title: A RANDOMIZED CLINICAL TRIAL OF 2-WEEK METHOTREXATE DISCONTINUATION IN RHEUMATOID ARTHRITIS PATIENTS VACCINATED WITH INACTIVATED SARS-COV-2 VACCINE

abstract:
ObjectivesTo evaluate the effect on immunogenicity and safety of 2-week methotrexate(MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in rheumatoid arthritis(RA) patients.

MethodsThis was a single-center, prospective, randomized, investigator-blinded, intervention study (#NCT04754698, CoronavRheum), including adult RA patients(stable CDAI<10, prednisone<7.5mg/day), randomized(1:1) to withdraw MTX(MTX-hold) for 2 weeks after each vaccine dose or maintain MTX(MTX-maintain), evaluated at D0, D28 and D69. Co-primary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion(SC) and neutralizing antibody(NAb) positivity at D69. Secondary outcomes were GMT and changes in disease activity scores. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and, for safety reasons, those unable to hold MTX twice(CDAI>10 at D28).

ResultsRandomization included 138 patients with 9 exclusions(5 COVID-19, 4 protocol violations). Safety evaluation included 60(MTX-hold) and 69(MTX-maintain) patients. Further exclusions consisted of 27 patients[13(21.7%) vs. 14(20.3%),p=0.848] with positive baseline IgG/NAb and 10 patients(21.3%) in MTX-hold with CDAI>10 at D28. At D69, a higher increase in SC[29(78.4%) vs 30(54.5%),p=0.019] was observed in MTX-hold(n=37) in comparison to MTX-maintain(n=55), with parallel augmentation in GMT[34.2(25.2-46.4) vs 16.8(11.9-23.6),p=0.006]. No differences were observed for NAb positivity[23(62.2%) vs 27(49.1%),p=0.217]. Longitudinal variations in disease activity scores were alike in both groups(CDAI,p=0.144; DAS28-CRP,p=0.718).

ConclusionWe provided novel data that 2-week MTX withdrawal after each vaccine dose improves anti-SARS-CoV-2 immunogenicity. The comparable longitudinal variations of disease activity in both groups suggest that discontinuation is a feasible and efficient strategy in well-controlled RA patients, and may be even safer for vaccines with longer interval between doses or single dose schedules.

FundingFAPESP/CNPq/B3-Bolsa de Valores-Brasil.


title: Mapping climate change and health into the medical curriculum: co-development of a "planetary health - organ system map" for graduate medical education

abstract:
PurposeWithin the context of a review of a Doctor of Medicine graduate curriculum, medical students partnered with faculty staff to co-develop a novel curriculum resource exemplifying the integration of planetary determinants of health into existing medical curricula.

MethodWe undertook qualitative methodologies involving a planetary health literature review and curriculum mapping exercise in three parts between April 2018 - May 2021. In part one, a student focus group sought students perceptions on opportunities for climate-change related teaching. Part two involved two 5-hour workshops that mapped planetary health principles to classical organ systems-based teaching areas. Part three consisted of curriculum mapping expert review.

ResultsParticipatory workshops involved 26 students and positioned students as leaders and partners in curriculum development alongside academics and clinicians. Final synthesis produced a comprehensive infographic rich document covering seven organ systems plus healthcares ecological footprint, the role of medical students and opportunities for applied skills and behaviours.

ConclusionsThe student-staff co-production method adopted here promotes higher order relational and extended abstract reasoning by students, the ultimate task of any higher education. This approach, and the open access resource generated, provides an integrated and novel planetary health framework, supporting students to be leaders for a sustainable future.

Practice Points[1] This project provides a methodology to overcome barriers to curriculum-wide integration of planetary determinants of health and a template to move beyond stand-alone planetary health workshops or population health case studies.
[2] Student and educator co-development of planetary health teaching and learning resources promotes higher order relational and extended abstract reasoning by students, the ultimate task of any higher education.
[3] Integrating planetary health supports emerging clinicians in all areas of medicine to be leaders for a sustainable future.

category: medical education


title: Reactogenicity of COVID-19 vaccine in hemodialysis patients: a single-center retrospective study

abstract:
IntroductionSome hemodialysis patients are reluctant to COVID-19 for the development of adverse events (AEs). The aim of this study was to verify the safety of mRNA-1273 vaccine in hemodialysis patients.

MethodsWe conducted a retrospective analysis of in-center hemodialysis patients who underwent mRNA-1273 vaccine from March 1st to April 30th, 2021. All AEs occurring after the first and the second doses were collected and classified as local or systemic.

ResultsOverall, 126 patients on chronic maintenance dialysis without a prior COVID-19 diagnosis were vaccinated with two doses of mRNA-1273 vaccine. Mean age was 68 (IQR, 54,7-76) years and 53.6% of patients were aged [≥] 65 years. During the observational period of 68 (IQR, 66-70) days, AEs occurred in 57.9% and 61.9% of patients after the first dose and second dose, respectively. The most common AEs were: injection-site pain (61.9%), erythema (4.8%), itching (4.8%), swelling (16.7%), axillary swelling/tenderness (2.4%), fever (17.5%) headache (7.9%), fatigue (23.8%), myalgia (17.5%), arthralgia (12.7%), dyspnoea (2.4%), nausea/vomiting (7.1%), diarrhoea (5.6%), shivers (4%) and vertigo (1.6%).

The rates of local AEs were similar after the first and second doses (P=0.8), whereas systemic AEs occurred more frequently after the second dose (P=0.001). Fever (P=0.03), fatigue (P=0.02) and nausea/vomiting (P=0.03) were significantly more frequent after the second dose of the vaccine. There were no age-related differences in the rate of AEs. Overall, vaccine-related AEs in hemodialysis patients seem to be lower than in the general population.

ConclusionRNA-1273 vaccine was associated with the development of transient AEs after the first (57.9%) and second doses (61.9%) in patients on chronic maintenance hemodialysis. Systemic AEs were more common after the second dose. Overall, all AEs lasted for a few days, without any apparent sequelae.

category: nephrology


title: Higher Limbic and Basal Ganglia volumes in surviving COVID-negative patients and the relations to fatigue.

abstract:
BackgroundAmong systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among  long-COVID patients. How morphometry in each group relate to work-related fatigue need to be investigated.

MethodCOVID survivors were MRI scanned two weeks after hospital discharge. We hypothesized, these survivors will demonstrate altered gray matter volume (GMV) and experience higher fatigue levels when compared to healthy controls, leading to stronger correlation of GMV with fatigue. Voxel-based morphometry was performed on T1-weighted MRI images between 46 survivors and 30 controls. Unpaired two-sample t-test and multiple linear regression were performed to observe group differences and correlation of fatigue with GMV.

ResultsThe COVID group experienced significantly higher fatigue levels and GMV of this group was significantly higher within the Limbic System and Basal Ganglia when compared to healthy controls. Moreover, while a significant positive correlation was observed across the whole group between GMV and self-reported fatigue, COVID subjects showed stronger effects within the Posterior Cingulate, Precuneus and Superior Parietal Lobule.

ConclusionBrain regions with GMV alterations in our analysis align with both single case acute patient reports and current group level neuroimaging findings. We also newly report a stronger positive correlation of GMV with fatigue among COVID survivors within brain regions associated with fatigue, indicating a link between structural abnormality and brain function in this cohort.

category: neurology


title: Identification of occupations susceptible to high exposure and risk associated with multiple toxicants in an observational study: National Health and Nutrition Examination Survey 1999-2014

abstract:
BackgroundAccording to the World Health Organization, occupational exposures to hazardous chemicals are estimated to cause over 370,000 premature annual deaths. The risks due to multiple workplace chemical exposures, and those occupations most susceptible to the resulting health effects, remain poorly characterized.

ObjectivesThe aim of this study is to identify occupations with elevated toxicant biomarker concentrations and increased health risk associated with toxicant exposures in a working US population from diverse categories of occupation. More specifically, we aim to 1) define differences in chemical exposures based on occupation description, 2) identify occupational groups with similar chemical exposure profiles, and 3) identify occupational groups with chemical biomarker levels exceeding acceptable health-based biomarker levels.

MethodsFor this observational study of 51,008 participants, we used data from the 1999-2014 National Health and Nutrition Examination Survey. We characterized differences in chemical exposures by occupational group for 129 chemicals by applying a series of generalized linear models with the outcome as biomarker concentrations and the main predictor as the occupational groups, adjusting for age, sex, race/ethnicity, poverty income ratio, study period, and biomarker of tobacco use. We identified groups of occupations with similar chemical exposure profiles via hierarchical clustering. For each occupational group, we calculated percentages of participants with chemical biomarker levels exceeding acceptable health-based guidelines.

ResultsBlue collar workers from "Construction", "Professional, Scientific, Technical Services", "Real Estate, Rental, Leasing", "Manufacturing", and "Wholesale Trade" have higher biomarker levels of toxic chemicals such as several heavy metals, acrylamide, glycideamide, and several volatile organic compounds compared to their white-collar counterparts. For these toxicants, 1-58% of blue-collar workers from these industries have toxicant concentrations exceeding acceptable levels.

DiscussionBlue collar workers have toxicant levels higher relative to their white-collar counterparts, often exceeding acceptable levels associated with noncancer effects. Our findings identify multiple occupations to prioritize for targeted interventions and health policies to monitor and reduce high toxicant exposures.

category: occupational and environmental health


title: Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants

abstract: SARS-CoV-2 infection hijacks signaling pathways and induces protein-protein interactions between human and viral proteins. Human genetic variation may impact SARS-CoV-2 infection and COVID-19 pathology; however, the role of genetic variation in these signaling networks remains uncharacterized. We studied human single nucleotide variants (SNVs) affecting phosphorylation sites modulated by SARS-CoV-2 infection, using machine learning to identify amino acid changes altering kinase-bound sequence motifs. We found 2033 infrequent phosphorylation-associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle processes and host responses, including regulators of RNA splicing and interferon response, as well as glucose homeostasis pathways with potential associations with COVID-19 co-morbidities. Certain pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs recognized by Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of infection signaling networks. Our analysis highlights potential genetic factors contributing to the variation of SARS-CoV-2 infection and COVID-19 and suggests leads for mechanistic and translational studies.

category: genetic and genomic medicine


title: Protocol for Development of a Reporting Guideline for Causal and Counterfactual Prediction Models

abstract:
IntroductionWhile there are protocols for reporting on observational studies (e.g., STROBE, RECORD), estimation of causal effects from both observational data and randomized experiments (e.g., AGREMA, CONSORT), and on prediction modelling (e.g., TRIPOD), none is purposely made for assessing the ability and reliability of models to predict counterfactuals for individuals upon one or more possible interventions, on the basis of given (or inferred) causal structures. This paper describes methods and processes that will be used to develop a reporting guideline for causal and counterfactual prediction models (tentative acronym: PRECOG).

Materials and MethodsPRECOG will be developed following published guidance from the EQUATOR network, and will comprise five stages. Stage 1 will be bi-weekly meetings of a working group with external advisors (active until stage 5). Stage 2 will comprise a scoping/systematic review of literature on counterfactual prediction modelling for biomedical sciences (registered in PROSPERO). In stage 3, we will perform a computer-based, real-time Delphi survey to consolidate the PRECOG checklist, involving experts in causal inference, statistics, machine learning, prediction modelling and protocols/standards. Stage 4 will involve the write-up of the PRECOG guideline (including its checklist) based on the results from the prior stages. In stage 5, we will work on the publication of the guideline and of the scoping/systematic review as peer-reviewed, open-access papers, and on their dissemination through conferences, websites, and social media.

ConclusionsPRECOG can help researchers and policymakers to carry out and critically appraise causal and counterfactual prediction model studies. PRECOG will also be useful for designing interventions, and we anticipate further expansion of the guideline for specific areas, e.g., pharmaceutical interventions.

category: health informatics


title: The experiences of 33 national COVID-19 dashboard teams during the first year of the pandemic in the WHO European Region: a qualitative study

abstract:
BackgroundGovernments across the WHO European Region prioritized dashboards for reporting COVID-19 data. The ubiquitous use of dashboards for public reporting is novel. This study explores the development of COVID-19 dashboards during the pandemics first year and common barriers, enablers and lessons from the experiences of teams responsible for their development.

MethodsMultiple methods were applied to identify and recruit COVID-19 dashboard teams using a purposive, quota sampling approach. Semi-structured group interviews were conducted between April- June 2021. Using elaborative coding and thematic analysis, descriptive and explanatory themes were derived from interview data. A validation workshop with study participants was held in June 2021.

ResultsEighty informants, representing 33 national COVID-19 dashboard teams across the WHO European Region participated. Most dashboards were launched swiftly in the first months of the pandemic, between February-May 2020. The urgency, intense workload, limited human resources, data and privacy constraints, and public scrutiny were common to the initial development stage. Themes related to barriers or enablers were identified pertaining to the pre-pandemic context, pandemic itself, people and processes, software, data, and users. Lessons emerged around the themes of simplicity, trust, partnership, software and data, and change.

ConclusionsCOVID-19 dashboards were developed in a learning-by-doing approach. The experiences of teams signal initial under-preparedness was compensated by high-level political endorsement, the professionalism of teams, accelerated data improvements, and immediate support of commercial software solutions. To leverage the full potential of dashboards, investments are needed at team-, national- and pan-European-level.


title: Development and Evaluation of AccuPower(R) COVID-19 Multiplex Real-Time RT-PCR Kit and AccuPower(R) SARS-CoV-2 Multiplex Real-Time RT-PCR Kit for SARS-CoV-2 Detection in Sputum, NPS/OPS, Saliva and Pooled Samples

abstract: Rapid and accurate detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for the successful control of the current global COVID-19 pandemic. The real-time reverse transcription polymerase chain reaction (Real-time RT-PCR) is the most widely used detection technique. This research describes the development of two novel multiplex real-time RT-PCR kits, AccuPower(R) COVID-19 Multiplex Real-Time RT-PCR Kit (NCVM) specifically designed for use with the ExiStation48 system (comprised of ExiPrep48 Dx and Exicycler96 by BIONEER, Korea) for sample RNA extraction and PCR detection, and AccuPower(R) SARS-CoV-2 Multiplex Real-Time RT-PCR Kit (SCVM) designed to be compatible with manufacturers on-market PCR instruments. The limit of detection (LoD) of NCVM was 120 copies/L and the LoD of the SCVM was 2 copies/mL for both the gene and the SARS-CoV-2 gene (N gene and RdRp gene). The AccuPower(R) kits demonstrated high precision with no cross reactivity to other respiratory-related microorganisms. The clinical performance of AccuPower(R) kits was evaluated using the following clinical samples: sputum and nasopharyngeal/oropharyngeal swab (NPS/OPS) samples. Overall agreement of the AccuPower(R) kits with a Food and Drug Administration (FDA) approved emergency use authorized commercial kit (STANDARD M nCoV Real-Time Detection kit, SD BIOSENSOR, Korea) was above 95% (Cohens kappa coefficient [≥] 0.95), with a sensitivity of over 95%. The NPS/OPS specimen pooling experiment was conducted to verify the usability of AccuPower(R) kits on pooled samples and the results showed greater than 90% agreement with individual NPS/OPS samples. The clinical performance of AccuPower(R) kits with saliva samples was also compared with NPS/OPS samples and demonstrated over 95% agreement (Cohens kappa coefficient > 0.95). This study shows the BIONEER NCVM and SCVM assays are comparable with the current standard confirmation assay and are suitable for effective clinical management and control of SARS-CoV-2.

category: infectious diseases


title: Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial

abstract:
BackgroundFavipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.

MethodsWe conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 deep sequencing, we assessed favipiravirs impact on mutagenesis.

ResultsFrom July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 - 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 - 1.29; sustained: HR 0.87, 95% CI 0.52 - 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.

ConclusionsOur data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

Trial registration numberNCT04346628

SummaryIn this phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or uncomplicated patients with COVID-19, we found no difference in time to shedding cessation or time to symptom resolution by treatment arm.


title: Investigating SARS-CoV-2 breakthrough infections per variant and vaccine type

abstract: Breakthrough SARS-CoV-2 infections have been reported in fully vaccinated individuals, in spite of the high efficacy of the currently available vaccines, proven in trials and real-world studies. Several variants of concern (VOC) have been proffered to be associated with breakthrough infections following immunization. In this study, we investigated 378 breakthrough infections recorded between January and July 2021 and compared the distribution of SARS-CoV-2 genotypes identified in 225 fully vaccinated individuals to the frequency of circulating community lineages in the region of South Limburg (The Netherlands) in a week-by-week comparison. Although the proportion of breakthrough infections was relatively low and stable when the Alpha variant was predominant, the rapid emergence of the Delta variant lead to a strong increase in breakthrough infections, with a higher relative proportion of individuals vaccinated with Oxford-AstraZeneca or J&J/Janssen being infected compared to those immunized with mRNA-based vaccines. A significant difference in median age was observed when comparing fully vaccinated individuals with severe symptoms (83 years) to asymptomatic cases (46.5 years) or individuals with mild-to-moderate symptoms (42 years). There was no association between SARS-CoV-2 genotype or vaccine type and disease symptoms. Interestingly, symptomatic individuals harbored significantly higher SARS-CoV-2 loads than asymptomatic vaccinated individuals and breakthrough infections caused by the Delta variant are associated with increased viral loads compared to those caused by the Alpha variant. Altogether, these results indicate that the emergence of the Delta variant might have lowered the efficiency of particular vaccine types to prevent SARS-CoV-2 infections and that, although rare, the elderly are particularly at risk of becoming severely infected as the consequence of a breakthrough infection.


title: Neutralization of SARS-CoV-2 variants by rVSV-ΔG-spike-elicited human sera

abstract: The emergence of rapidly spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a major challenge to the ability of vaccines and therapeutic antibodies to provide immunity. These variants contain mutations at specific amino acids that might impede vaccine efficacy. BriLife(R) (rVSV-{Delta}G-spike) is a newly developed SARS-CoV-2 vaccine candidate currently in Phase II clinical trials. It is based on a replication competent vesicular stomatitis virus (VSV) platform. rVSV-{Delta}G-spike contains several spontaneously-acquired spike mutations that correspond to SARS-CoV-2 variants mutations. We show that human sera from BriLife(R) vaccinees preserve comparable neutralization titers towards alpha, gamma and delta variants, and show less than 3-fold reduction in neutralization capacity of beta and omicron compared to the original virus. Taken together, we show that human sera from BriLife(R) vaccinees overall maintain neutralizing antibody response against all tested variants. We suggest that BriLife(R) acquired mutations may prove advantageous against future SARS-CoV-2 VOCs.


title: Germany's low SARS-CoV-2 seroprevalence confirms effective containment in 2020: Results of the nationwide RKI-SOEP study

abstract: Pre-vaccine SARS-CoV-2 seroprevalence data from Germany are scarce outside hotspots, and socioeconomic disparities remained largely unexplored. The nationwide RKI-SOEP study with 15,122 adult participants investigated seroprevalence and testing in a supplementary wave of the Socio-Economic-Panel conducted predominantly in October-November 2020. Self-collected oral-nasal swabs were PCR-positive in 0.4% and Euroimmun anti-SARS-CoV-2-S1-IgG ELISA from dry capillary blood in 1.3% (95% CI 0.9-1.7%, population-weighted, corrected for sensitivity=0.811, specificity=0.997). Seroprevalence was 1.7% (95% CI 1.2-2.3%) when additionally adjusting for antibody decay. Overall infection prevalence including self-reports was 2.1%. We estimate 45% (95% CI 21-60%) undetected cases and analyses suggest lower detection in socioeconomically deprived districts. Prior SARS-CoV-2 testing was reported by 18% from the lower educational group compared to 25% and 26% from the medium and high educational group (p<0.0001). Symptom-triggered test frequency was similar across educational groups. However, routine testing was more common in low-educated adults, whereas travel-related testing and testing after contact with an infected person was more common in highly educated groups. In conclusion, pre-vaccine SARS-CoV-2-seroprevalence in Germany was very low. Notified cases appear to capture more than half of infections but may underestimate infections in lower socioeconomic groups. These data confirm the successful containment strategy of Germany until winter 2020.


title: Serological responses to COVID-19 booster vaccine in England

abstract:
IntroductionThere are limited data on immune responses after COVID-19 vaccine boosters in individuals receiving primary immunisation with BNT162b2 (Pfizer-BioNTech) or AZD1222 (AstraZeneca).

MethodsA prospective, cohort study to assess SARS-CoV-2 antibody responses before and after booster vaccination with BNT162b2 in adults receiving either (i) two BNT162b2 doses <30 days apart (BNT162b2-control), (ii) two BNT162b2 doses [≥]30 days apart (BNT162b2-extended) or (iii) two AZD1222 doses [≥]30 days apart (AZD1222-extended) in London, England. SARS-CoV-2 spike protein antibody geometric mean titres (GMTs) before and 2-4 weeks after booster were compared.

ResultsOf 750 participants, 626 provided serum samples for up to 38 weeks after their second vaccine dose. Antibody GMTs peaked at 2-4 weeks after the second dose, before declining by 68% at 36-38 weeks after dose 2 for BNT162b2-control participants, 85% at 24-29 weeks for BNT162b2-extended participants and 78% at 24-29 weeks for AZD1222-extended participants. Antibody GMTs was highest in BNT162b2-extended participants (942 [95%CI, 797-1113]) than AZD1222-extended (183 [124-268]) participants at 24-29 weeks or BNT162b2-control participants at 36-38 weeks (208; 95%CI, 150-289). At 2-4 weeks after booster, GMTs were significantly higher than after primary vaccination in all three groups: 18,104 (95%CI, 13,911-23,560; n=47) in BNT162b2-control (76.3-fold), 13,980 (11,902-16,421; n=118) in BNT162b2-extended (15.9-fold) and 10,799 (8,510-13,704; n=43) in AZD1222-extended (57.2-fold) participants. BNT162b2-control participants (median:262 days) had a longer interval between primary and booster doses than BNT162b2-extended or AZD1222-extended (both median:186 days) participants.

ConclusionsWe observed rapid serological responses to boosting with BNT162b2, irrespective of vaccine type or schedule used for primary immunisation, with higher post-booster responses with longer interval between primary immunisation and boosting. Boosters will not only provide additional protection for those at highest risk of severe COVID-19 but also prevent infection and, therefore, interrupt transmission, thereby reducing infections rates in the population. Ongoing surveillance will be important for monitoring the duration of protection after the booster.


title: Determination of NK cell immunophenotype and cytokine profile in patients with Rocky Mountain spotted fever

abstract: The intracellular pathogen Rickettsia rickettsii causes tick-borne spotted fever (also called Rocky Mountain spotted fever (RMSF) and is increasingly recognized as an emerging cause of febrile illness in Mexico. However, little is known about the early immune responses to infection. Four RMSF pediatric patients on acute phase and eight healthy controls from Chihuahua, Mexico were recruited. The natural killer cell (NK) immunophenotype and the cytokine profile in peripheral blood were characterized by flow cytometry. The population of cytotoxic NK cells expressing NKG2D was significantly decreased in patients on 3rd day of hospitalization compared to the first sampling on admission. Interleukins IL-6, IL-8, and IL-10 levels were significantly increased in patients upon admission compared to controls. This study shows that circulating NK cells are numerically decreased, while cytokines induce a pro-inflammatory process in patients.


title: In Vitro Nasal Tissue Model for the Validation of Nasopharyngeal and Mid-turbinate Swabs for SARS-CoV-2 Testing

abstract: Large-scale population testing is a key tool to mitigate the spread of respiratory pathogens, as in the current COVID-19 pandemic, where swabs are used to collect samples in the upper airways (e.g. nasopharyngeal and mid-turbinate nasal cavities) for diagnostics. However, the high volume of supplies required to achieve large-scale population testing has posed unprecedented challenges for swab manufacturing and distribution, resulting in a global shortage that has heavily impacted testing capacity world-wide and prompted the development of new swabs suitable for large-scale production. Newly designed swabs require rigorous pre-clinical and clinical validation studies that are costly and time consuming (i.e. months to years long); reducing the risks associated with swab validation is therefore paramount for their rapid deployment. To address these shortages, we developed a 3D-printed tissue model that mimics the nasopharyngeal and mid-turbinate nasal cavities, and we validated its use as a new tool to rapidly test swab performance. In addition to the nasal architecture, the tissue model mimics the soft nasal tissue with a silk-based sponge lining, and the physiological nasal fluid with asymptomatic and symptomatic viscosities of synthetic mucus. We performed several assays comparing standard flocked and injection-molded swabs. We quantified the swab pick-up and release, and determined the effect of viral load and mucus viscosity on swab efficacy by spiking the synthetic mucus with heat-inactivated SARS-CoV-2 virus. By molecular assays, we found that injected molded swabs performed similarly or superiorly in comparison to standard flocked swabs and we underscored a viscosity-dependent difference in cycle threshold values between the asymptomatic and symptomatic mucus for both swabs. To conclude, we developed an in vitro nasal tissue model, that corroborated previous swab performance data from clinical studies, with the potential of providing researchers with a clinically relevant, reproducible, safe, and cost-effective validation tool for the rapid development of newly designed swabs.


title: The role of multi-generational household clusters in COVID-19 in England

abstract:
BackgroundHousehold transmission has been demonstrated to be an important factor in the population-level growth of COVID-19. UK Health Security Agency (UKHSA) maintains data on positive tests for COVID-19 and the residential addresses of cases. We sought to use this information to characterise clusters of COVID-19 in multi-generational households in England.

MethodsUsing cross-sectional design, cases of COVID-19 were assigned to clusters if they occurred in the same residential property in a 14-day rolling window. Patient demographic data were supplemented with reference to the ONS index of multiple deprivation and population density. Multi-generational households were defined as a cluster with at least three people, with one case in a person who was 0-16 years old and one case in a person who was [≥] 60 years old, with at least 16 years between two members of each age group.

ResultsA total of 3,647,063 COVID-19 cases were reported between 01 April 2020 and 20 May 2021. Of these, 1,980,527 (54.3 %) occurred in residential clusters. Multi-generational households formed 1.5 % of clusters, with these more likely to occur in areas of higher population density and higher relative deprivation. Multi-generational clusters were more common among households of non-White ethnicity and formed larger clusters than non-multi-generational clusters (median cluster size 6, IQR 4-11 vs 3, IQR 3-4, respectively).

ConclusionMulti-generational clusters were not highly prevalent in England during the study period, however were more common in certain populations.

O_TEXTBOXBOX TEXT

What is already known on this subjectGreater risk of infection with SARS-CoV-2 in England is associated with being of non-White ethnicity, residence in an area of greater deprivation and higher population density. What is less clear is the role of household composition in the risk of COVID-19 transmission. It has been hypothesised that multi-generational housing (in which at least three different generations are resident in the same property) accounted for a substantial proportion of COVID-19 cases. We sought to test this hypothesis.

What this study addsThis study provides descriptive evidence around the role of multi-generational households in the COVID-19 pandemic in England between April 2020 and March 2021. It does not support the hypothesis that this period (a period of low incidence in England), a substantial proportion of COVID-19 cases occurred in multi-generational households.

C_TEXTBOX


title: In vitro, classical complement activation differs by disease severity and between SARS-CoV-2 antigens

abstract:
Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of anti-SARS-CoV-2 antibodies from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the antigen and subjects studied. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending on the specific antigen targeted and the disease status of the subject.

O_LISpike- and nucleocapsid-specific antibodies activate complement in vitro
C_LIO_LIC1q binding correlates with IgG1 antibody levels
C_LIO_LIGeneration of C4b, C3b and C5b relates to the antigen targeted and the patient group tested
C_LI

category: allergy and immunology


title: The Frequency, Penetrance and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants

abstract:
BackgroundThere is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general, adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional and arrhythmic disease features.

MethodsUK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiovascular magnetic resonance (CMR) imaging were selected for study. Three different variant calling strategies (one primary and two secondary) were used to identify subjects with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded to either 1) DCM (clinical or CMR diagnosis); 2) early DCM features, including arrhythmia and/or conduction disease, isolated ventricular dilation, and hypokinetic non-dilated cardiomyopathy; or 3) phenotype-negative.

ResultsAmong 18,665 individuals included in the study, 1,463 (7.8%) subjects possessed [≥]1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and CMR analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in 15.9% of individuals with putative pathogenic variants. Arrhythmias and/or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic non-dilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was [≤]30% with all three variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes, as compared to those with variants in moderate/limited evidence genes.

ConclusionsIn the UK Biobank, approximately 1/6 of adults with putative pathogenic variants in DCM genes exhibited a subclinical phenotype based on ECG and/or CMR, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation/dysfunction.

Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIAmong individuals with putative pathogenic DCM gene variants, subclinical DCM and early DCM features, detected by ECG and/or CMR, were nearly four times more common than clinically manifest DCM or early features (23.7% vs. 6.1%).
C_LIO_LIOver 90% of subjects with a putative pathogenic variant in DCM-associated genes did not have a prior history of DCM.
C_LIO_LIClinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes (13.9% for clinical and subclinical), as compared to those with variants in moderate/limited evidence genes, but there was no significant difference in combined clinical/subclinical phenotype by cluster.
C_LIO_LIThe overall clinical/subclinical penetrance of DCM-associated single putative pathogenic variants was highly variable between genes, ranging from 0 to 66.7%.
C_LI

What are the clinical implications?O_LIArrhythmias and cardiac conduction disease are the most common early manifestation of putative pathogenic variants implicated in DCM, mostly occurring prior to the development of structural/functional abnormalities.
C_LIO_LIA genotype-first screening approach for DCM using a large genetic panel is currently not suitable in the general population due to incomplete understanding of DCM genetic architecture and reduced penetrance of DCM-associated putative pathogenic variants.
C_LI

Journal Subject TermsCardiomyopathy; Genetics; Sudden Cardiac Death

category: cardiovascular medicine


title: Simulating the impact of vaccination rates on the initial stages of a COVID-19 outbreak in New Zealand (Aotearoa) with a stochastic model

abstract:
AimThe August 2021 COVID-19 outbreak in Auckland has caused the New Zealand government to transition from an elimination strategy to suppression, which relies heavily on high vaccination rates in the population. As restrictions are eased and as COVID-19 leaks through the Auckland boundary, there is a need to understand how different levels of vaccination will impact the initial stages of COVID-19 outbreaks that are seeded around the country.

MethodA stochastic branching process model is used to simulate the initial spread of a COVID-19 outbreak for different vaccination rates.

ResultsHigh vaccination rates are effective at minimizing the number of infections and hospitalizations. Increasing vaccination rates from 20% (approximate value at the start of the August 2021 outbreak) to 80% (approximate proposed target) of the total population can reduce the median number of infections that occur within the first four weeks of an outbreak from 1011 to 14 (25th and 75th quantiles of 545-1602 and 2-32 for V=20% and V=80%, respectively). As the vaccination rate increases, the number of breakthrough infections (infections in fully vaccinated individuals) and hospitalizations of vaccinated individuals increases. Unvaccinated individuals, however, are 3.3x more likely to be infected with COVID-19 and 25x more likely to be hospitalized.

ConclusionThis work demonstrates the importance of vaccination in protecting individuals from COVID-19, preventing high caseloads, and minimizing the number of hospitalizations and hence limiting the pressure on the healthcare system.

category: epidemiology


title: Final sizes and durations of new COVID-19 pandemic waves in Ukraine and around the world predicted by generalized SIR model

abstract: New waves of the COVID-19 pandemic in Ukraine, which began in the summer of 2021, and after holidays in the middle of October 2021, were characterized by almost exponential growth of smoothed daily numbers of new cases. This is a matter of great concern and the need to immediately predict the epidemic dynamics in order to assess the possible maximum values of new cases, the risk of infection and the number of deaths. The generalized SIR-model and corresponding parameter identification procedure was used to simulate and predict the dynamics of two new epidemic waves in Ukraine and one in the whole world. Results of calculations show that new cases in Ukraine will not stop to appear before November 2022. If the global situation with vaccination, testing and treatment will not change, the pandemic could continue for another ten years.


title: Determining international spread of novel B.1.1.523 SARS-CoV-2 lineage

abstract: Here we report the emergence of variant lineage B.1.1.523 that contains a set of mutations including 156_158del, E484K and S494P in Spike protein. E484K and S494P are known to significantly reduce SARS-CoV-2 neutralization by convalescent and vaccinee sera and are considered as mutations of concern. Lineage B.1.1.523 has presumably originated in Russian Federation and spread across European countries with the peak of transmission in April - May 2021. The B.1.1.523 lineage has now been reported from 27 countries.


title: The Failures of an Ideal COVID-19 Vaccine: A Simulation Study

abstract:
This paper simulates an ideal COVID-19 vaccine that confers immediate sterilizing immunity against all SARS-CoV-2 variants. The purpose was to explore how well this ideal vaccine could protect a population against common conditions (such as vaccine hesitancy) that might impair vaccine effectiveness. Simulations were done with an SEIRS spreadsheet model that ran two parallel subpopulations: one that accepted vaccination, and another that refused it. The two subpopulations could transmit infections to one another. Success was judged by the rate of new cases in the period from 1-5 years after the introduction of the vaccine.

Under good conditions, including a small subpopulation that refused vaccination, rapid distribution of the vaccine, duration of vaccinal immunity longer than 12 months, good retention of interest in getting vaccinated after the first year, strict maintenance of nonpharmaceutical interventions (NPIs) such as masking, and new variants with R0s less than 4.0, the vaccine was able to end the epidemic. With violation of these conditions, the post-vaccine era futures ranged from endemic COVID at a low or medium level to rates of COVID cases worse than anything seen in the US up to late 2021. The most important conditions for keeping case rates low were a fast speed of vaccine distribution, a low percentage of the population that refuses vaccination, a long duration of vaccinal immunity, and continuing maintenance of NPIs after vaccination began. On the other hand, a short duration of vaccinal immunity, abandonment of NPIs, and new variants with a high R0 were powerful barriers to disease control. New variants with high R0s were particularly damaging, producing high case rates except when vaccination speed was unrealistically rapid. A recurring finding was that most disease afflicting the vaccinated population in these simulations originated in the unvaccinated population, and cutting off interaction with the unvaccinated population caused a sharp drop in the case rate of the vaccinated population.

In conclusion, multiple common conditions can compromise the effectiveness of even an "ideal" vaccine.


title: Development and Performance verification of colloidal gold labeled SARS-CoV-2 antigen detection method for routine popular screening of COVID-19 with clinical samples in Poland and China

abstract: In this research, we have constructed and optimized the colloidal gold labeled lateral flow strip (LFS) for rapid detection of antigen of SARS-CoV-2 and rapid screening of COVID-19. Based on the constructed and optimized colloidal gold lateral flow strip, the parameters of the LFS have been well evaluated with the clinical samples in the professional labs. The screening performance have also been evaluated from the aspects including the CT values, age distribution and onset of symptoms. Finally, based on the detection results of 420 clinical samples, the LFS can achieve the screening of COVID-19 with the positive percentage agreement (PPA, sensitivity), negative percent agreement (NPA, specificity), the positive predictive value (PPV) and the negative predictive value (NPV) of 96.8%, 100%, 100% and 96.6%, respectively, indicating the powerful potential for practical screening applications in pandemic control. Of great significance, this developed SARS-CoV-2 antigen detection method has also been successfully utilized for screening of delta-variant of SARS-CoV-2.


title: Probing Gut-Brain Links in Alzheimer's Disease with Rifaximin

abstract:
Gut-microbiome-inflammation interactions have been linked to neurodegeneration in Alzheimers disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut-specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open-label trial, we treated 10 subjects with mild to moderate probable AD dementia (MMSE = 17 {+/-} 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament-light levels (p <0.004) and a significant increase in fecal phylum Firmicutes microbiota. Serum pTau181 and GFAP levels were reduced (effect sizes of -0.41 and -0.48 respectively) but did not reach significance. There was also a non-significant downward trend in serum cytokine IL-6 and IL-13 levels. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau 181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo-controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

Research in ContextO_ST_ABSSystematic ReviewC_ST_ABSPubMed reviews showed emerging evidence for gut-microbiome-inflammation links in Alzheimers disease (AD).

InterpretationOur pilot study revealed that rifaximin, a minimally absorbed, gut-specific antibiotic, reduced surrogate markers of neurodegeneration while increasing, potentially beneficial, microbiota in phylum Firmicutes. These data provide initial support to the hypothesis that microbiome related products may play a role in neurodegenerative disorders.

Future DirectionsWe plan to conduct additional human and pre-clinical studies to confirm these findings and determine the potential of rifaximin as a therapeutic for AD.

category: pharmacology and therapeutics


title: Bibliometric Analysis of Academic Journal Articles Reporting Results of Psychedelic Clinical Studies

abstract: After a decades long period of investigational dormancy, there is renewed interest in employing psychedelics as treatments for mental illness and addiction. The academic journals, journal articles, academic institutions, and countries that have helped sustain clinical psychedelic research and the evolution of the literature on clinical studies of psychedelic compounds have only been minimally investigated. Therefore, in we conducted a bibliometric analysis of clinical studies of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), ayahuasca, dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), ibogaine, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin published from 1965-2018. Our search revealed 320 articles published across 106 journals. After a nearly quarter century lull between the 1970s and 1990s, publications in this area have resurged over the last two decades and continue on an upward trajectory, with most clinical studies now focusing on LSD, MDMA, and psilocybin. A subanalysis of the ten most cited articles in psychedelic research prior to 2010 and afterwards demonstrated a shift from research on risks of psychedelics, primarily those of MDMA, to research on therapeutic applications, predominantly those of psilocybin. We also conducted network analyses of inter-country collaborations in psychedelic research, which suggested that psychedelic researchers in the United Kingdom have more diverse international collaborations.

category: psychiatry and clinical psychology


title: Factors associated with COVID-19 vaccine acceptance and hesitancy among residents of Northern California jails

abstract:
BackgroundCarceral facilities are high-risk settings for COVID-19 transmission. Understanding of factors associated with COVID-19 vaccine acceptance and hesitancy among incarcerated individuals is incomplete, especially for people living in jails.

MethodsWe conducted a retrospective review of COVID-19 vaccination data from the electronic health record (EHR) of residents in two Northern California county jails to examine factors associated with vaccine uptake in this population. We additionally administered a survey in four jails to assess reasons for vaccine hesitancy, sources of COVID-19 information, and medical mistrust. We performed multivariate logistic regression to determine associations with vaccine uptake or hesitancy.

ResultsOf 2,584 jail residents offered a COVID-19 vaccine between March 19, 2021 and June 30, 2021, 1,464 (56.7%) accepted at least one dose. Among vaccinated residents, 538 (36.7%) initially refused the vaccine. Vaccine uptake was higher among older individuals, women, those with recent flu vaccination, and those living in shared cells or open dorms. Leading reasons for vaccine hesitancy included concerns around side effects and suboptimal efficacy. Television and friends/family were the most commonly cited and the most trusted sources of COVID-19 information, respectively. Vaccine acceptance was associated with increased trust in COVID-19 information sources and in medical personnel both in and out of jail.

ConclusionOngoing evidence-based COVID-19 vaccination efforts are needed in high-risk carceral settings. Effective interventions to improve vaccination rates in this population should utilize accessible and trusted sources of information to address concerns about vaccine side effects and efficacy and foster medical trust.

category: public and global health


title: Trait and state mindfulness modulate EEG microstates

abstract:
IntroductionMicrostates are consistent and discrete brain potential topographies reflecting transient large network dynamics underlying specific brain processes. The present study aimed to characterize microstate dynamics induced by open-monitoring meditation (OM), which is an attentional-based practice emphasizing a non-reactive state towards lived experience.

MethodElectroencephalogram signals from eighteen trained meditators and a matched non-meditators group were recorded before, during, and after an open-monitoring meditation or during three resting periods respectively, while they were passively exposed to auditory stimuli. In a multimodal approach, microstate clusters decompositions, personality trait questionnaires, phenomenological reports, and microstates sources localization were analyzed for characterizing mindfulness traits and mindfulness state.

ResultsIn meditators, microstate A decreased in frequency after OM and was negatively correlated with mindfulness trait. Microstate B was of longer duration and was positively correlated to the non-reactivity trait of mindfulness after OM. Microstate C at rest was less frequent and shorter than in the non-meditators group, and it decreased in frequency after OM. Further, the occurrence of microstate C was negatively correlated to the non-reactivity trait of meditators for the three recording sessions. Source localization analysis revealed that the mindfulness trait effect on microstate C at rest was explained by the lower activity of the salience network (identified by the anterior cingulate cortex, thalamus, and insula), while the mindfulness state effect relied on a strong contribution of (anterior and posterior) cerebellum during OM.

DiscussionThe decreased microstate A occurrence is discussed as being related to rumination processes weakening. The decrease of microstate C occurrence might represent the index of a cognitive defusion enabled by non-reactive monitoring of mindfulness meditation, for which the cerebellum appears to play a crucial role.

HIGHLIGHTO_LIThe present study aimed to characterized microstate dynamics induced by open-monitoring (OM) meditation which emphasizes a non-reactive state towards experience, by the use of multimodal analysis including EEG microstate temporal measures, personality trait questionnaires, phenomenological reports, and source localization analysis.
C_LIO_LIThe occurrence of microstate A, recognized to be related to phonological processing and depressive disorders, was negatively correlated to mindfulness trait and was decreased after OM meditation. These findings suggested that the occurrence of microstate A could represent a useful biomarker to monitor depression course and mental well-being, as well as objectify the efficiency of mindfulness-based interventions to prevent depression relapse.
C_LIO_LITemporal parameters of microstate C, recognized to be related to mind wandering, were lower at rest in meditators than non-meditators reflecting a trait effect of mindfulness on the activity of the salient network. Besides, the occurrence of microstate C decreased after meditation and was negatively correlated to the non-reactivity facet of mindfulness. These findings suggested that C occurrence might represent an index of the cognitive defusion enabled by non-reactive monitoring of mindfulness meditation.
C_LI

category: radiology and imaging


title: Is It Really Musculoskeletal Pain? Differential diagnosis and screening for referral in paediatric musculoskeletal disorders: a scoping review protocol

abstract:
IntroductionMusculoskeletal disorders are common in children and adolescents. They could have a broad spectrum of causes, which the most are self-limiting and usually do not need a referral to specialistic care. It is mandatory for the healthcare professionals working primary care settings to be able to understand when to perform a "wait and see" approach or when further investigations are needed. This study aims to identify signs and symptoms reliable to serious or life-threatening conditions that could be detected during the screening process and the physical examination of children and adolescent with common musculoskeletal disorders by a healthcare professional in direct access clinical setting.

Materials and MethodsThe scoping review (ScR) will be performed following the six-stage methodology suggested by Arksey and OMalley and the extensions to the original framework that are recommended by the Joanna Briggs Institute. Fourteen electronic databases will be investigated since their inception. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist will be used to meet the required standards of quality and reproducibility. Review tools will be used for the quality assessment of the included studies. This protocol received input from all authors who have expertise in research methodology and paediatric and musculoskeletal disorders.

Ethics and DisseminationThe results of this ScR will be relevant given that screening for referral in paediatric musculoskeletal disorders has not been addressed in the literature properly yet. Dissemination will include submission to peer-reviewed journal. Ethical approval is not required for scoping reviews.

PROTOCOL INFORMATIONAnticipated or actual start date: January 2021

Anticipated completion date: December 2021

category: rehabilitation medicine and physical therapy


title: Sex disparities in authorship in pulmonary hypertension research: a scoping review protocol

abstract: From protocol introduction: "Our aim is to examine female authorship and sex disparities in the domain of pulmonary hypertension (PH) research. Despite PH disproportionately affecting females, we hypothesize that the proportion of studies with women as first or senior author will be < 50% and women will be underrepresented in publications in more prestigious journals."

category: respiratory medicine


title: Association Between a 22-feature Genomic Classifier and Biopsy Gleason Upgrade During Active Surveillance for Prostate Cancer

abstract:
BackgroundAlthough the Decipher genomic classifier has been validated as a prognostic tool for several prostate cancer endpoints, little is known about its role in assessing risks of biopsy reclassification among patients on active surveillance, a key event that often triggers treatment.

ObjectiveTo evaluate the association between Decipher genomic classifier and biopsy Gleason upgrade among patients on active surveillance.

Design, Setting, and ParticipantsRetrospective cohort study among patients with low- and favorable-intermediate-risk prostate cancer on active surveillance who underwent biopsy-based Decipher testing as part of clinical care.

Outcomes measures and statistical analysisAny increase in biopsy Gleason grade group (GG). We evaluated the association between Decipher score using univariable and multivariable logistic regression. We compared area under the receiver operating characteristic curve (AUC) of models comprised of baseline clinical variables with or without Decipher score.

Results and limitationsWe identified 133 patients of median age 67.7 years and median PSA 5.6 ng/mL. At enrollment 75.9% were GG1 and 24.1 GG2. Forty-three patients experienced biopsy upgrade. On multivariable logistic regression, Decipher score was significantly associated with biopsy upgrade (OR 1.37 per 0.10 unit increase, 95% CI 1.05-1.79 p=0.02). Decipher score was associated with upgrade among patients with biopsy Grade group 1, but not Grade Group 2 disease. The discriminative ability of a clinical model (AUC 0.63, 95% CI 0.51-0.74) was improved with the integration of Decipher score (AUC 0.69, 95% CI 0.58-0.80).

ConclusionsThe Decipher genomic classifier was associated with short-term biopsy Gleason upgrading among patients on active surveillance.

Patient summaryThe results from this study indicate that among patients with prostate cancer undergoing active surveillance, those with higher Decipher scores were more likely to have higher-grade disease found over time. These findings indicate that the Decipher test might be useful for guiding the intensity of monitoring during active surveillance.

category: urology


title: Oxidative stress and antioxidant defenses in mild cognitive impairment: a systematic review and meta-analysis.

abstract: This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.


title: Dimensional characterizations of gender diversity are associated with higher polygenic propensity for cognitive performance in a neurodiverse sample

abstract: Both sex and gender are characteristics that play a key role in risk and resilience in health and well-being. Current research lacks the ability to quantitatively describe gender and gender diversity and is limited to endorsement of categorical gender identities, which are contextually and culturally dependent. A multidimensional data-driven approach to characterizing gender diversity will enable researchers to advance the health of gender-diverse people by better understanding how genetic factors interact to determine health outcomes. In N = 450 independent adults with or without autism in the SPARK cohort, we used the Gender Self-Report (GSR), a self-report tool that psychometrically captures two quantitative dimensions of gender diversity: Binary, the extent to which one identifies with the binary gender opposite that of their sex at birth, and Nonbinary gender diversity, the extent to which one identifies with a neutral gender and/or both binary genders. We correlated the two GSR scores with two mental health outcomes and 20 human behavior polygenic scores in a subset of N = 450 participants. Same-sex sexual behavior polygenic scores were positively correlated with Binary ({rho} = 0.12, p < 0.05) and Nonbinary ({rho} = 0.11, p < 0.05). Interestingly, cognitive performance polygenic scores were also correlated with Binary ({rho} = 0.09, p = 0.07) and Nonbinary ({rho} = 0.13, p < 0.05). In agreement with this, an association was also observed in a larger SPARK sample (N = 3,466, with less granular gender identity data), in which the sex/gender discordant group had higher mean polygenic scores for educational attainment (p < 0.05). Binary and Nonbinary were positively correlated with poorer mental health, and accounting for genetic effects had minimal impact on these associations. However, when stratifying individuals by polygenic scores quartiles, we observed dramatic differences in genetic risk and resilience, with individuals in the high risk quartile for schizophrenia and bipolar polygenic risk having strong positive correlations of gender diversity with mental health, whereas the lower quartile had no significant associations. Overall, our results suggest (1) cognitive ability and gender diversity share overlapping genetic factors, (2) greater gender diversity is correlated with poorer mental health outcomes and this effect is not directly explained by neuropsychiatric polygenic risk, but rather an interaction effect, and (3) quantitatively measuring gender diversity facilitates a better understanding of the role of gender in health outcomes.


title: Dimensional gender diversity is associated with greater polygenic propensity for cognitive performance and interacts with other genetic factors in predicting health outcomes


title: Impacts of vaccination and asymptomatic testing on SARS-CoV-2 transmission dynamics in a university setting

abstract: We investigate the impact of vaccination and asymptomatic testing uptake on SARS-CoV-2 transmission in a university student population using a stochastic compartmental model. We find that the magnitude and timing of outbreaks is highly variable depending on the transmissibility of the most dominant strain of SARS CoV-2 and under different vaccine uptake levels and efficacies. When delta is the dominant strain, low level interventions (no asymptomatic testing, 30% vaccinated with a vaccine that is 80% effective at reducing infection) lead to 53-71% of students become infected during the first term. Asymptomatic testing is most useful when vaccine uptake is low: when 30% of students are vaccinated, 90% uptake of asymptomatic testing leads to almost half the case numbers. With high interventions (90% using asymptomatic testing, 90% vaccinated) cumulative incidence is 7-9%, with around 80% of these cases estimated to be asymptomatic. However, under emergence of a new variant that is at least twice as transmissible as delta and with the vaccine efficacy against infection reduced to 55%, large outbreaks are likely in universities, even with very high (90%) uptake of vaccination and 100% uptake of asymptomatic testing. If vaccine efficacy against infection against this new variant is higher (70%), then outbreaks can be mitigated if there is least 50% uptake of asymptomatic testing additional to 90% uptake of vaccination. Our findings suggest that effective vaccination is critical for controlling SARS-CoV-2 transmission in university settings with asymptomatic testing ranging from additionally useful to critical, depending on effectiveness and uptake of vaccination. Other measures may be necessary to control outbreaks under the emergence of a more transmissible variant with vaccine escape.


title: The Substrate of Sudden Death in Long-QT Syndrome is localized in the Epicardium

abstract: Despite significant advances in the prevention of cardiovascular diseases, sudden cardiac death (SCD) persists as a major public health problem. Among young and apparently healthy individuals, Long-QT syndrome (LQTS) represents a leading progenitor of SCD owing to fatal ventricular arrhythmia. Scientific understanding of this association has grown in recent years, and the mortality rate after LQTS diagnosis has significantly decreased. However, despite medical treatment advances, life-threatening ventricular arrhythmias still occur. Until now, no research has established the degree to which this inherited condition arises from an underlying arrhythmogenic electroanatomical substrate. Here, we present direct evidence showing that LQTS patients who survive spontaneous malignant arrhythmias harbor structural electrophysiological abnormalities localized in the epicardium of the right ventricle. We further show that the elimination of these abnormalities by means of catheter ablation successfully suppresses malignant arrhythmias, offering a new approach for the effective treatment of LQTS patients.


title: Establishing and characterising large COVID-19 cohorts after mapping the Information System for Research in Primary Care in Catalonia to the OMOP Common Data Model

abstract:
BackgroundFew datasets have been established that capture the full breadth of COVID-19 patient interactions with a health system. Our first objective was to create a COVID-19 dataset that linked primary care data to COVID-19 testing, hospitalisation, and mortality data at a patient level. Our second objective was to provide a descriptive analysis of COVID-19 outcomes among the general population and describe the characteristics of the affected individuals.

MethodsWe mapped patient-level data from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). More than 3,000 data quality checks were performed to assess the readiness of the database for research. Subsequently, to summarise the COVID-19 population captured, we established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or positive test results for SARS-CoV-2, hospitalisations with COVID-19, and COVID-19 deaths during follow-up, which went up until 30th June 2021.

FindingsMapping data to the OMOP CDM was performed and high data quality was observed. The mapped database was used to identify a total of 5,870,274 individuals, who were included in the general population cohort as of 1st March 2020. Over follow up, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation with COVID-19, 5,642 had an ICU admission with COVID-19, and 11,233 had a COVID-19 death. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised in general and those who died.

InterpretationWe have established a comprehensive dataset that captures COVID-19 diagnoses, test results, hospitalisations, and deaths in Catalonia, Spain. Extensive data checks have shown the data to be fit for use. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19 outcomes over time were described.

FundingGeneralitat de Catalunya and European Health Data and Evidence Network (EHDEN).


title: Efficacy of Sofosbuvir, Daclatasvir and Ribavirin combination therapy in treatment naive hepatitis C patients at tertiary care hospital of South Punjab

abstract:
IntroductionHepatitis C has gradually become endemic in Pakistan, with infectivity rates one of the highest in the world. The emergence of direct acting antivirals (DAAs) has become a ray of sunshine in eradicating this menace from this region. The combination of sofosbuvir, daclatasvir and ribavirin (SOF/DACLA/RIBA) has had phenomenal success all over the world in eradicating this virus. Our study aims to see the effectiveness of this regime in this part of the world.

MethodsAfter approval from the institutional review board (IRB), retrospective analysis of data of treatment naive patients who have been treated with the above mentioned regimen was collected to assess the efficacy by calculating the sustained virological response (SVR) at 12 weeks after completion of therapy.

ResultsData of 300 patients (172 females, 128 males) was collected. Mean age was 39.66 years. Majority (almost 90%) of patients were from District Multan Age range was from 18 years to 60 years. Eighty-three percent of the patients were non-cirrhotics, 15.7% had compensated cirrhosis, while only 1 % had decompensated cirrhosis. Out of the 300 patients, 291 patients had undetectable HCV RNA on polymerase chain reaction (PCR) at 12 weeks after completion of treatment, achieving SVR rates of 97%. There was no significant association of SVR rates with gender and age of patients.

ConclusionThe combination of SOF/DACA/RIBA is highly efficacious for treatment of hepatitis C patients.

category: gastroenterology


title: Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study

abstract:
ObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD).

MethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls.

ResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients.

ConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.

category: rheumatology


title: Measure by Measure: Resting Heart Rate Across the 24 Hour Cycle.

abstract:
BackgroundPhotoplethysmography (PPG) sensors, typically found in wrist-worn devices, can continuously monitor heart rate (HR) in large populations in real-world settings. Resting heart rate (RHR) is an important biomarker of morbidities and mortality, but no universally accepted definition nor measurement criteria exist. In this study, we provide a working definition of RHR and describe a method for accurate measurement of this biomarker, recorded using PPG derived from wristband measurement across a 24 hour cycle.

Methods433 healthy subjects wore a wrist device that measured activity and HR for up to 3 months. HR during inactivity was recorded and the duration of inactivity needed for HR to stabilise was ascertained. We identified the lowest HR during each 24-hour cycle (true RHR) and examined the time of day or night this occurred. The variation of HR during inactivity through the 24-hour cycle was also assessed. The sample was also subdivided according to daily activity levels for subset analysis.

FindingsAdequate data was obtained for 19,242 days and 18,520 nights. HR stabilised in most subjects after 4 minutes of inactivity. Mean (SD) RHR for the sample was 54.5 (8.0) bpm (day) and 50.5 (7.6) bpm (night). RHR values were highest in the least active group (lowest MET quartile). A circadian variation of HR during inactivity was confirmed, with the lowest values being between 0300 and 0700 hours for most subjects.

InterpretationRHR measured using a PPG-based wrist-worn device is significantly lower at night than in the day, and a circadian rhythm of HR during inactivity was confirmed. Since RHR is such an important health metric, clarity on the definition and measurement methodology used is important. A minimum rest time of 4 minutes provides a reliable measurement of HR during inactivity and true RHR in a 24-hour cycle is best measured between 0300 and 0700 hours.

FundingThis study was funded by Google.

O_TEXTBOXResearch In contextResting heart rate is one of the most fundamental and relevant biomarkers in health and disease. Its measurement, particularly in large population studies, is increasingly reliant on sensor devices. No universally accepted definition nor measurement criteria exist. In this study, we provide a working definition of RHR and describe a method for measurement of RHR recorded using PPG derived from wristband measurement. We make recommendations to support future studies of resting heart rate using wearable sensors.

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title: Recurring Spatiotemporal Patterns of COVID-19 in the United States

abstract:
We analyzed the waxing and waning patterns ("surges") of reported SARS-CoV-2 cases from January 1, 2020 through Oct 31, 2021 in all states and provinces (n = 93) in the USA, Mexico, and Canada, and across all counties (N = 3142) in the USA. A correlation matrix of the 576 x 576 daily case incidence rates in the 50 US states generates a distinctive "checkerboard" pattern showing that the epidemic has consisted of seven distinct internally coherent spatiotemporal wave patterns, four in the first year of the epidemic, and three thus far in the second year. Geoclustering of state case rate trajectories reveals three dominant co-varying spatial clusters of similar case rate trajectories, in the northeastern, southeastern and central/western regions of the USA. The spatiotemporal patterns of epidemic year 1 have thus far been repeated (p<.001) in epidemic year 2. The "checkerboard" pattern of the correlation matrix of case trajectories can be closely simulated as three sets of interacting sine waves with annual frequencies of 1:1:2 major cycles per year, corresponding to the northeastern, central/western, and southeastern state clusters. Case incidence patterns in Mexico and Canada have been similar to nearby regions in the southern US and the northern US, respectively. Time lapse videos allow visualization of the wave patterns. These highly structured geographical and temporal patterns, coupled with emerging evidence of annual repetition of these same patterns, show that SARS-CoV-2 case rates are driven at least in part by predictable seasonal factors.

Significance StatementLocal COVID-19 rates wax and wane. Often these epidemic changes are attributed to localized human behavioral factors. Our finding of highly structured continental scale spatiotemporal patterns that cross state and national boundaries, coupled with emerging evidence of annual repetition of these same patterns, shows that COVID-19 transmission is driven at least in part by seasonal factors. Other epidemic factors such as vaccine coverage rates, or emergence of new strains like the Delta variant of SARS-CoV-2 appear to modify, but not totally eclipse, these underlying seasonal patterns. COVID-19 seasonal transmission patterns are associated with, and may be driven by, seasonal weather patterns. Predictability of these patterns can provide opportunities for forecasting the epidemic and for guiding public health preparedness and control efforts.


title: Vaccination strategies in structured populations under partial immunity and reinfection

abstract:
Optimal protocols of vaccine administration to minimize the effects of infectious diseases depend on a number of variables that admit different degrees of control. Examples include the characteristics of the disease and how it impacts on different groups of individuals as a function of sex, age or socioeconomic status, its transmission mode, or the demographic structure of the affected population. Here we introduce a compartmental model of infection propagation with vaccination and reinfection and analyse the effect that variations on the rates of these two processes have on the progression of the disease and on the number of fatalities. The population is split into two groups to highlight the overall effects on disease caused by different relationships between vaccine administration and various demographic structures. We show that optimal administration protocols depend on the vaccination rate, a variable severely conditioned by vaccine supply and acceptance. As a practical example, we study COVID-19 dynamics in various countries using real demographic data. The model can be easily applied to any other disease and demographic structure through a suitable estimation of parameter values. Simulations of the general model can be carried out at this interactive webpage [1].

Author summaryVaccination campaigns can have varying degrees of success in minimizing the effects of an infectious disease. It is often very difficult to assess a priori the importance and effect of different relevant factors. To gain insight into this problem, we present a model of infection propagation with vaccination and use it to study the effects of vaccination rate and population structure. We find that when the disease affects in different ways distinct population groups, the best vaccination strategy depends non-trivially on the rate at which vaccines can be administered. The application of our analysis to COVID-19 reveals that, in countries with aged populations, the best strategy is always to vaccinate first the elderly, while for youthful populations maximizing vaccination rate regardless of other considerations may save more lives.


title: Are disturbances in mentalization ability similar between schizophrenic patients and borderline personality disorder patients? A pilot study

abstract: There is a growing interest in theory of mind (ToM) performance among individuals with psychiatric disorders, however, the difference and the performance level between different diagnoses is unclear. Here, we compared the ToM abilities of schizophrenia, schizoaffective and borderline personality individuals (BPD) with healthy individuals, and searched for a correlation between ToM ability, social skills, and empathy. Overall, diagnostic groups performed worse in the Reading the Mind in the Eyes test and recognized fewer Faux Pax motifs than healthy individuals recognize. No difference was observed in the ability to perform the eyes test between schizophrenic patients with and without the affective components and BPD patients. Both schizophrenia and BPD patients received a higher score in the autism-spectrum questioner, while all the diagnostic groups scored lower on the empathy quotient scale than healthy individuals. Finally, a correlation was found between ToM ability and empathy, but not with autistic-related traits. Results indicate that both cognitive and affective aspects of ToM are impaired across all the diagnostic groups, challenge the ability to use ToM as a differential diagnostic tool, and strengthens the correlation between decreased empathy and impaired ToM.


title: A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors

abstract:
The number of occupants in a space influences the risk of far-field airborne transmission of SARS-CoV-2 because the likelihood of having infectious and susceptible people both correlate with the number of occupants. This paper explores the relationship between occupancy and the probability of infection, and how this affects an individual person and a population of people. Mass-balance and dose-response models determine far-field transmission risks for an individual person and a population of people after sub-dividing a large reference space into 10 identical comparator spaces.

For a single infected person, the dose received by an individual person in the comparator space is 10-times higher because the equivalent ventilation rate per infected person is lower when the per capita ventilation rate is preserved.

However, accounting for population dispersion, such as the community prevalence of the virus, the probability of an infected person being present and uncertainty in their viral load, shows the transmission probability increases with occupancy and the reference space has a higher transmission risk. Also, far-field transmission is likely to be a rare event that requires a high emission rate, and there are a set of Goldilocks conditions that are just right when ventilation is effective at mitigating against transmission. These conditions depend on the viral load, because when they are very high or low, ventilation has little effect on transmission risk.

Nevertheless, resilient buildings should deliver the equivalent ventilation rate required by standards as minimum.


title: In vivo myelin imaging and tissue microstructure in white matter hyperintensities and perilesional white matter

abstract:
IntroductionWhite Matter hyperintensities (WMHs) relate to cognitive decline in aging, due to their deleterious effect on white matter structure. Diffusion tensor imaging (DTI) detects changes to white matter microstructure, both within the WMH and extending in a penumbra-like pattern in surrounding (perilesional) normal appearing white matter (NAWM). However, DTI markers are not specific to tissue components, complicating interpretation of previous DTI findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction: MWF) and interstitial fluid (geometric mean T2: GMT2). Here we combined DTI and myelin water imaging to examine tissue characteristics in WMHs and perilesional NAWM. Our goal was to establish a multimodal neuroimaging approach to track WMH progression.

Methods80 individuals (47 older adults and 33 individuals with chronic stroke) underwent neuroimaging and tissue segmentation. To measure perilesional NAWM, WMH masks were dilated in 2mm segments up to 10mm in distance from the WMH to measure perilesional NAWM. Fractional anisotropy (FA), mean diffusivity (MD), MWF, and GMT2 were extracted from WMHs and perilesional NAWM. We examined whether white matter metrics showed a spatial gradient of effects in perilesional NAWM, as a function of Distance from the WMH, and Group. We tested whether white matter metrics in the WMH lesion related to severity of cerebrovascular disease across the whole sample, indexed by whole brain WMH volume.

ResultsWe observed a spatial gradient of higher MD and GMT2, and lower FA, in perilesional NAWM and the WMH. In the chronic stroke group, MWF was reduced in the WMH lesion but did not show a spatial gradient in perilesional NAWM. Across the whole sample, white matter metrics within the WMH lesion related to whole-brain WMH volume; MD and GMT2 increased, and MWF decreased, with increasing WMH volume.

ConclusionsNAWM adjacent to WMHs exhibits characteristics of a transitional stage between healthy NAWM tissue and WMH lesions. This was observed in markers sensitive to interstitial fluid, but not in the specific marker of myelin concentration (MWF). Within the WMH, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests that fluid-sensitive imaging metrics (such as DTI) can identify NAWM at high risk of conversion to a WMH. In contrast, specific markers of myelin concentration (e.g., MWF) can be used to measure levels of demyelination in the WMH itself, which may be a useful marker for disease staging of advanced WMHs.


title: The Understanding persistent Pain Where it ResiDes study of low back pain cohort profile

abstract:
BackgroundDespite chronic low back pain (LBP) being considered a biopsychosocial condition for diagnosis and management, few studies have investigated neurophysiological or neurobiological risk factors thought to underpin the transition from acute to chronic LBP. The aim of this cohort profile is to describe the methodology, compare baseline characteristics between acute LBP participants and pain-free controls, and compare LBP participants with or without completed follow-up.

Methods120 individuals experiencing acute LBP and 57 pain-free controls were recruited to participate in the Understanding Persistent Pain Where it Resides (UPWaRD) study. Screening was conducted via email and phone. Neurobiological, psychological, and sociodemographic data were collected at baseline, three- and six-months. LBP status was assessed using the numerical rating scale and Roland-Morris disability questionnaire at three and six-month follow-up.

Results95 participants (79%) provided outcome data at three-month follow-up and 96 participants (80%) at six-months. Participants who did not complete follow-up at three- and six-months within the UPWaRD LBP cohort had higher psychological distress, higher pain interference, higher levels of moderate physical activity, and reported occupational difficulties due to pain (P = <0.05). Compared to controls, LBP participants in the UPWaRD cohort were older, had a higher BMI, a higher prevalence of comorbidities and higher medication usage. Higher depression, anxiety and stress, lower pain self-efficacy and higher pain catastrophizing during acute LBP were correlated with higher six-month pain and disability (P = < 0.01).

ConclusionsThis cohort profile reports baseline characteristics of the UPWaRD LBP and pain-free control cohort.


title: Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimers Disease

abstract:
1.BackgroundSynaptic loss and neurite dystrophy are early events in Alzheimers Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.

MethodsMRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.

ResultsThe AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 x 10-9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.

ConclusionsWe interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD.

category: neurology


title: Severe COVID-19 induces molecular signatures of aging in the human brain

abstract: Coronavirus disease 2019 (COVID-19) is predominantly an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and remains a significant threat to public health. COVID-19 is accompanied by neurological symptoms and cognitive decline, but the molecular mechanisms underlying this effect remain unclear. As aging induces distinct molecular signatures in the brain associated with cognitive decline in healthy populations, we hypothesized that COVID-19 may induce molecular signatures of aging. Here, we performed whole transcriptomic analysis of human frontal cortex, a critical area for cognitive function, in 12 COVID-19 cases and age- and sex-matched uninfected controls. COVID-19 induces profound changes in gene expression, despite the absence of detectable virus in brain tissue. Pathway analysis shows downregulation of genes involved in synaptic function and cognition and upregulation of genes involved in immune processes. Comparison with five independent transcriptomic datasets of aging human frontal cortex reveals striking similarities between aged individuals and severe COVID-19 patients. Critically, individuals below 65 years of age exhibit profound transcriptomic changes not observed among older individuals in our patient cohort. Our data indicate that severe COVID-19 induces molecular signatures of aging in the human brain and emphasize the value of neurological follow-up in recovered individuals.


title: Deep learning to estimate gestational age from blind ultrasound sweeps of the gravid abdomen

abstract:
BackgroundUltrasound is indispensable to gestational age estimation, and thus to quality obstetric care, yet high equipment cost and need for trained sonographers limit its use in low-resource settings.

MethodsFrom September 2018 through June 2021, we recruited 4,695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloops) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test sets, assessed performance of the model and biometry against previously established gestational age.

ResultsIn our main test set, model mean absolute error (MAE) was 3.9 days (standard error [SE] 0.12) vs. 4.7 days (SE 0.15) for biometry (difference -0.8 days; 95% CI -1.1, -0.5; p<0.001). Results were similar in North Carolina (difference -0.6 days, 95% CI -0.9, -0.2) and Zambia (-1.0 days, 95% CI -1.5, -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (model MAE 2.8 days [SE 0.28] vs. 3.6 days [SE 0.53] for biometry; difference -0.8 days, 95% CI -1.7, 0.2), and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (model MAE 4.9 days [SE 0.29] vs. 5.4 days [SE 0.28] for biometry; difference -0.6, 95% CI -1.3, 0.1).

ConclusionsOur model estimated gestational age more accurately from blindly obtained ultrasound sweeps than did trained sonographers performing fetal biometry. These results presage a future where all pregnant people - not just those in rich countries - can access the diagnostic benefits of sonography.

category: obstetrics and gynecology


title: The effect of secretor status and the vaginal microbiome on birth outcome

abstract: Mutations in the FUT2 gene that result in a lack of expression of histo-blood group antigens on secreted glycoproteins may shape the vaginal microbiota with consequences for birth outcome. To test this, we analysed the relationship between secretor status, vaginal microbiota and gestational length in an ethnically diverse cohort of 313 pregnant women, including 91 who delivered prematurely. Lactobacillus species were found to co-occur less often with other microbial taxa in non-secretors. Moreover, non-secretors with Lactobacillus spp. depleted vaginal microbiota in early pregnancy had significantly shorter gestational length than Lactobacillus spp. dominated non-secretors (mean of 245.5 (SD=44.5) versus 265.9 (23.6)); p=0.045), but not compared to Lactobacillus spp. dominated (261.8 (27.5)) and depleted (264.3 days (21.2)) secretors. In identifying a relationship between blood-group antigen expression and vaginal microbiota-host interactions, our results point towards stratification by secretor status as an important factor for considering preterm birth risk and prevention.


title: A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes

abstract: AbstractWe describe the results of the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE). In sex-disaggregated genome-wide studies of COVID-19 hospitalization, we found two known loci associated among males (SLC6A20-LZTFL1 and IFNAR2), and a novel one among females (TLE1). Meta-analyses with independent studies revealed two novel associations (AQP3 and ARHGAP33) and replicated ELF5. A genetic risk score predicted COVID-19 severity, especially among younger males. We found less SNP-heritability and larger heritability differences by age (<60/[≥]60 years) among males than females. Inbreeding depression was associated with COVID-19 hospitalization and severity, and the effect was stronger among older males.

category: genetic and genomic medicine


title: Genome sequencing in the Parkinson disease clinic

abstract:
Background and ObjectivesGenetic variants impact both Parkinsons disease (PD) risk and manifestations. While genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to perform genome sequencing and examine patient interest in comprehensive genetic testing for PD in 2 academic movement disorder clinics.

MethodsIn 208 subjects with PD (age=63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Separately, 231 patients (age=67 years, 63% male) were surveyed on interest in genetic testing at baseline and in response to vignettes covering (i) familial risk of PD (LRRK2); (ii) risk of PD dementia (GBA); (iii) PD genetic risk score; and (iv) secondary, medically-actionable variants (BRCA1).

ResultsGenome sequencing revealed a LRRK2 variant in 3.4% and a GBA risk variant in 10.1% of our clinical sample. The genetic risk score was normally distributed, identifying 42 subjects with high risk of PD. Medically-actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with potential risk for dementia or medically- actionable findings, and most (75%) expressed interest in learning their PD genetic risk score.

DiscussionOur results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.