact tests, Spearman correlations and linear regression models.

ResultsThe median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term ([≥]37 weeks), and gestational age at delivery did not differ between the SARS-CoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants.

DiscussionSARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring.

category: sexual and reproductive health


title: Three-month follow-up of heterologous vs homologous third vaccination in kidney transplant recipients

abstract:
ImportanceResponse to SARS-CoV-2 vaccines in kidney transplant recipients (KTR) is severely reduced. Heterologous 3rd vaccination combining mRNA and vector vaccines did not increase seroconversion at four weeks after vaccination but evolution of antibody levels beyond the first month remain unknown.

ObjectiveTo assess changes in antibody response following a 3rd vaccination with mRNA or vector vaccine in KTR from month one to month three after vaccination.

Design, Setting and ParticipantsThree-month follow-up (pre-specified secondary endpoint) of a single-center, single-blinded, 1:1 randomized, controlled trial on 3rd vaccination against SARS-CoV-2 in 201 KTR who did not develop SARS-CoV-2 spike protein antibodies following two doses of an mRNA vaccine.

Intervention(s)mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as 3rd SARS-CoV-2 vaccine

Main Outcomes and MeasuresMain outcome was seroconversion at the second follow-up between 60-120 days after the 3rd vaccination. Subsequently, higher cut-off levels associated with neutralizing capacity and protective immunity were applied (i.e. >15, >100, >141 and >264 BAU/mL). In addition, trajectories of antibody levels from month one to month three were analyzed. Finally, SARS-CoV-2 specific CD4 and CD8 T-cells at four weeks were compared among the 18 top responders in both groups.

ResultsA total of 169 patients were available for the three-month follow-up. Overall, seroconversion at three months was similar between both groups (45% versus 50% for mRNA and vector group, respectively; OR=1.24, 95%CI=[0.65, 2.37], p=0.539). However, when applying higher cut-off levels, a significantly larger number of individual in the vector group reached antibody levels > 141 and > 264 BAU/mL at the three-month follow-up (141 BAU/mL: 4% vs. 15% OR=4.96, 95%CI=[1.29, 28.21], p=0.009 and 264 BAU/mL: 1% vs. 10% OR=8.75, 95%CI=[1.13, 396.17], p=0.018 for mRNA vs. vector vaccine group, respectively). In line, antibody levels in seroconverted patients further increased from month one to month three in the vector group while remaining unchanged in the mRNA group (median increase: mRNA= 1.35 U/mL and vector = 27.6 U/mL, p = 0.004). Of particular note, there was no difference in the CD4 and CD8 T-cell response between the mRNA and vector vaccine group at month one.

Conclusions and RelevanceDespite a similar overall seroconversion rate at three months following 3rd vaccination in KTR, a heterologous 3rd booster vaccination with Ad26COVS1 resulted in significantly higher antibody levels in responders.

Trial RegistrationEurdraCT: 2021-002927-39

category: transplantation


title: Undergraduate Pharmacology Written Question Papers of Different Universities of Bangladesh: Analysis of One Decade

abstract:
BackgroundIt is expected that pharmacology education should prepare students as rational prescriber. Credibility of undergraduate pharmacology curricula is rather questionable in this aspect. As assessment shapes learning priorities, it is crucial to design assessment methods of pharmacology in right way to achieve the expected learning outcomes of future physicians.

Materials and MethodsThis descriptive cross-sectional study was conducted to compare the reflection of curricular objectives, content coverage and national health priorities in undergraduate pharmacology written question papers (SAQ) of different universities of Bangladesh in last 10 years (January 2010 to November 2019). Total 131 question papers were collected, and reflection of curricular objectives, content coverage and selective disease burdens were evaluated and compared.

ResultOne objective regarding factual knowledge (pharmacological effects, mechanisms of action, pharmacokinetic characteristics and adverse reactions of drugs) had significant higher weightage throughout the decade in all universities. There were statistically significant differences in weightage of reflection of five curricular objectives (p value <0.00001, 0.001, 0.003, 0.004, 0.02) among different universities. There was not a single question reflecting the ethical and legal issues involved in drug prescribing, development, manufacture and marketing in the decade in any university. Chemotherapy was the highest covered area (19.4{+/-}3.3), followed by central nervous system (16.0{+/-}3.4) and general principles of pharmacology (1 4.3{+/-}3.2) throughout the last ten years in all universities. There was statistically also significant difference among different universities in weightage of all content areas except Gastrointestinal pharmacology. Statistically significant difference (p value < 0.00001) among different universities in cardiovascular diseases burden was observed.

ConclusionCurrent study found variation in pharmacology written question papers of different universities in the aspects of reflection of curricular objectives, content coverage and cardiovascular disease burden.

category: medical education


title: A Multi-Component Telehealth Intervention to Improve Oncofertility Care Delivery among Young Cancer Patients: A Pilot Study

abstract:
PurposeOncofertility care for pediatric, adolescent, and young adult cancer patients remains under-implemented across adult and pediatric oncology settings. We pilot tested an electronic health record (EHR)-enabled multi-component oncofertility intervention (including screening, referral, and fertility consult) in an adult academic oncology program and systematically assessed intervention fit to pediatric and community oncology programs.

MethodsUsing surveys (n=33), audits (n=143), and interviews (n=21) guided by implementation science frameworks, we pilot tested the EHR-enabled intervention for oncofertility care in young cancer patients at an adult oncology program and evaluated implementation outcomes. We interviewed healthcare providers from seven regional oncology and fertility programs about intervention fit to their clinical contexts.

ResultsWe recruited 33 healthcare providers from an adult oncology setting and 15 healthcare providers from seven additional oncology and fertility settings. At the adult oncology setting, the intervention was found to be appropriate, acceptable, and feasible and improved the screening of fertility needs (from 30% pre- to 51% post-intervention), yet some patients did not receive appropriate referrals to fertility consults. Providers across all settings suggested content and context modifications, such as adding options to the intervention or allowing the screening component to pop up at a second visit, to improve and adapt the intervention to better fit their clinical care contexts.

ConclusionsWe found that the EHR-enabled intervention increased the rate of goal-concordant oncofertility care delivery at an adult oncology program. We also identified facilitators, barriers, and needed adaptations to the intervention required for implementation and scaling up across diverse oncology settings.


title: Impact of key meteorological parameters on the spread of COVID-19 in Mumbai: Correlation and Regression Analysis

abstract:
PurposeTo understand key meteorological parameters that influence the spread of COVID-19 in Mumbai, India (based on data from April 2020 - April 2021).

MethodsThe meteorological parameters chosen were Temperature, Dew Temperature, Humidity, Pressure, Wind Speed. The underlying basic relationships between meteorological parameters and COVID-19 information for Mumbai was understood using Spearmans rank correlation coefficients. After establishing basic relationships, Linear analysis and Generalized Additive Models (GAM) were used to figure out statistically significant weather parameters and model them to explain the best possible variance in the pandemic data.

ResultsA model of temperature and windspeed could explain 17.3% and 8.3% of variance in Daily new cases and Daily recoveries respectively. As for deaths occurring due to the virus, a model comprising of only pressure best explains a variance of 17.3% in the data. Non-Linear modelling based on GAM confirms the findings of linear analysis and establishes certain non-linear relationships as well.

ConclusionSARS-CoV-2 belongs to the class of Human Coronaviruses (HCoV) which show seasonality depending on weather conditions. The above article focuses on understanding the underlying relationships between SARS-CoV-2 and meteorological parameters that would help progress basic research and formulation of policies around the disease for each weather/season.

Competing interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


title: Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) Network study

abstract:
BackgroundPregnant individuals have been receiving COVID-19 vaccines following pre-authorization clinical trials in non-pregnant people. This study aimed to determine significant health events amongst pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals.

MethodsStudy participants were pregnant and non-pregnant females aged 15-49 years who had received any COVID-19 vaccine, and pregnant unvaccinated controls. Participants reported significant health events occurring within seven days of vaccination. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines.

FindingsOverall 226/5,597(4.0%) vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227/3,108(7.3%) after dose two, compared with 11/339(3.2%) pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event after dose two of mRNA-1273 (aOR 4.4,95%CI 2.4-8.3) compared to pregnant unvaccinated controls, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant females had decreased odds of a significant health event compared to non-pregnant females after both dose one (aOR 0.63,95%CI 0.55-0.72) and dose two (aOR 0.62,95%CI 0.54-0.71) of mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention.

InterpretationCOVID-19 mRNA vaccines have a good safety profile in pregnancy. Rates of significant health events were higher after dose two of mRNA-1273 compared with unvaccinated controls, with no difference when considering events leading to medical consultation. Rates of significant health events were lower in pregnant females than similarly aged non-pregnant individuals.

FundingThis work was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980 and by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force.


title: SARS-CoV-2 RNA wastewater settled solids surveillance frequency and impact on predicted COVID-19 incidence using a distributed lag model

abstract: SARS-CoV-2 RNA concentrations in wastewater settled solids correlate well with COVID-19 incidence rates (IRs). Here, we develop distributed lag models (DLMs) to estimate IRs using concentrations of SARS-CoV-2 RNA from wastewater solids and investigate the impact of sampling frequency on model performance. SARS-CoV-2 N gene and PMMoV RNA concentrations were measured daily at four wastewater treatment plants in California. Artificially reduced datasets were produced for each plant with sampling frequencies of once every 2, 3, 4, and 7 days. Sewershed-specific models that related daily N/PMMoV to IR were fit for each sampling frequency with data from mid-Nov 2020 through mid-July 2021, which included the period of time during which Delta emerged. Models were used to predict IRs during a subsequent out-of-sample time period. When sampling occurred at least once every 4 days, the in- and out-of-sample root mean square error (RMSE) changed less than 7 cases/100,000 compared to daily sampling across sewersheds. This work illustrates that real-time, daily predictions of IR are possible with small error, despite changes in circulating variants, when sampling frequency is once every 4 days or more. However, reduced sampling frequency may not serve other important wastewater surveillance use cases.


title: Who Is Hospitalized With Whom? Inpatient Contact Networks and Mixing Patterns

abstract:
ImportancePerson-to-person contact is important for the transmission of healthcare-associated pathogens. Quantifying these contact patterns is crucial for modeling disease transmission and understanding routes of potential transmission.

ObjectiveGenerate and analyze the mixing matrices of hospital patients based on their contacts within hospital units.

Design, Setting, and ParticipantsThe study was conducted in 24 hospitals in the Southeastern United States that were part of the Duke Antimicrobial Stewardship Outreach Network (DASON) between January 2015 and December 2017. There were a total of 1,569,413 patients and 299 hospital units.

Main Outcome and MeasuresThe mixing matrices of patients for each hospital unit using age, Elixhauser Score, and a measure of antibiotic exposure.

ResultsMixing matrices were calculated from a database of 24 hospitals, which included 2.9 million admission records for nearly 1.6 million patients. Some units had highly similar patterns across multiple hospitals although the number of patients might vary to a great extent. Within a period of 26 months (October 2015 and December 2017), the highest daily average is 765 patients in the ED of Hospital-12 and lowest daily average is only 2 patients in some of the smaller hospital units. For most of the adult inpatient units, frequent mixing was observed for older adult groups while outpatient units e.g. ED and Behavioral Health etc. units showed mixing between different age groups. From the mixing matrices by Elixhauser Score, we observed mixing between patients with relatively higher comorbidity index on the ICUs. Mixing matrices by Antibiotic Rank, a 4-point scale based on priority for antibiotic stewardship programs, resulted in six major distinct patterns due to the variation of the type of antibiotics used in different units.

Conclusions and RelevanceThe mixing patterns of patients both within and between hospitals followed broadly expected patterns, though with a considerable amount of heterogeneity. These patterns can be used to evaluate the appropriateness of policies and guidelines for smaller community hospitals, as well as improve the design of interventions that rely on altering patient contact patterns.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the mixing patterns among hospitalized patients who could be susceptible to infection?

FindingIn this study of 299 hospital units from 24 hospitals, we analyzed the mixing patterns between patients based on a number of variables namely Age, Antibiotic Ranks (4-point scale based on priority for antibiotic stewardships programs) and Elixhauser Comorbidity Score. While some units showed highly similar patterns across hospitals, variation has also been observed in concentration of mixing on different age groups and antibiotic usage among the patients who are coming into contact.

MeaningHow patients mix, can impact their risk of acquiring an infection. While patterns followed what was expected heuristically, there is considerable between-hospital heterogeneity, which can help in risk assessments and modeling approaches.


title: Cortico-cortical connectivity is normalised by levodopa in tremor-dominant Parkinson's disease.

abstract:
BackgroundResting tremor, which involves involuntary and rhythmic movements of one or more body parts, is the most common presenting motor symptom in Parkinsons disease. As Parkinsons disease tremor is not associated with the severity of dopaminergic cell loss in the basal ganglia, other brain regions might play a role in its pathophysiology. The supplementary motor area is one of the main targets of the basal ganglia-thalamo-cortical circuit. In turn, the supplementary motor area has direct connections with the primary motor cortex, which is important for the execution of voluntary movement.

ObjectiveThe aim of this study was to examine whether supplementary motor area-- primary motor cortex connectivity and dopaminergic neurotransmission are implicated in Parkinsons disease resting tremor.

MethodsDual-site transcranial magnetic stimulation was used to measure supplementary motor area--primary motor cortex connectivity ON and OFF levodopa medication, and resting tremor was measured using electromyography and accelerometry.

ResultsStimulating the supplementary motor area had an inhibitory influence on primary motor cortex excitability OFF levodopa, which was normalised ON levodopa. The normalisation of supplementary motor area--primary motor cortex connectivity in the ON state might be mediated by an increase in dopamine levels in the basal ganglia, which reduces nett inhibition of the motor thalamic nuclei and increases excitation of the cerebral cortex. Supplementary motor area--primary motor cortex connectivity ON medication was inhibitory rather than facilitatory in patients with the strongest resting tremor, suggesting that supplementary motor area--primary motor cortex connectivity might play an important role in resting tremor.

DiscussionThe current findings contribute to our understanding of the neural networks involved in Parkinsons disease and provide a neurophysiological basis for the development of interventions to reduce Parkinsons disease resting tremor severity.

category: pathology


title: Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population

abstract:
BackgroundGenome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants.

MethodsWe sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n=1,672).

ResultsOur analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n=314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1.

ConclusionsOur findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.


title: MRI connectivity-based spread of microglial activation in early Alzheimer's disease

abstract:
BackgroundAlzheimers disease (AD) is characterized by amyloid-{beta} (A{beta}) plaques, neurofibrillary tau tangles and neuroinflammation leading to brain functional connectivity changes and cognitive decline. There is evidence, that microglial activity is increased in AD and cognitive decline. A{beta} and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive if microglial activation follows a similar distribution pattern.

MethodsThirty-two early AD subjects and 18 age-matched healthy cognitively normal controls were included from the prospective ActiGliA study. Differences between the diagnostic groups were explored for translocator protein (TSPO) positron emission tomography (PET) microglial activation, diffusion tensor imaging (DTI) structural connectivity and magnetic resonance imaging (MRI) functional connectivity. Associations between PET microglial activation with cognitive impairment, dementia severity and MRI connectivity measures were investigated within the diagnostic groups.

ResultsAD patients showed increased TSPO PET tracer uptake bilaterally in the parahippocampal region compared to cognitively normal controls. Higher TSPO PET was associated with cognitive impairment and dementia severity in a disease stage dependent fashion. Inter-regional covariance in TSPO PET and standardized uptake value ratio (SUVR) was found to be preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation.

ConclusionNeuroinflammation in AD is associated with clinical disease presentation, and like tau pathology, microglial activation seems to spread preferentially along highly connected brain regions. These findings support the important role of microglia in neurodegeneration and suggest that disease spreading throughout the brain along vulnerable connectivity pathways could guide future interventional anti-inflammatory therapy approaches to prevent disease progression.


title: Preliminary Evidence of a Link between COVID-19 Vaccines and Otologic Symptoms

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSHypothesisC_ST_ABSThis study investigates whether U.S. Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (VAERS) data suggest an association between vertigo, tinnitus, hearing loss, Bells palsy and the COVID-19 vaccines administered in the United States.

BackgroundPublished case reports suggest a possible association between various otologic symptoms and the COVID-19 vaccines, but the only published analysis of VAERS data, which did not account for underreporting of late-appearing adverse events, found no association between hearing loss and the vaccines.

MethodsThe incidence in VAERS of vertigo, tinnitus, hearing loss, and Bells palsy associated with COVID-19 vaccinations administered between December 14, 2020 and June 7, 2021 was compared with published rates for the general population. To account for underreporting of late-appearing adverse events, incidences were calculated using only the initial part of the observation period, during which reported events spike above expected events.

ResultsThe COVID-19 vaccines were associated with statistically significant increases in the incidence of vertigo, tinnitus, hearing loss, and Bells palsy of 1877, 50, 12, and 14 cases per 100,000, respectively. In relation to the mRNA-1273 or BNT162b2 vaccines, the Ad26.COV2.S vaccine was associated with a statistically significant excess incidence of vertigo, tinnitus, and hearing loss of at least 723, 57, and 55 cases per 100,000, respectively.

ConclusionThese results suggest an association between the COVID-19 vaccines and vertigo, tinnitus, hearing loss, and Bells palsy. They also suggest that, with respect to vertigo, tinnitus, and hearing loss, the association is relatively strong for the Ad26.COV2.S vaccine.

category: otolaryngology


title: Measuring the seasonality of human contact patterns and its implications for the spread of respiratory infectious diseases

abstract: Considerable uncertainties surround the seasonality of respiratory infectious diseases. To which extent the observed seasonality is associated with biological reasons (e.g., virus survival rates, host immune dynamics) or human behavior remains unclear. Here, we investigate the association between temperature and human contact patterns using data collected through a contact diary-based survey between December 24, 2017 and May 30, 2018 in Shanghai, China. We found a significant inverse relationship between number of contacts and temperature seasonal trend (p=0.003) and temperature daily variation (p=0.009), with contacts increasing from 19.6 (95%CI: 14.9-22.2) in December to 24.4 (95%CI: 19.0-28.0) in January and declining to 10.9 (95%CI: 10.1-11.9) in May. This seasonal trend in number of contacts translates into a seasonal trend in the basic reproduction number - mean number of secondary cases generated by a typical infector in a fully susceptible population. By setting the basic reproduction number at 1.4 on December 24, weekly mean estimates showed a clear increasing trend during the fall, beginning at 1.14 (95%CI: 0.78-1.39) in October and reaching 2.02 (95%CI: 1.60-1.35) in February and then remaining below 1 in the summer. Epidemic dynamics comparable with those of seasonal influenza are obtained through model simulations when the infection is seeded during the fall; however, their dynamics become more complex when seeded after February (e.g., double peaks or no epidemic until after the summer). Our findings indicate a distinct seasonal trend among human contact patterns and highlight a behavioral mechanism contributing to the seasonality of respiratory infectious diseases.


title: Third dose of COVID-19 vaccine, CVnCoV, increased neutralizing activity against SARS-CoV-2 wild-type and Delta variant

abstract: A third dose of CVnCoV, a former candidate mRNA vaccine against SARS-CoV-2, was previously shown to boost neutralizing antibody responses against SARS-CoV-2 wild-type in adults aged 18-60 and >60 years in a phase 2a clinical study. Here we report neutralizing antibody responses to wild-type and a variant of concern, Delta, after a third dose on day (D) 57 and D180. Neutralization activity was assessed using a microneutralization assay. Comparable levels of neutralizing antibodies against wild-type and Delta were induced. These were higher than those observed after the first two doses, irrespective of age or pre-SARS-CoV-2-exposure status, indicating that the first two doses induced immune memory. Four weeks after the third dose on D180, neutralizing titers for wild-type and Delta were two-fold higher in younger participants than in older participants; seroconversion rates were 100% for wild-type and Delta in the younger group and for Delta in the older group. A third CVnCoV dose induced similar levels of neutralizing responses against wild-type virus and the Delta variant in both naive and pre-exposed participants, aligning with current knowledge from licensed COVID-19 vaccines that a third dose is beneficial against SARS-CoV-2 variants.


title: Increase in SARS-CoV-2 RBD-specific IgA and IgG Antibodies in Breast Milk from Lactating Women Following the COVID-19 Booster Vaccination

abstract: The CDC recommended a booster dose of the Pfizer-BioNTech Comirnaty (BNT162b2) COVID-19 mRNA vaccine in September 2021 for high-risk individuals. Pregnant and high-risk lactating women were encouraged to receive the booster to obtain potential prolonged protection for themselves and their infants. This study investigated the ability of the booster vaccine to increase IgA and IgG antibodies specific to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein in breast milk compared to levels pre-booster. We found a significant increase in both anti-RBD-specific IgA and IgG antibodies in breast milk following the Pfizer-BioNTech booster and this increase was present in the majority of participants at the study endpoint (60 days post-booster). These results suggest the booster enhances SARS-CoV-2 specific immunity in human breast milk, which may be protective for infants.

category: allergy and immunology


title: Increase in SARS-CoV-2 RBD-specific IgA and IgG Antibodies in Human Milk from Lactating Women Following the COVID-19 Booster Vaccination


title: Frailty in individuals with depression, bipolar disorder and anxiety disorders: longitudinal analyses of all-cause mortality

abstract:
BackgroundFrailty is a medical syndrome that is strongly associated with mortality risk, and an emerging global health burden. Mental disorders are associated with reduced life expectancy and elevated levels of frailty. In this study, we examined the mortality risk associated with frailty in individuals with a lifetime history of mental disorders compared to non-psychiatric controls.

MethodsThe UK Biobank study recruited >500,000 adults, aged 37-73, between 2006-2010. We derived the two most common albeit distinctive measures of frailty, the frailty phenotype and the frailty index. Individuals with lifetime depression, bipolar disorder or anxiety disorders were identified from multiple data sources. The primary outcome was all-cause mortality. We have also examined differences in frailty, separately by sex and age.

OutcomesAnalyses included up to 297,380 middle-aged and older adults with a median follow-up of 12.19 (IQR = 1.31) years, yielding 3,516,706 person-years of follow-up. We observed higher levels of frailty in individuals with mental disorders for both frailty measures. For key comparisons, individuals with a mental disorder had greater all-cause mortality hazards than their controls. The highest hazard ratio (3.65, 95% CI 2.40-5.54) was observed among individuals with bipolar disorder and frailty, relative to the non-frail controls.

InterpretationOur findings highlight elevated levels of frailty across three common mental disorders. The increased mortality risk associated with frailty and mental disorders represents a potentially modifiable target for prevention and treatment to improve life expectancy.

FundingBiotechnology and Biological Sciences Research Council.

category: epidemiology


title: Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study

abstract:
BackgroundIt is unclear whether receiving two COVID-19 vaccinations before SARS-CoV-2 infection reduces the risk of developing Long Covid symptoms. We examined whether the likelihood of symptoms 12 weeks after infection differed by vaccination status.

MethodsWe included COVID-19 Infection Survey participants aged 18-69 years who tested positive for SARS-CoV-2 between 26 April 2020 and 30 November 2021; we excluded participants who, before their first test-confirmed infection, had suspected COVID-19 or Long Covid symptoms, or were single-vaccinated. Participants who were double-vaccinated [≥]14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms [≥]12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants.

ResultsThe study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25).

ConclusionsCOVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.


title: Bounce backs amid continued losses: Life expectancy changes since COVID-19

abstract:
BackgroundThe COVID-19 pandemic triggered an unprecedented rise in mortality that translated into life expectancy losses around the world, with only a few exceptions. In 2021, life expectancy trends globally diverged more due to the unequal impact of the pandemic across countries, variation in the age-patterns of mortality, and differences in vaccination. We estimate life expectancy changes in 29 countries since 2020, attribute them to mortality changes by age group, and compare them to historic life expectancy shocks.

DataTotal death counts by age and sex came from the Short-term Mortality Fluctuations and Human Mortality databases. Registered COVID-19 deaths and vaccination counts by age and sex were sourced from the COVerAGE-DB database. Midyear population counts were extracted from the UN World Population Prospects database.

MethodsLife expectancy for females, males, and the total population were calculated for 29 countries for 2020 and 2021. Additionally, we calculated life expectancy deficits for 2020 and 2021 based on pre-pandemic Lee-Carter forecasts of short-term life expectancy trends. Using demographic decomposition techniques, age- and COVID-19 specific contributions to changes and deficits in life expectancy were calculated. Deficits in life expectancy in 2021 across countries were compared to country vaccination rates. 95% uncertainty intervals were derived from Poisson replications of death counts.

FindingsOut of 29 countries, 14 countries lost life expectancy in both 2020 and 2021, 12 recovered losses in 2020 but not all of them back to 2019 levels, 2 exceeded pre-pandemic life expectancy, and 1 dropped below 2019 levels only in 2021. All 29 countries had lower life expectancy in 2021 than expected had pre-pandemic trends continued. The female life expectancy advantage increased for most countries, consistent with hypotheses that females are more resilient to mortality crises than men. Life expectancy losses were moderately correlated with measures of vaccination uptake. One notable change from 2020 was that mortality at younger ages contributed more to life expectancy losses in 2021. Registered COVID-19 deaths accounted for most losses of life expectancy.

InterpretationIn 2021 we saw divergence in the impact of the pandemic on population health. While some countries saw bounce-backs from stark life expectancy losses, others experienced sustained and substantial life expectancy deficits. While COVID-19 has been the most severe global mortality shock since the Second World War, this observed heterogeneity in 2021 indicates that pathways to long-term recovery of life expectancy trends remain unclear.

FundingBritish Academys Newton International Fellowship grant NIFBA19/190679 (J.M.A., R.K.); ROCK-WOOL Foundations Excess Deaths grant (J.M.A., I.K.); Leverhulme Trust Large Centre Grant (J.M.A., L.Z., R.K., J.B.D.); European Research Council grant ERC-2021-CoG-101002587 (MOR-TAL) (J.B.D.); University of Oxford John Fell Fund (J.M.A., L.Z., R.K., J.B.D.); Estonian Research Council grant PSG 669 (H.J.).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe COVID-19 pandemic disrupted mortality trends around the world. Most high-income countries experienced life expectancy declines in 2020, and emerging evidence from low-to-middle income shows substantial losses in life expectancy with large regional variation. These analyses emphasise the impact of COVID-19 deaths and also highlight the effect of excess mortality at older ages as the main contributor to life expectancy losses, although in some countries working-age mortality also contributed substantially to life expectancy reductions. Only a few countries including Denmark, Norway, Finland, Australia, South Korea, Iceland and New Zealand did not experience life expectancy losses.

Added value of this studyWe estimate life expectancy for 29 countries in 2020/21 and assess bounce-backs versus mounting losses. We determine which age groups contributed most to life expectancy changes in 2021, and analyze how age patterns of excess mortality changed between 2020 and 2021. By projecting pre-pandemic mortality trends into 2020/21 we calculate the life expectancy deficit induced by the pandemic. We compare age-specific life expectancy deficits in 2021 against vaccination uptake by age group and further decompose the deficit into contributions from COVID-19 versus non-COVID mortality. To contextualize the magnitude of life expectancy loss, we compare the 2020/21 COVID-19 pandemic with historic mortality shocks over the 20th century. We report results for females, males and the total population.

Implications of all the available evidenceLife expectancy is an important summary measure of population health. Over the past decade, improvements in life expectancy have slowed in several countries. The COVID-19 pandemic has compounded these trends and disrupted life expectancy improvements across the globe. The pandemic increased life expectancy inequalities between countries, as life expectancy losses were higher among countries with lower pre-pandemic life expectancy. COVID-19 may be a short-term mortality shock, but it is unclear whether countries will bounce back to increasing life expectancy trends in the short- or medium-term. New variants continue the spread of SARS-CoV-2 globally. Variation in preventive measures and vaccine uptake has led to disparate mortality burdens across countries. The long-term mortality impacts of social and economic stressors due to the pandemic are not known, neither are the mortality implications of regular re-infection or Long-COVID. Going forward, it is crucial to understand how and why death rates vary across and within countries.


title: Fourth Wave of COVID-19 in India : Statistical Forecasting

abstract: The spread of COVID-19 pandemic has wave nature. This article proposes a statistical methodology to study and forecast the future waves. The methodology is applied to COVID-19 data from India to statistically forecast the occurrence of fourth wave in India. In the course of this study, the data is fitted by the mixture of Gaussian distribution, and Bootstrap methodology is used to compute the confidence interval of the time point of peak of the fourth wave. This methodology can also be used to forecast the fourth and other waves in other countries also.


title: Dynamics of the Delta and Omicron variants of SARS-CoV-2 in the United States: the battle of supremacy in the presence of vaccination, mask usage and antiviral treatment

abstract: Multiple safe and effective vaccines and antiviral drugs have been approved or authorized for use against the COVID-19 pandemic in the United States. The effectiveness of these and other intervention measures is threat-ened by the emergence of numerous SARS-CoV-2 variants of concern. We present a model for studying the transmission dynamics of two of these variants (Delta and Omicron) in the presence of vaccination, treatment of individuals with clinical symptoms of the disease and the use of face masks in the community. The model was fitted using daily case data for the COVID-19 pandemic in the United States corresponding to the period starting from when Omicron first emerged (end of November 2021) to date. It is shown, based on simulating the model with the current COVID-19 data, that the reproduction number of the Delta variant (denoted by [R]vd) is much smaller than one ([R]vd = 0.28), while that of Omicron (denoted by [R]vo) is approximately equal to unity ([R]vo = 0.96). This shows that the Delta variant has essentially died out, and that Omicron is currently the predominant variant of concern in the United States. Furthermore, if the current baseline levels of the control measures being implemented in the United States are maintained, the Omicron variant will also be on a rapid decline (towards elimination). The analysis and simulations of the calibrated model show that vaccine-derived immunity can be achieved in the United States if at least 68% of the population is fully-vaccinated with either the Pfizer or Moderna vaccine. It is shown that the COVID-19 pandemic can be eliminated in the United States by June of 2022 if the current baseline level of the proportion of individuals that is fully-vaccinated is increased by about 20%. The threshold vaccination coverage needed to achieve the vaccine-derived herd immunity decreases if the vaccination program is combined with a face mask use strategy, particularly one that emphasizes the use of moderate to high quality masks (e.g., surgical or N95 masks). Greater reduction in disease burden (in comparison to the baseline scenario) are recorded if the very high quality N95 masks are prioritized in the community, followed by the moderately-effective surgical masks and then the lowly-effective cloth masks. We also showed that having high percentage of the populace wearing the moderately-effective surgical mask is more beneficial to the community than having low percentage of the populace wearing the highly-effective N95 masks (this result does not hold for the case when cloth masks compliance is compared with that of N95 masks). However, if a certain (fixed) percentage is to give up masking, our study showed that it is more beneficial if they give up wearing surgical masks and not N95 masks (in other words, in a head-to-head comparison, N95 is always superior than surgical mask). This study showed that waning natural and vaccine-derived immunity (if considered individually) offer marginal impact on disease burden, except for the case when they wane at a much faster rate (e.g., within three months), in comparison to the baseline (estimated to be within 9 months to a year). Greater reduction or increase in disease burden is recorded if both the vaccine-derived and natural immunity wane at the same time (rather than the case when we considered only one of them varying, while the other is at baseline). For instance, if both vaccine-derived and natural immunity wane within three months, a 14% increase in the peak daily cases will be recorded, in comparison to the baseline. For this case, where immunity wanes within three months, our study predicts another (but milder) Omicron wave in the United States that peaks around July 2022 (with the peak 72% lower than the original Omicron peak). Under this (fast waning) scenario, our study suggests that a fourth dose of the two mRNA vaccines would need to be approved in the United States to aid and accelerate the prospect of SARS-CoV-2 elimination in 2022. It is shown that while the treatment of symptomatic individuals has marginal effect in reducing daily cases of SARS-CoV-2, in comparison to the baseline, it has significant impact in reducing daily hospitalizations. It is further shown that, while treatment significantly reduces hospitalization, the prospects of COVID-19 elimination in the United States is more significantly enhanced if investments in control resources are focused on mask usage and vaccination rather than on treatment.


title: The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis.

abstract: Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.


title: When mistrust in the government and scientists reinforce social inequalities in vaccination against Covid-19

abstract:
ObjectiveTo assess whether mistrust in the government and scientists reinforces social and racial inequalities in vaccination practises

DesignA follow-up of a random population-based cohort survey.

SettingIn July 2021, in France.

Participants80,971 participants aged 18 years and more.

Main outcome measuresAdjusted odds ratios of Covid-19 vaccination status (received at least one dose/ intends to get vaccinated/ does not know whether to get vaccinated/refuses vaccination) were assessed using multinomial regressions to test associations with social and mistrust factors and to study how these two factors interacted with each other.

ResultsIn all, 72.2% were vaccinated at the time of the survey. The population of unvaccinated people was younger, less educated, had lower incomes, and more often belonged to racialised minorities, as compared to vaccinated people. Mistrust of government and scientists to curb the spread of the epidemic were the factors most associated with refusing to be vaccinated: OR=8.86 (7.13 to 11.00) for the government and OR=9.07 (7.71 to 10.07) for scientists, compared to vaccinated people. Mistrust was more prevalent among the poorer which consequently reinforced social inequalities in vaccination. The 10% poorest who did not trust the government reached an OR of 16.2 (11.9 to 22) for refusing to be vaccinated compared to the 10% richest who did.

ConclusionThere is a need to develop depoliticised outreach programmes targeted at the most socially disadvantaged groups, and to design vaccination strategies conceived with people from different social and racial backgrounds to enable them to make fully informed choices.


title: Monitoring peripheral hemodynamic response to changes in blood pressure via photoacoustic imaging.

abstract: Chronic wounds and amputations are common in chronic kidney disease patients needing hemodialysis (HD). HD is often complicated by drops in blood pressure (BP) called intra-dialytic hypotension. Whether intra-dialytic hypotension is associated with detectable changes in foot perfusion, a risk factor for wound formation and impaired healing remains unknown. Photoacoustic (PA) imaging is ideally suited to study perfusion changes. We scanned the feet of 20 HD and 11 healthy subjects. HD patients were scanned before and after a dialysis session whereas healthy subjects were scanned twice at rest and once after a 10 min exercise period while BP was elevated. Healthy (r=0.70, p<0.0001) and HD subjects (r=0.43, p<0.01) showed a significant correlation between PA intensity and systolic BP. Furthermore, HD cohort showed a significantly reduced PA response to changes in BP compared to the healthy controls (p<0.0001). Hence showing that PA can monitor hemodynamic changes due to changes in BP.

category: radiology and imaging


title: Resident microbes shape the vaginal epithelial glycan landscape

abstract: Epithelial cells are covered in carbohydrates. This glycan coat or "glycocalyx" interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including Gardnerella, produce glycosyl hydrolase enzymes. However, glycans of the vaginal epithelial surface have not been studied in detail. Here we elucidate key characteristics of the vaginal epithelial glycan landscape and determine the impact of resident microbes on the surface glycocalyx. In BV, the glycocalyx was visibly diminished. We show that the "normal" vaginal epithelium displays sialylated N- and O-glycans by biochemical and mass spectrometric analysis. In contrast, BV-epithelial cell glycans were strikingly depleted of sialic acids, with underlying galactose residues exposed on the surface. Treatment of cells from BV-negative women with recombinant Gardnerella sialidases generated BV-like glycan characteristics. Together these data provide the first evidence that the vaginal epithelial glycocalyx is attacked by hydrolytic enzymes in BV. Given the widespread structural and functional roles of sialoglycans in biology and disease, these findings may point to a shared epithelial pathophysiology underlying the many adverse outcomes associated with BV.


title: Genome-wide study on 72,298 Korean individuals in Korean biobank data for 76 traits identifies hundreds of novel loci

abstract: Genome-wide association studies (GWAS) on diverse ancestry groups are lacking, resulting in deficits of genetic discoveries and polygenic scores. We conducted GWAS for 76 phenotypes in Korean biobank data, namely Korean Genome and Epidemiology Study (KoGES, n=72,298). Our analysis discovered 2,237 associated loci, including 117 novel associations, many of which replicated in Biobank Japan (BBJ) GWAS. We also applied several up-to-date methods for genetic association tests to increase the power, discovering additional associations that are not identified in simple case-control GWAS. We evaluated genetic pleiotropy to investigate genes associated with multiple traits. Following meta-analysis of 32 phenotypes between KoGES and Biobank Japan (BBJ), we further identified 379 novel associations and demonstrated the improved predictive performance of polygenic risk scores by using the meta-analysis results. The summary statistics of 76 KoGES GWAS phenotypes are publicly available, contributing to a better comprehension of the genetic architecture of the East Asian population.


title: Long-term Durable Humoral Immune Response to Heterologous Antigenic Exposure Post six months by Natural SARS-CoV-2 Infection and Vaccination

abstract:
ImportanceBoth vaccination and natural infection lead to immunity and may augment mutual immune response against SARS-CoV-2. There is a need for an evidence-driven booster vaccination policy depending on durability of immune response.

ObjectiveTo determine the durability of humoral immune response with varying age, vaccine type, duration, and previous natural infection at least six months after complete vaccination with ChAdOx1 nCov-19 or BBV152.

DesignCross-sectional observational study conducted between November 2021 and January 2022.

SettingParticipants were drawn from a DBT COVID-19 Research Consortium cohort in Delhi National Capital Region, India.

ParticipantsWe included 2003 individuals who had completed six months after complete vaccination: (i) vaccination with ChAdOx1 nCoV-19 and aged 18-59 years, (ii) vaccination with ChAdOx1 nCoV-19 and aged [≥]60 years (iii) vaccination with BBV152 and aged 18-59 years (iv) vaccination with BBV152 and aged [≥]60 years (v) vaccination with either vaccine plus SARS-CoV-2 infection referred as those having hybrid immunity. A group of 94 unvaccinated individuals was also included for comparison.

ExposureAge, vaccination type, prior SARS-CoV-2 infection and duration from vaccination/infection.

Main Outcome(s) and Measure(s)Humoral immune response determined by anti-RBD IgG concentrations and the presence of anti-nucleocapsid IgG.

ResultsThe serum anti-RBD IgG antibodies were detected (cut-off 24 BAU/ml) in 85% participants with a median titer of 163 (IQR 73, 403) BAU/ml. In the hybrid immunity group, 97.6% [295 (IQR 128, 687) BAU/mL] tested positive for anti-RBD IgG compared to 81.3% [139 (IQR 62, 326) BAU/ml] of only vaccinated participants [{chi}2 test: p <0.001]. The median anti-RBD IgG titers were higher in the ChAdOx1 nCoV-19 versus BBV152 groups. The median anti-RBD IgG titer in the anti-nucleocapsid positive participants [326 (IQR 132, 739) BAU/ml] was significantly higher than in those without anti-nucleocapsid antibodies [131 (IQR 58, 288) BAU/ml; p <0.001]. The IgG anti-RBD antibodies was present in 85% of participants beyond a median of 8 months after complete vaccination.

Conclusions and RelevanceConsidering the wide seropositivity rates due to natural SARS-CoV-2 infection, recommendation for boosters should take into account past infections in the population.

Key pointsO_ST_ABSQuestionC_ST_ABSWhat is the extent of waning of humoral immune response in various groups of vaccinated individuals at least six months after complete vaccination with ChAdOx1 nCov-19 or BBV152 with or without prior natural infection?

FindingsCross-sectional observational study demonstrates persistence of anti-RBD IgG in 85% of participants even beyond a median of 8 months after complete vaccination. The antibody concentrations were significantly higher in those with hybrid immunity.

MeaningHumoral immunity may last longer due to heterologous antigenic exposure following vaccination and natural infection emphasizing the need for contextualizing the booster policy.


title: Quantifying antibody dynamics of severe and non-severe patients with COVID-19

abstract: COVID-19 pandemic is a major public health threat with unanswered questions regarding the role of the immune system in the severity level of the disease. In this paper, based on antibody kinetic data of patients with different disease severity, topological data analysis highlights clear differences in the shape of antibody dynamics between three groups of patients, which were non-severe, severe, and one intermediate case of severity. Subsequently, different mathematical models were developed to quantify the dynamics between the different severity groups. The best model was the one with the lowest media value of Akaike Information Criterion for all groups of patients. Although it has been reported high IgG level in severe patients, our findings suggest that IgG antibodies in severe patients may be less effective than non-severe patients due to early B cell production and early activation of the seroconversion process from IgM to IgG antibody.


title: Adverse effects of antipsychotic drugs on metabolism depend on drug dosing and feeding times

abstract: Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side effects is not well known. In these studies, we investigated the impact of time of AP dosing on the development of metabolic side effects. In mice, AP dosing at the start of the light cycle (AM) resulted in significant increase in food intake, weight gain compared with equivalent dose before the onset of darkness (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. To examine the possibility of time-dependent AP effects in humans, we conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness. Using pharmacy records to estimate the time of RIS dosing, we observed a significant association between time of dosing and severity of RIS-induced metabolic side effects. Eating within a restricted time window (Time restricted feeding/eating, TRF/TRE) has been shown in both mouse and human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions to mitigate AP-induced metabolic side effects.

category: endocrinology


title: Genomic surveillance of SARS-CoV-2 reveals emergence of Omicron BA.2 in Islamabad, Pakistan

abstract: The Omicron variant of SARS-CoV-2 has rapidly replace previous variants of SARS CoV2 around the globe and is now a major variant of concern. The genomic surveillance of Omicron variant also reveals spread of its subvariant BA.2 which has differing transmissibility in comparison to its other subvariant BA.1. BA.1 and BA.2 harbors different mutational profile. One of the important change in both the subvariants is the presence of 69-70 deletion in BA.1 and absence of this deletion in BA.2. This deletion can be used as tool for the detection of omicron sub variants using real time PCR. In the current study we have used the TaqPath COVID-19 PCR kit for the detection of 69-70 deletion followed by genotyping using SNPsig(R) SARS-CoV-2 (EscapePLEX) kit (PrimerDesign, UK) that target K417N, E484K, and P681R mutations. The samples with the amplification of spike gene and K417N were termed as probable BA.2 cases. A subset of samples (n=13) were further subjected to whole genome sequencing. The results showed all the 13 samples were of BA.2. Hence, this assay can be used as a cost effective method for the detection of omicron BA.2 variant using real time PCR in resource limiting settings. Moreover, the detection of BA.2 with highly transmissible mutations in Islamabad, Pakistan may potentially increase the number of positive cases. In that scenario, there has to be stringent genomic surveillance to understand the circulating lineages in the country.