title: Fractals disruption as the footprint of subthreshold depressive symptoms on the heart rate

abstract:
IntroductionPsychopathology, and in particular depression, is a cardiovascular risk factor independent from co-occurring pathology. This link is traced back to the mind-heart-body connection, whose underlying mechanisms are, to date, not completely known. To study psychopathology in relation to the heart, it is necessary to observe the autonomic nervous system, which mediates among the parts of that connection. Its gold standard of evaluation is the study of heart rate variability (HRV).

ObjectiveTo assess whether any association exists between the HRV parameters and sub-threshold depressive symptoms in a sample of healthy subjects

MethodsTwo short-term HRV recordings (5 min - supine and sitting) were analysed in 77 healthy subjects. Here we adopted a three-fold approach to evaluate HRV: a set of scores belonging to the time domain (SDNN, pNN50, RMSSD); to the frequency domain (high, low, and very low frequencies) and a set of  nonlinear parameters. The PHQ-9 scale was used to detect depressive symptoms.

ResultsDepressive symptoms were associated only with a parameter from the non-linear approach and specifically the long-term fluctuations of fractal dimensions (DFA-2). This association remained significant even after controlling for age, gender, BMI, arterial hypertension, anti-hypertensive drugs, dyslipidaemia, and smoking habit. Moreover, the DFA-2 was not affected by the baroreflex (postural change), unlike other autonomic markers.

ConclusionIn conclusion, fractal analysis of HRV (DFA-2) allows to predict depressive symptoms below diagnostic threshold in healthy subjects regardless of their health status. DFA-2 may be then considered as an imprint of subclinical depression on the heart rhythm.


title: Heart Rate fractality disruption as a footprint of subthreshold depressive symptoms

category: psychiatry and clinical psychology


title: Prediction of ADHD diagnosis using brief, low-cost, clinical measures: a competitive model evaluation

abstract: Proper diagnosis of ADHD is costly, requiring in-depth evaluation via interview, multi-informant and observational assessment, and scrutiny of possible other conditions. The increasing availability of data may allow the development of machine-learning algorithms capable of accurate diagnostic predictions using low-cost measures. We report on the performance of multiple classification methods used to predict a clinician-consensus ADHD diagnosis. Classification methods ranged from fairly simple (e.g., logistic regression) to more complex (e.g., random forest), and also included a multi-stage Bayesian approach. All methods were evaluated in two large (N>1000), independent cohorts. The multi-stage Bayesian classifier provides an intuitive approach that is consistent with clinical workflows, and is able to predict ADHD diagnosis with high accuracy (>86%)--though not significantly better than other commonly used classifiers, including logistic regression. Results suggest that data from parent and teacher surveys is sufficient for high-confidence classifications in the vast majority of cases using relatively straightforward methods.


title: An experimental feasibility study evaluating the adequacy of sportswear-type wearables for recording physical exercise intensity

abstract: Sportswear-type wearables with integrated inertial sensors and electrocardiogram (ECG) electrodes, have been developed. We examined the feasibility of using sportswear-type wearables to evaluate exercise intensity within a controlled laboratory setting. Six male college athletes were asked to wear a sportswear-type wearable while performing a treadmill test that reached up to 20 km/h. The magnitude of the filtered tri-axial acceleration signal, recorded by the inertial sensor, was used to calculate the acceleration index. The R-R intervals of ECG were used to determine heart rate; the external validity of the heart rate was then evaluated according to oxygen uptake, which is the gold standard physiological exercise intensity. Single regression analyses between treadmill speed and the acceleration index in each participant showed that the slope of the regression line was significantly greater than zero with a high coefficient of determination (walking, 0.95; jogging, 0.96; running, 0.90). Another single regression analyses between heart rate and oxygen uptake showed that the slope of the regression line was significantly greater than zero, with a high coefficient of determination (0.96). Together, these results indicate that sportswear-type wearables are a feasible technology for evaluating physical and physiological exercise intensity across a wide range of physical activities and sport performances.

category: sports medicine


title: Detection of the omicron variant in international travellers and their family contacts in India

abstract: HighlightsWith the emergence of the Variant of Concern, omicron (B.1.1.529), India has enhanced genomic surveillance in international travellers. The omicron variant was detected in 59 cases from different States; 40 from Maharashtra, 17 from Rajasthan and one each from Gujrat and Tamil Nadu. The positive cases and their contacts were asymptomatic and genomic surveillance could identify two clusters, one from Maharashtra and another from Rajasthan.

category: infectious diseases


title: Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection

abstract: Monoclonal antibodies (mAbs) are the treatment of choice for high-risk ambulatory persons with mild to moderate COVID-19. We studied viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial. Viral load by qPCR and viral culture were performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAb resulted in rapid clearance of culturable virus in participants without treatment-emergent resistance. One day after treatment, 0 of 28 (0%) participants receiving mAb and 16 of 39 (41%) receiving placebo still had culturable virus (p <0.0001); nasal viral loads were only modestly lower in the mAb-treated group at days 2 and 3. Recrudescence of culturable virus was detected in three participants with emerging mAb resistance and viral load rebound. The rapid reduction in shedding of viable SARS-CoV-2 after mAb treatment highlights the potential role of mAbs in preventing disease transmission.


title: An online atlas of human plasma metabolite signatures of gut microbiome composition

abstract: Summary paragraphThe human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota-host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas "GUTSY" as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.

category: epidemiology


title: Temporal trends of hepatitis C virus transmission in internally displaced people who inject drugs in Odessa, Ukraine

abstract:
BackgroundDue to practical challenges associated with genetic sequencing in low resource environments, the burden of hepatitis C virus (HCV) in forcibly displaced people is understudied. We examined the use of field-applicable HCV sequencing methods and phylogenetic analysis to determine HCV transmission dynamics in internally displaced people who inject drugs (IDPWID) due to war in eastern Ukraine.

MethodsIn this cross-sectional study, we used modified respondent-driven sampling to recruit IDPWID who have settled in Odessa, Ukraine. We generated partial and near full length genome (NFLG) HCV sequences using Oxford Nanopore MinION in a simulated field environment. Maximum likelihood and Bayesian methods were used to establish phylodynamic relationships.

FindingsBetween June and September 2020, we collected epidemiological data and whole blood samples from 164 IDPWID. Rapid testing identified an HIV, anti-HCV, and HIV/HCV co-infection prevalence of 39%, 67.7%, and 31.1%, respectively. We generated 57 partial or NFLG HCV sequences and identified eight transmission clusters, of which at least two originated within a year and a half post-migration. Unstable housing post-migration was associated with more reports of injection drug use in the past 30 days (p=0.048).

InterpretationLocal generation of viral sequencing data and phylogenetic analysis in rapidly changing low-resource environments, such as those faced by forcibly displaced people, can inform timely adaptation of prevention and treatment.

FundingOxford University John Fell Fund, ISS Wellcome Trust, Branco Weiss Fellowship.

category: public and global health


title: Leveraging global multi-ancestry meta-analysis in the study of Idiopathic Pulmonary Fibrosis genetics

abstract:
The research of rare and devastating orphan diseases such as Idiopathic Pulmonary Fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor - the prevalence of IPF is only [~]4-times the incidence of the condition, limiting the recruitment of patients to trials and studies of the underlying biology of the disease. However, global biobanking efforts can dramatically alter the future of IPF research.

Here we describe the largest meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine the meta-analysis with the largest available meta-analysis of IPF so far, reaching 11,160 patients and 1,364,410 population controls in analysis.

We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection, beyond what is known to date. We also note a significant unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.

category: genetic and genomic medicine


title: The Effect of Weather Pattern on the Second Wave of Coronavirus: A cross study between cold and tropical climates of France, Italy, Colombia, and Brazil

abstract: This study aims to explore and understand the common belief that COVID infection rate is highly dependent on either the outside temperature and/or the humidity. Thirty-six regions/states from two humid-tropical countries, namely Brazil and Colombia and two countries with temperate climate, France and Italy, are studied over the period of October to December. Daily outside temperature, relative humidity and hospitalization/cases are analyzed using Spearmans correlation. The eighteen cold regions of France and Italy has seen an average drop in temperature from 10{degrees}C to 6{degrees}C and 17{degrees}C to 7{degrees}C, respectively, and France recorded an addition of 2.3 million cases, while Italy recorded an addition of 1.8 million cases. Outside temperature did not fluctuate much in tropical countries, but Brazil and Colombia added 4.17 million and 1.1 million cases, respectively. Koppen-Geiger classification showed the differences in weather pattern between the four countries, and the analysis showed that there is very weak correlation between either outside weather and/or relative humidity alone to the COVID-19 pandemic.

category: health informatics


title: Transition of antibody titers after the SARS-CoV-2 mRNA vaccine in Japanese healthcare workers

abstract: Since February 2021, health care workers in Japan have been preferentially vaccinated with a messenger RNA vaccine (BNT162b2/Pfizer) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While many studies have confirmed that this vaccine is highly effective in reducing hospitalizations and deaths from coronavirus disease 2019 (COVID-19), antibody titers tend to decline at 3 months, leading to a risk of breakthrough infections. Thus, information is needed to support decision making regarding the third vaccination. In this study, we investigated transition of the anti-SARS-CoV-2 receptor-binding domain (RBD) IgG and neutralizing antibody titers of 41 vaccinated Japanese healthcare workers. Samples were collected seven times starting 1 week before vaccination until 6 months post-vaccination. Anti-SARS-CoV-2 RBD IgG levels peaked at 7 days after the booster, then declined over time and decreased to <10% at 6 months after the booster. Workers with low anti-SARS-CoV-2 RBD IgG levels also had low neutralizing antibody titers. These data support the active use of boosters for healthcare workers, especially for those with low anti-SARS-CoV-2 RBD IgG levels.


title: A cohort study of the effect of SARS-CoV-2 point of care rapid RT-PCR at the Emergency Department on targeted admission

abstract:
(ii)BackgroundTo prevent nosocomial transmission of SARS-CoV-2, infection control measures are implemented for patients with symptoms compatible with COVID-19 until reliable test results are available. This delay targeted admission to the most appropriate ward based on the medical condition. SARS-CoV-2 rapid antigen detection (RAD) tests and point of care (POC) rapid RT-PCR were introduced at emergency departments (EDs) in late 2020, but the consequence on targeted admission is unknown.

ObjectivesTo assess the effect of RAD tests and POC rapid RT-PCR (VitaPCR, Credo Diagnostics, Singapore) on targeted admission.

MethodsPatients presenting at the ED of a referral hospital (N = 2,940) between 13-Nov-2020 and 12-Jan-2021 were included. The study period was delimited by introduction of RAD tests and VitaPCR. Participant data was collected retrospectively, and outcome variables were length-of-stay (LoS), intrahospital transfers and targeted admission to COVID-19 ward.

ResultsRAD tests reduced ED LoS for participants with positive tests or that were not tested. Negative VitaPCR results reduced mean hospital LoS by 1.5 (95%CI: 0.3-2.7) days and admissions to COVID-19 wards from 34.5 (95%CI: 28.9-40.5) to 14.7 (95%CI: 11.1-19.1) per 100 admissions. Introduction of VitaPCR reduced transfers between hospital wards in the first 5 days from 50.0 (95%CI: 45.0-55.0) to 34.0 (95%CI: 30.3-37.9) per 100 admissions.

ConclusionRAD tests enabled rapid detection of SARS-CoV-2 infection which had pronounced effects on LoS at the ED. VitaPCR added the possibility of exclusion of the infection which increased targeted admissions, reduced intrahospital transfers and lead to shorter stay at the hospital.


title: Neutralization of ancestral SARS-CoV-2 and variants Alpha, Beta, Gamma, Delta, Zeta and Omicron by mRNA vaccination and infection-derived immunity through homologous and heterologous variants

abstract:
Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. As the population immunity to SARS-CoV-2 has become more complex due to prior infection and/or vaccination, understanding the antigenic relationship between variants is needed.

Here, we have assessed in total 104 blood specimens from convalescent individuals after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination after double-dose mRNA-vaccination and break through infections due to Delta or Omicron. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, Omicron) was assessed by plaque-reduction neutralization assay.

We found highest neutralization titers against the homologous (previously infecting) variant, with lower neutralization efficiency against heterologous variants. Significant loss of neutralization for Omicron was observed but to a varying degree depending on previously infecting variant (23.0-fold in Beta-convalescence up to 56.1-fold in Alpha-convalescence), suggesting that infection-derived immunity varies, but independent of the infecting variant is only poorly protective against Omicron. Of note, Zeta VOI showed also pronounced escape from neutralization of up to 28.2-fold in Alpha convalescent samples. Antigenic mapping reveals both Zeta and Omicron as separate antigenic clusters.

Double dose vaccination showed robust neutralization for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction of only 2.8 (for Alpha) up to 6.9 (for Beta). Escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron still showed a loss of neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2.

Combined immunity from infection followed by vaccination or vaccine breakthrough infection showed highest titers and most robust neutralization for heterologous variants. Breakthrough infection with Delta showed only 12.5-fold reduced neutralization for Omicron, while breakthrough infection with Omicron showed only a 1.5-fold loss for Delta, suggests that infection with antigenically different variants can boost immunity for antigens closer to the vaccine strain. Antigenic cartography showed also a tendency towards broader neutralizing capacity for heterologous variants.

We conclude that the complexity of background immunity needs to be taken into account when assessing new VOCs. Development towards separate serotypes such as Zeta was already observed before Omicron emergence, thus other factors than just immune escape must contribute to Omicrons rapid dominance. However, combined infection/vaccination immunity could ultimately lead to broad neutralizing capacity also against non-homologous variants.


title: COVID-19 vaccine effectiveness among immunocompromised populations: a targeted literature review of real-world studies

abstract:
IntroductionFrom July through October of 2021, several countries issued recommendations for increased COVID-19 vaccine protection for individuals with one or more immunocompromised (IC) conditions. It is critically important to understand the vaccine effectiveness (VE) of COVID-19 vaccines among IC populations as recommendations are updated over time in response to the evolving COVID-19 pandemic.

Areas coveredA targeted literature review was conducted to identify real-world studies that assessed COVID-19 VE in IC populations between December 2020 and September 2021. A total of 10 studies from four countries were identified and summarized in this review.

Expert opinion/commentaryVE of the widely available COVID-19 vaccines, including BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), and ChAdOx1 nCoV-19 (Oxford/AstraZeneca), ranged from 64%-90% against SARS-CoV-2 infection, 73%-84% against symptomatic illness, 70%-100% against severe illness, and 63%-100% against COVID-19-related hospitalization among the fully vaccinated IC populations included in the studies. COVID-19 VE for most outcomes in the IC populations included in these studies was lower than in the general populations. These findings provide preliminary evidence that the IC population requires greater protective measures to prevent COVID-19 infection and associated illness, hence should be prioritized while implementing recommendations of additional COVID-19 vaccine doses.

category: pharmacology and therapeutics


title: Immunomodulation by intravenous omega-3 fatty acid treatment in older subjects hospitalized for COVID-19: a single-blind randomized controlled trial

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) with respiratory distress and systemic hyperinflammation. The primary objective of this single-blind randomized controlled proof-of-concept clinical trial was to establish the effects of intravenous (i.v.) omega-3 (n-3) polyunsaturated fatty acid (PUFA) treatment compared to placebo on inflammatory markers in COVID-19, represented by leukocytes as well as inflammatory protein and lipid mediators. Here we also present an exploratory analysis of the mechanisms of action to elucidate the potential to resolve the COVID-19 hyperinflammation through interfering with lipid mediators. Inclusion criteria were COVID-19 diagnosis and clinical status requiring hospitalization. Randomization was 1:1 to a once daily i.v. infusion (2 mL/kg) of either n-3 PUFA emulsion containing 10g of fish oil per 100 mL or placebo (NaCl) for 5 days. Results from 22 older subjects (mean age 81{+/-}6.1 years) were analyzed. The neutrophil to lymphocyte ratio was significantly decreased after n-3 PUFA administration. Liquid chromatography-mass spectrometry (LC-MS/MS) -based lipid metabolite analysis established increased proresolving lipid mediator precursor levels and decreased formation of leukotoxin and isoleukotoxin diols by n-3 PUFA treatment. The mechanistic exploration revealed decreased immunothrombosis and preserved interferon-response. Finally, n-3 PUFA treatment may serve to limit cortisone-induced immunosuppression, including preserving leukocyte phagocytic capacity. In conclusion, i.v. n-3 PUFA administration was safe and feasible during hospitalization of multimorbid older subjects for COVID-19. The results identified n-3 PUFA treatment mediated lipid signature of increased proresolving precursor levels and decreased leukotoxin diols in parallel to beneficial immune responses. EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.

category: respiratory medicine


title: Perceived Timing of Cutaneous Vibration and Intracortical Microstimulation of Human Somatosensory Cortex

abstract:
BackgroundElectrically stimulating the somatosensory cortex can partially restore the sense of touch. Though this technique bypasses much of the neuroaxis, prior studies with non-human primates have found that conscious detection of touch elicited by intracortical microstimulation (ICMS) lags behind the detection of vibration applied to the skin. These findings may have been influenced by a mismatch in stimulus intensity; typically, vibration is perceived as more intense than ICMS, which can significantly impact temporal perception.

ObjectiveThe goal of this study was to evaluate the relative latency at which intensity-matched vibration and ICMS are perceived in a human subject.

MethodsA human participant implanted with microelectrode arrays in somatosensory cortex performed a reaction time task and a temporal order judgment (TOJ) task. In the reaction time task, the participant was presented with vibration or ICMS and verbal response times were obtained. In the TOJ task, the participant was sequentially presented with a pair of stimuli - vibration followed by ICMS or vice versa - and reported which stimulus occurred first.

ResultsWhen vibration and ICMS were matched in intensity at a "high" stimulus level, the reaction time to vibration was 48 ms faster than ICMS. When both stimuli were perceived as lower in intensity, the difference in reaction time was even larger: vibration was perceived 90 ms before ICMS. However, in the TOJ task, vibratory and ICMS sensations arose at comparable latencies, with points of subjective simultaneity that were not significantly different from zero.

ConclusionsBecause the perception of ICMS is slower than that of intensity-matched vibration, it may be necessary to stimulate at stronger ICMS intensities (thus decreasing reaction time) when incorporating ICMS sensory feedback into neural prostheses.

category: neurology


title: Effective Connectivity of LSD-induced Ego Dissolution

abstract:
Classic psychedelic-induced ego dissolution involves a shift in the sense of self and blurring of boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated to the balance of anticorrelated activity between the default mode network (DMN) - which directs attention inwards - and the salience network (SN) - which recruits the dorsal attention network (DAN) to direct attention outward. To test whether change in anticorrelated networks underlie the peak effects of LSD, we applied dynamic causal modeling to infer effective connectivity of resting state functional MRI scans from a study of 25 healthy adults who were administered 100mg of LSD, or placebo. We found that change in inhibitory effective connectivity from the SN to DMN became excitatory, and inhibitory effective connectivity from DMN to DAN decreased under the peak effect of LSD. These changes in connectivity reflect diminution of the anticorrelation between resting state networks that may be a key neural mechanism of LSD-induced ego dissolution. Our findings suggest the hierarchically organised balance of resting state networks is a central feature in the construct of self.

SignificanceThe findings can inform the parallel between the maintenance of subject-object boundary and changes to anticorrelated canonical resting state brain networks. Effective connectivity informs the hierarchical organisation of brain networks underlying modes of perception. Moreover, the anticorrelation of brain networks is an important measure of mental function. Understanding the neural mechanisms of anticorrelation change under psychedelics help identify its relationship to psychosis and its association to psychedelic assisted therapeutic outcomes.


title: Quantitation of SARS-CoV-2 neutralizing antibodies with a virus-free, authentic test

abstract:
Neutralizing antibodies (NAbs), and their concentration in sera of convalescents and vaccinees are a solid correlate of protection from COVID-19. The antibody concentrations in clinical samples that neutralize SARS-CoV-2 are difficult and very cumbersome to assess with conventional virus neutralization tests (cVNTs), which require work with the infectious virus and biosafety level 3 containment precautions. Alternative virus neutralization tests currently in use are mostly surrogate tests based on direct or competitive ELISA formats or use viral vectors with the spike protein as the single structural component of SARS-CoV-2. To overcome these obstacles, we developed a virus-free, safe and very fast (4.5 h) in vitro diagnostic test based on engineered yet authentic SARS-CoV-2 virus-like-particles (VLPs). They share all features of the original SARS-CoV-2 but lack the viral RNA genome and thus are non-infectious. NAbs induced by infection or vaccination, but also potentially neutralizing monoclonal antibodies can be reliably quantified and assessed with ease and within hours with our test, because they interfere and block the ACE2-mediated uptake of VLPs by recipient cells. Results from the VLP neutralization test (VLPNT) show excellent correlation to a cVNT with fully infectious SARS-CoV-2 and allow to estimate the reduced neutralization capacity of COVID-19 vaccinee sera with variants of concern of SARS-CoV-2.

Author summaryThe current pandemic caused by SARS-CoV-2 is a major challenge not only for COVID-19 patients, medical staff, healthcare systems and the general public, but also virologists and clinical laboratories. A particular challenge are safety issues which require biological safety level 3 to work with and study the pathogen. An alternative are virus-like particles (VLPs) of SARS-CoV-2, which are authentic in terms of viral structure and function but are harmless bioproducts in nature. We engineered VLPs which are close-to-perfect mimics of SARS-CoV-2 by all structural, biochemical, physical and functional criteria tested. SARS-CoV-2 VLPs were used in virus neutralization tests (VNTs). Because high concentrations of neutralizing antibodies correlate with protection from COVID-19 practical VNTs are urgently needed. We developed an authentic, virus-free, thus safe yet very fast in vitro diagnostic test with SARS-CoV-2 VLPs. Virus neutralizing antibodies induced by natural infection or vaccination but also certain monoclonal antibodies inhibit VLP fusion with recipient cells carrying ACE2. Quantitative results from a conventional neutralization test with fully infectious SARS-CoV-2 and results from the VLP-based neutralization test correlate perfectly. The setup of the test is very flexible and allows to analyze sera for their neutralizing capacity against different variants of concern and in a standardized assay format.


title: Long-lasting cellular immunity to SARS-CoV-2 following infection or vaccination and implications for booster strategies

abstract: Immunization against SARS-CoV-2, the causative agent of coronavirus disease-19 (COVID-19) occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last. We performed a longitudinal evaluation of immunological memory to SARS-CoV-2 following mRNA vaccination in naive and COVID-19 recovered individuals. We found that cellular immunity is still detectable 8 months after vaccination, while antibody levels decline significantly especially in naive subjects. We also found that a booster injection is more efficacious in reactivating immunological memory to spike protein in naive than in previously SARS-CoV-2 infected subjects. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to one year following natural infection in a cohort of unvaccinated individuals. Short-term persistence of humoral immunity may account for reinfections and breakthrough infections, although long-lived memory B and CD4+ T cells may protect from severe disease. A booster dose restores optimal anti-spike immunity in naive subjects, while the need for vaccinated COVID-19 recovered subjects has yet to be defined.


title: Estimating the direct Disability-Adjusted Life Years (DALYs) associated with SARS-CoV-2 (COVID-19) in the Republic of Ireland: The first full year

abstract:
ObjectivesBurden of Disease frameworks facilitate estimation of the health impact of diseases to be translated into a single measure, such as the Disability-Adjusted-Life-Year (DALY).

MethodsDALYs were calculated as the sum of Years of Life Lost (YLL) and Years Lived with Disability (YLD) directly associated with COVID-19 in the Republic of Ireland (RoI) from March 01, 2020, to February 28, 2021. Life expectancy is based on the Global Burden of Disease (GBD) Study life tables for 2019.

ResultsThere were 220,273 confirmed cases with a total of 4,500 deaths as a direct result of COVID-19. DALYs were estimated to be 51,532.1 (95% Uncertainty Intervals [UI] 50,671.6, 52,294.3). Overall, YLL contributed to 98.7% of the DALYs. Of total symptomatic cases, 6.5% required hospitalisation and of those hospitalised 10.8% required intensive care unit treatment. COVID-19 was likely to be the second highest cause of death over our studys duration.

ConclusionEstimating the burden of a disease at national level is useful for comparing its impact with other diseases in the population and across populations. This work sets out to standardise a COVID-19 BoD methodology framework for the RoI and comparable nations in the EU.


title: Performance of a Multisensor Smart Ring to Evaluate Sleep: In-Lab and Home-Based Evaluation Relative to Polysomnography and Actigraphy: Importance of Generalized Versus Personalized Scoring

abstract:
Study ObjectivesWearable sleep technology has rapidly expanded across the consumer market due to advances in technology and increased interest in personalized sleep assessment to improve health and mental performance. In this study, we tested the performance of a novel device, the Happy Ring, alongside other commercial wearables, against in-lab polysomnography (PSG) and an at-home EEG-derived sleep monitoring device, the Dreem 2 Headband.

Methods36 healthy adults with no diagnosed sleep disorders and no recent use of medications or substances known to affect sleep pattern were assessed across 77 nights while wearing the Happy Ring, as well as a set of other consumer wearable devices. Subjects participated in a single night of in-lab PSG and 2 nights of at-home data collection. The Happy Ring includes sensors for skin conductance, movement, heart rate, and skin temperature. The Happy Ring utilized two machine-learning derived scoring algorithms: a "generalized" algorithm that applied broadly to all users, and a "personalized" algorithm that adapted to individual subjects data. Epoch-by-epoch analyses compared the wearable devices to both in-lab PSG and to the Dreem 2 EEG Headband ("Dreem 2 Headband") at home.

ResultsCompared to in-lab PSG, the "generalized" and "personalized" algorithms demonstrated good sensitivity (94% and 93%, respectively) and specificity (70% and 83%, respectively). Accuracy was 91% for "generalized" and 92% for "personalized" algorithms. The generalized algorithm demonstrated an accuracy of 67%, 85%, and 85% for light, deep, and REM sleep, respectively. The personalized algorithm was 81%, 95%, and 92% accurate for light, deep, and REM sleep, respectively.

ConclusionsThe Happy Ring performed well at home and in the lab, especially regarding sleep detection. The personalized algorithm demonstrated improved detection accuracy over the generalized approach and other devices, suggesting that adaptable, dynamic algorithms can enhance sleep detection accuracy.


title: Longitudinal serologic and viral testing post-SARS-CoV-2 infection and post-receipt of mRNA COVID-19 vaccine in a nursing home cohort--Georgia, October 2020-April 2021

abstract:
ImportanceThere are limited data describing SARS-CoV-2-specific immune responses and their durability following infection and vaccination in nursing home residents.

ObjectiveTo evaluate the quantitative titers and durability of binding antibodies detected after SARS-CoV-2 infection and subsequent COVID-19 vaccination.

DesignA prospective longitudinal evaluation included nine visits over 150 days; visits included questionnaire administration, blood collection for serology, and paired anterior nasal specimen collection for testing by BinaxNOW COVID-19 Ag Card (BinaxNOW), reverse transcription polymerase chain reaction (RT-PCR), and viral culture.

SettingA nursing home during and after a SARS-CoV-2 outbreak.

Participants11 consenting SARS-CoV-2-positive nursing home residents.

Main Outcomes and MeasuresSARS-CoV-2 testing (BinaxNOW, RT-PCR, viral culture); quantitative titers of binding SARS-CoV-2 antibodies post-infection and post-vaccination (beginning after the first dose of the primary series).

ResultsOf 10 participants with post-infection serology results, 9 (90%) had detectable Pan-Ig, IgG, and IgA antibodies and 8 (80%) had detectable IgM antibodies. At first antibody detection post-infection, two-thirds (6/9, 67%) of participants were RT-PCR-positive but none were culture positive. Ten participants received vaccination; all had detectable Pan-Ig, IgG, and IgA antibodies through their final observation [≤]90 days post-first dose. Post-vaccination geometric means of IgG titers were 10-200-fold higher than post-infection.

Conclusions and RelevanceNursing home residents in this cohort mounted robust immune responses to SARS-CoV-2 post-infection and post-vaccination. The augmented antibody responses post-vaccination are potential indicators of enhanced protection that vaccination may confer on previously infected nursing home residents.


title: Interictal SEEG resting-state connectivity localizes seizure onset zone and predicts seizure outcome

abstract: Stereotactic-electroencephalography (SEEG) is a common neurosurgical method to localize epileptogenic zone in drug resistant epilepsy patients and inform treatment recommendations. In the current clinical practice, localization of epileptogenic zone typically requires prolonged recordings to capture seizure, which may take days to weeks. Although epilepsy surgery has been proven to be effective in general, the percentage of unsatisfactory seizure outcomes is still concerning. We developed a method to identify the seizure onset zone (SOZ) and predict seizure outcome using short-time resting-state SEEG data. In a cohort of 43 drug resistant epilepsy patients, we estimated the information flow via directional connectivity and inferred the excitation-inhibition ratio from the 1/f power slope. We hypothesized that the antagonism of information flow at multiple frequencies between SOZ and non-SOZ underlying the relatively stable epilepsy resting state could be related to the disrupted excitation-inhibition balance. We found higher excitability in non-SOZ regions compared to the SOZ, with dominant information flow from non-SOZ to SOZ regions, probably reflecting inhibitory input from non-SOZ to prevent seizure initiation. Greater differences in information flow between SOZ and non-SOZ regions were associated with favorable seizure outcome. By integrating a balanced random forest model with resting-state connectivity, our method localized the SOZ with an accuracy of 85% and predicted the seizure outcome with an accuracy of 77% using clinically determined SOZ. Overall, our study suggests that brief resting-state SEEG data can significantly facilitate the identification of SOZ and may eventually predict seizure outcomes without requiring long-term ictal recordings.


title: Identifying the critical time window for the association of the early-life gut microbiome and metabolome with childhood neurodevelopment

abstract: It has been widely recognized that a critical time window for neurodevelopment occurs in early life, and that the hosts gut microbiome plays an important role in neurodevelopment. While murine models have demonstrated that the maternal gut microbiome also influences offspring brain development, for humans it is still unclear if the critical time window for the association between the gut microbiome and neurodevelopment is prenatal, postnatal or both. Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers and their children with the childrens neurodevelopment. We show, for the first time, that the maternal gut microbiome is more relevant than the childrens gut microbiome to the childrens neurodevelopment in the first year of life. Interestingly, the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment. These findings shed light on potential therapeutic interventions to prevent neurodevelopmental disorders.


title: Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

abstract: Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with solid cancers including prostate and lung. Additionally, contrary to previous findings from the initial 50,000 UKB exomes, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogenous phenotypes with shared and unique germline genetic causes and varied clinical implications.


title: Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukaemia patients with hypogammaglobulinaemia and infection; analysis of total national utilisation data in Australia 2008-2013

abstract:
ObjectivesTo analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections.

MethodsIn 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive.

ResultsFrom 2008-2013 across Australia, 2,734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926 grams of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam(R)P accounting for 89.7% of supply. The average age for first dose was 74 years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03g/L{+/-}2.03g/L (range 0.30-10.50g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories.

ConclusionThis study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a six year period.

O_LIWhat is the NEW aspect of your work? (ONE sentence)
The first and only comprehensive analysis of total national immunoglobulin replacement therapy (IgRT) facts and data of supply, demand and patterns of utilisation in Chronic Lymphocytic Leukaemia (CLL).
C_LIO_LIWhat is the CENTRAL finding of your work? (ONE sentence)
Utilisation of IgRT (in this study period solely as IVIg) reflects the demographics of CLL patients with more advanced disease with hypogammaglobulinaemia and recurrent / severe infection (and hence in need of IgRT for infection prophylaxis), but utilisation can vary considerably.
C_LIO_LIWhat is (or could be) the SPECIFIC clinical relevance of your work? (ONE sentence)
Immune failure occurs in virtually all patients with CLL and the resulting increase in infection risk is a major contributor to morbidity and mortality; this totally comprehensive, national data set over 6 years of IgRT use will inform all Haematologists (especially CLL clinicians and those managing patients with immunocompromise), State and National Blood Banks, State and National Departments of Health, immunoglobulin manufacturers and supply chains, and CLL and immunoglobulin replacement guideline authors in their understanding of IgRT supply, demand and utilisation.
C_LI

category: hematology


title: Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancies and COVID-19: a longitudinal cohort and propensity score analysis

abstract:
Patients with hematological malignancies and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatment impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2.

We report the effect of CCP in a cohort of 112 patients with hematological malignancies and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n=81) or not (n=120) with CCP between 1 May 2020 and 1 April 2021. The overall survival of the whole cohort was 65% [56-74.9] and 77.5% [68.5-87.7] for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibodies therapy was associated with better overall survival whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20-exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI=31%-80%) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses.

Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.


title: COVIDFast: A high-throughput and RNA extraction-free method for SARS-CoV-2 detection in swab (SwabFAST) or saliva (SalivaFAST)

abstract: There is an urgent need of having a rapid, high throughput, yet accurate SARS-COV-2 PCR testing to control the COVID19 pandemic. However, the RNA extraction step in conventional PCR creates a major bottle neck in the diagnostic process. In this paper we modified the CDC COVID-19 assay and developed an RNA-extraction free RT-qPCR assay for SARS-CoV-2, i.e. COVIDFast. Depending on sample types, the assay is further divided into SwabFAST, which uses anterior nares nasal swab, and SalivaFAST, which uses saliva. By utilizing the proprietary buffer for either swab or saliva samples, the performance of SwabFAST or SalivaFAST is equivalent to RNA-extraction SARS-CoV-2 RT-qPCR in both contrived and clinical samples. The limit of detection of either assay is 4 copies/L. We further developed a semi-automatic system, which is easy to adapt by clinical lab for implementation of a high-throughput SARS-CoV-2 test. Working together with the COVIDCheck Colorado, we have tested over 400,000 samples using COVIDFast (83.62% SwabFAST and 16.38% SalivaFAST) in less than a year, resulting in significant clinical contribution in the battle against COVID-19 during the pandemic.


title: Improvement of field-deployable metagenomic virus detection by a simple pretreatment method.

abstract:
As both the current COVID-19 pandemic and earlier pandemics have shown, animals are the source for some of the deadliest viral pathogens, which can spread to humans. Therefore, early detection at the point of incidence is crucial to both prevent and understand the threats posed to human health from pathogens in animal reservoirs. Often, the exact genetic nature of these zoonotic pathogens is unknown and advanced laboratory facilities do not exist in most field settings and therefore the development of methods for unbiased metagenomic and point of incidence detection is crucial in order to identify novel viral pathogens in animals with zoonotic and pandemic potential.

Here we addressed some of these issues by developing a metagenomic Nanopore next-generation sequencing (mNGS) method for nucleic acids extracted from clinical samples from patients with SARS-CoV-2. To reduce the non-RNA viral genetic components in the samples, we used DNase pretreatment in a syringe followed by filtration and found that these pretreatments increased the number of SARS-CoV2 reads by > 500-fold compared with no pretreatment.

The simple protocol, described here, allows for fast (within 6 hours) metagenomic detection of RNA viruses in biological samples exemplified by SARS-CoV-2 detection in clinical throat swabs. This method could also be applied in field settings for point of incidence detection of virus pathogens, thus eliminating the need for transport of infectious samples, cold storage and a specialized laboratory.

HighlightsO_LIHere we present a field-deployable metagenomic Nanopore protocol for RNA virus detection.
C_LIO_LISARS-CoV-2 detection used as proof-of-concept.
C_LIO_LIAnalysis of simple methods for non-viral nucleic acid depletion were tested on SARS-CoV-2 clinical samples.
C_LIO_LIDNase I treatment followed by 0.22{micro}M syringe filtration dramatically increased the number of SARS-CoV-2 reads and virus genome coverage.
C_LI


title: Point-of-care lung ultrasound predicts severe disease and death due to COVID-19: a prospective cohort study.

abstract:
ObjectiveThe clinical utility of point-of-care lung ultrasound (LUS) for disease severity triage of hospitalized patients with COVID-19 is unclear.

DesignProspective cohort study

SettingA large tertiary care center in Maryland, USA between April 2020 to September 2021.

PatientsHospitalized adults ([≥]18 years of age) with positive SARS-CoV-2 RT-PCR results.

InterventionsNone.

Measurements and Main ResultsAll patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28-days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean Lung Ultrasound Score (ranging from 0 to 3) across lung zones (mLUSS) was determined. The primary outcome was time to ICU-level care, defined as high flow oxygen, noninvasive, or mechanical ventilation, within 28-days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 59 years and 114 (43.2) % of participants were female. The median mLUSS was 1 (interquartile range: 0.5 to 1.3). Following enrollment, 29 (11.0%) participants went on to require ICU-level care and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (aHR = 3.63; 95% CI: 1.23 to 10.65) and 28-day mortality (aHR = 4.50; 95% CI: 1.52 to 13.31). Pleural line abnormalities were independently associated with disease progression to ICU-level care (aHR = 18.86; CI: 1.57 to 226.09).

ConclusionsParticipants with a mLUSS [≥]1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.


title: Viral cultures, PCR Cycle threshold values and viral load estimation for COVID-19 infectious potential assessment in transplant patients: systematic review - Protocol Version 29 December 2021

abstract:
This is the protocol for a systematic review focussing on people receiving solid organ or hematopoietic stem cell transplants.

Our research questions are as follows:

What is the relationship between serial PCR Ct value or other measures of viral burden, and the likelihood and duration of the presence of infectious virus from viral culture, among transplant recipients with SARS-CoV-2 infection?

What is the influence of age, sex, underlying pathologies, degree of immunosuppression, vaccination status, COVID-19 symptoms and COVID-19 disease course on viral burden and the likelihood of presence of infectious SARS-CoV-2?

We will include single studies reporting serial Cts from sequential rt-PCR testing or other measures of viral burden such as RNA gene copies of respiratory samples (from nasopharyngeal specimens) along with viral culture data on the same samples, from patients about to receive a transplant or who are post transplant with SARS-CoV-2 infection.


title: EARLY LENZILUMAB TREATMENT OF COVID-19 PATIENTS USING C-REACTIVE PROTEIN AS A BIOMARKER IMPROVES EFFICACY: RESULTS FROM THE PHASE 3 LIVE-AIR TRIAL

abstract:
ObjectiveThe LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab.

DesignLIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28.

SettingSecondary and tertiary care hospitals in the US and Brazil.

Participants520 hospitalized COVID-19 participants with SpO2[≤] 94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included.

InterventionsLenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir.

Main outcome measuresA multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values.

ResultsThe multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP[≥]150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade [≥] 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab.

ConclusionThese finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention.

Trial RegistrationClinicalTrials.gov NCT04351152

WHAT IS ALREADY KNOWN ON THIS TOPICGM-CSF is one of the early upstream mediators and orchestrators of the hyperinflammatory immune response following SARS-CoV-2 infection. Baseline levels of GM-CSF and CRP have each been shown to correlate with COVID-19 disease progression. Increases in CRP are driven by elevations of IL-6 during the hyperinflammatory response following SARS-CoV-2 infection. In the phase 3, randomized, double-blind, placebo-controlled LIVE-AIR study, GM-CSF neutralization with lenzilumab significantly improved the likelihood of survival without invasive mechanical ventilation (SWOV, primary endpoint, also referred to as ventilator-free survival) vs. placebo (HR:1.54; 95% CI, 1.02 to 2.32; p=0.0403), which included standard supportive care including corticosteroids and remdesivir. No treatment-emergent serious adverse events attributable to lenzilumab have been reported to date.

WHAT THIS STUDY ADDSA comprehensive analysis of LIVE -AIR CRP data provides evidence for the utility of baseline CRP to predict progression to IMV and death. Baseline CRP was identified to be the strongest predictor of SWOV in this study. Patients with baseline CRP<150 mg/L represented 78% of the study population and demonstrated the greatest clinical benefit with lenzilumab, including SWOV through day 28 (HR: 2.54; 95%CI; 1.46-4.41; nominal p=0.0009). A biomarker-driven approach using baseline CRP levels to guide therapeutic intervention may improve outcomes in those hospitalized with COVID-19. Participants with baseline CRP levels above 150 mg/L were described as experiencing COVID-19-associated hyperinflammation and were at risk of imminent escalation of respiratory support or death. Elevated baseline plasma CRP was the most predictive feature for progression to IMV or death (OR, 0.15; 95%CI, 0.07-0.29; nominal p<0.001). These findings suggest that baseline CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.

category: intensive care and critical care medicine


title: Cross reactivity of spike glycoprotein induced antibody against delta and omicron variants before and after third SARS-CoV-2 vaccine dose

abstract:
Variants of SARS-CoV-2 may evade natural and vaccine induced immunity and monoclonal antibody immunotherapeutics. There is an urgent need to know how well antibodies, induced by healthy and Clinically Extremely Vulnerable (CEV) patients, will bind and thus help reduce transmission and severity of infection from variants of concern (VOC). This study determines the cross-reactive binding of serum antibodies obtained prior to and 28 days after a third vaccination in three cohorts; a health care worker cohort who received three doses of Pfizer-BioNtech (PPP), a cohort of CEV patients received two doses of the AstraZeneca-ChAdOx1-nCoV-19 (AAP) vaccine, followed by a third PFZ vaccine and a haemodialysis cohort that had a mixture of two AZ or PFZ vaccines followed by a PFZ booster. Six months post second vaccine there was evidence of antibody waning with 58.9% of individuals in the HD cohort seropositive against Wuhan, 34.4% Delta and 62.2% Omicron strains. For the AAP cohort, equivalent figures were 62.5%, 45.8% and 91.7% and the PPP cohort 92.2%, 90% and 91.1%. Post third dose vaccination there were universal increases in seropositivity and median optical density. For the HD cohort, 98.8% were seropositive to the Wuhan strain, 97.6% against Delta and 100% against Omicron strains. For the PPP and AAP cohorts, 100% were seropositive against all 3 strains. Lastly, we examined the WHO NIBSC 20/136 standard and there was no loss of antibody binding to either VOC. Similarly, a dilution series of Sotrovimab (GSK) found this therapeutic monoclonal antibody bound similarly to all VOC.

HighlightsO_LIIgG anti-SARS-CoV-2 Omicron spike glycoprotein antibody levels were high in 100% of health care workers (HCW), a general practice population considered clinically extremely vulnerable (CEV) and haemodialysis patients (HD) 4 weeks after a third SARS-CoV-2 vaccine dose (Pfizer-BioNtech-PFZ).
C_LIO_LIFor both Delta and Omicron variant spike glycoproteins these antibody levels were highest in the CEV cohort who had previously received two doses of AstraZeneca ChAdOx1 nCoV-19 vaccine (AAP), lower in HCW who had previously received two doses of PFZ (PPP) and lowest in HD who had a mix of vaccines for the first and second dose
C_LIO_LIPrior to this third vaccine dose and 6 months post second vaccine dose there was evidence of significant waning of antibodies against VOC.
C_LI

category: allergy and immunology


title: Endothelin-1 is Increased in the Plasma of Patients Hospitalized with Covid-19

abstract:
ImportanceThe coronavirus disease 2019 (Covid-19) pandemic continues to place a devastating strain on healthcare services worldwide and there remains an ongoing requirement for new treatments. A key mechanism recognised in progressive severe disease is virus-induced endothelial dysregulation. Endothelin-1 (ET-1), being the most highly expressed peptide in endothelial cells and potent vasoconstrictor of human blood vessels, represents a potential therapeutic target through the use of Endothelin receptor antagonists.

ObjectiveTo investigate the association of plasma ET-1 with Covid-19 disease severity

DesignRetrospective longitudinal cohort study of Covid-19 patients divided into Group A (asymptomatic or symptoms not requiring hospitalisation), Group B (symptoms requiring hospitalisation) and Group C (symptoms requiring supplemental oxygen therapy or assisted ventilation) recruited between March and July 2020 (the first wave of the Covid-19 pandemic in the UK). Data were compared with a contemporaneous cross-section of non-infected volunteers (Controls).

SettingSingle Tertiary National Health Service Hospital.

ParticipantsTissue banked plasma samples were obtained from 194 patients.

ExposuresQuantitation of ET-1 in plasma by specific enzyme linked immunosorbent assay.

Main outcome and measuresPairwise comparison of ET-1 levels (median [IQR]) between patient categories, and subgroups defined by clinical outcomes.

ResultsBaseline ET-1 plasma levels (pg/ml) were elevated in patients requiring hospitalisation compared with controls and patients with asymptomatic or mild infection (Group B: 1.59 [1.13-1.98], and Group C: 1.65 [1.02-2.32] versus controls: 0.68 [0.47-0.87], p=<0.001 and Group A: 0.72 [0.57-1.10], p=<0.001). ET-1 levels were also elevated in patients that died (2.09 [1.66-3.15]), developed acute kidney (1.70 [1.07-2.36]) or myocardial injury (1.50 [0.92-2.28]) compared with patients with an uncomplicated infection (1.00 [0.61-1.57], p=<0.01). Amongst surviving hospitalised patients, ET-1 concentrations decreased when measured at 28 days (Group B: 0.86 [0.60-1.61] and Group C: 1.17 [0.66-1.62] versus baseline, p=<0.05) and 90 days (Group B: 0.69 [0.59-1.38] and Group C: 1.01 [0.64-1.21] versus baseline, p=<0.05).

Conclusions and relevanceHospitalised Covid-19 patients demonstrate elevated ET-1 levels during the acute phase of infection and this is associated with increasing clinical severity of the disease. The results support the hypothesis that endothelin receptor antagonists may be beneficial for certain Covid-19 patients.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the association of the endothelial peptide and potent vasoconstrictor: endothelin-1 with disease severity in Covid-19 infection?

FindingsHospitalised Covid-19 patients (especially those requiring supplemental oxygen and assisted ventilation, dying patients, and those who developed acute myocardial or kidney injury) have higher circulating endothelin-1 levels during the acute phase of their infection, compared with patients with asymptomatic or only mildly symptomatic Covid-19 infection.

MeaningEndothelial dysregulation is a well-recognised mechanism for progressive severe Covid-19 infection and these results suggest targeting endothelin-1 activity through the use of Endothelin receptor antagonists may be of benefit.

category: cardiovascular medicine


title: Increased Risk of Poor Clinical Outcome in COVID-19 Patients with Diabetes Mellitus and in-hospital Mortality Predictors: A Retrospective Cohort from a Tertiary Hospital in Indonesia

abstract:
AimTo determine association between diabetes in confirmed cases of COVID-19 and intensive care admission and in-hospital mortality, evaluate several laboratory parameters as mortality predictor, and develop predictors of in-hospital mortality among diabetics with COVID-19.

MethodsThis retrospective cohort recruited all cases of COVID-19 hospitalized in Fatmawati General Hospital during March to October 2020. Inclusion criteria was RT-PCR confirmed cases of COVID-19 who aged 18 years and older while exclusion criteria were incomplete medical record or cannot be found and pregnant women.

ResultsWe enrolled 506 participants to this study with median age of 51 years (IQR:22), female (56.32%), and diabetes (28.46%). Diabetes increased intensive care admission (adjusted OR:6.07;95%CI:3.52-10,43) and in-hospital mortality (adjusted OR:50;95%CI:1.61-3.89). In predicting in-hospital mortality, ferritin and lactate dehydrogenase offered an acceptable discrimination, AUC:0.71 (95%CI: 0.62-0.79) and AUC:0.70 (95%CI: 0.61-0.78), respectively. The optimal cut-off of predicting mortality for ferritin was 786 g/mL and for LDH was 514.94 u/L. Factors include age above 70 years old, RBGs level on admission above 250 mg/dL or below 140 mg/dL, ferritin level above 786 ng/mL, and presence of ARDS increased the odds of mortality among individuals with diabetes.

ConclusionsDiabetes increases risk of intensive care admission and in hospital mortality in COVID-19. Multivariate analysis showed that older age, RBG on admission, high ferritin level, presence of ARDS increased the odds of mortality among individuals with diabetes.

category: endocrinology


title: Inferring effects of mutations on SARS-CoV-2 transmission from genomic surveillance data

abstract: New and more transmissible variants of SARS-CoV-2 have arisen multiple times over the course of the pandemic. Rapidly identifying mutations that affect transmission could facilitate outbreak control efforts and highlight new variants that warrant further study. Here we develop an analytical epidemiological model that infers the transmission effects of mutations from genomic surveillance data. Applying our model to SARS-CoV-2 data across many regions, we find multiple mutations that strongly affect the transmission rate, both within and outside the Spike protein. We also quantify the effects of travel and competition between different lineages on the inferred transmission effects of mutations. Importantly, our model detects lineages with increased transmission as they arise. We infer significant transmission advantages for the Alpha and Delta variants within a week of their appearances in regional data, when their regional frequencies were only around 1%. Our model thus enables the rapid identification of variants and mutations that affect transmission from genomic surveillance data.


title: Sample Size Calculations for Variant Surveillance in the Presence of Biological and Systematic Biases

abstract: As demonstrated during the SARS-CoV-2 pandemic, detecting and tracking the emergence and spread of pathogen variants is an important component of monitoring infectious disease outbreaks. Pathogen genome sequencing has emerged as the primary tool for variant characterization, so it is important to consider the number of sequences needed when designing surveillance programs or studies, both to ensure accurate conclusions and to optimize use of limited resources. However, current approaches to calculating sample size for variant monitoring often do not account for the biological and logistical processes that can bias which infections are detected and which samples are ultimately selected for sequencing. In this manuscript, we introduce a framework that models the full process from infection detection to variant characterization and demonstrate how to use this framework to calculate appropriate sample sizes for sequencing-based surveillance studies. We consider both cross-sectional and continuous sampling, and we have implemented our method in a publicly available tool that allows users to estimate necessary sample sizes given a specific aim (e.g., variant detection or measuring variant prevalence) and sampling method. Our framework is designed to be easy to use, while also flexible enough to be adapted to other pathogens and surveillance scenarios.


title: A Web-based Spatial Decision Support System of Wastewater Surveillance for COVID-19 Monitoring: A Case Study of a University Campus

abstract: The ongoing COVID-19 pandemic has produced substantial impacts on our society. Wastewater surveillance has increasingly been introduced to support the monitoring, and thus mitigation, of COVID-19 outbreaks and transmission. Monitoring of buildings and sub-sewershed areas via a wastewater surveillance approach has been a cost-effective strategy for mass testing of residents in congregate living situations such as universities. A series of spatial and spatiotemporal data are involved with wastewater surveillance, and these data must be interpreted and integrated with other information to better serve as guidance on response to a positive wastewater signal. The management and analysis of these data poses a significant challenge, in particular, for the need of supporting timely decision making. In this study, we present a web-based spatial decision support system framework to address this challenge. Our study area is the main campus of the University of North Carolina at Charlotte. We develop a spatiotemporal data model that facilitates the management of space-time data related to wastewater surveillance. We use spatiotemporal analysis and modeling to discover spatio-temporal patterns of COVID-19 virus abundance at wastewater collection sites that may not be readily apparent in wastewater data as they are routinely collected. Web-based GIS dashboards are implemented to support the automatic update and sharing of wastewater testing results. Our web-based SDSS framework enables the efficient and automated management, analytics, and sharing of spatiotemporal data of wastewater testing results for our study area. This framework provides substantial support for informing critical decisions or guidelines for the prevention of COVID-19 outbreak and the mitigation of virus transmission on campus.


title: Early signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas

abstract: Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology and clinical severity and disease course. A comprehensive genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 862 symptomatic patients with infections caused by Omicron from late November 2021 through December 18, 2021. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with decreased disease severity. Although the number of Omicron patients we studied is relatively small, in the aggregate the data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and provide information about disease character.

category: pathology


title: Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas


title: Predicting the distribution of arsenic in groundwater by machine learning technique in two worst hit districts of Assam, India: a risk to public health

abstract: Arsenic (As) is a well-known human carcinogen and a significant chemical contaminant in groundwater. The spatial heterogeneity in the distribution of As in groundwater makes it difficult to predict the location of safe areas for tube well installations for consumption and agricultural use. Geospatial machine learning techniques have been used to predict the location of safe and unsafe areas of groundwater As contaminations. Here we used a similar machine learning approach to determine the risk and extent of As >10 g/L in groundwater at a finer spatial resolution (250m x 250m) in two worst-hit districts of Assam, India, to advise policymakers for targeted campaigning for mitigation. Random Forest Model was employed in Python environments to predict probabilities of the occurrences of As at concentrations >10 {micro}g/L using several intrinsic and extrinsic predictor variables. The selection of predictor variables was based on their inherent relationship with the occurrence of As in groundwater. The relationships between predictor variables and proportions of As occurrences >10 g/L follow the well-documented processes leading to As release in groundwater. We identified extensive areas of potential As hotspots based on the probability of [≥]0.7 for As >10 {micro}g/L. These identified areas include areas that were not previously surveyed and extended beyond previously known As hotspots. Twenty-five percent of the land area (1,500 km2) was identified as a high-risk zone with an estimated population of 155,000 potentially consuming As through drinking water or food cooked with water containing As >10 g/L. The ternary hazard map (i.e., high, moderate, and low risk for As >10 {micro}g/L) could inform the policymakers to target the regions by establishing newer drinking water treatment plants and supplying safe drinking water.


title: Humoral immune responses against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine

abstract:
BackgroundSolid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.

MethodsWe performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.

ResultsPrior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.

ConclusionsOnly a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.

category: transplantation


title: Retinal fundus photographs capture hemoglobin loss after blood donation

abstract: Recently it was shown that blood hemoglobin concentration could be predicted from retinal fundus photographs by deep learning models. However, it is unclear whether the models were quantifying current blood hemoglobin level, or estimating based on subjects pretest probability of having anemia. Here, we conducted an observational study with 14 volunteers who donated blood at an on site blood drive held by the local blood center (ie, at which time approximately 10% of their blood was removed). When the deep learning model was applied to retinal fundus photographs taken before and after blood donation, it detected a decrease in blood hemoglobin concentration within each subject at 2-3 days after donation, suggesting that the model was quantifying subacute hemoglobin changes instead of predicting subjects risk. Additional randomized or controlled studies can further validate this finding.


title: Effectiveness of COVID-19 vaccines against Omicron or Delta infection

abstract:
BackgroundThe incidence of SARS-CoV-2 infection, including among those who have received 2 doses of COVID-19 vaccines, increased substantially following the emergence of Omicron in Ontario, Canada.

MethodsApplying the test-negative study design to linked provincial databases, we estimated vaccine effectiveness (VE) against symptomatic infection and severe outcomes (hospitalization or death) caused by Omicron or Delta between December 6 and 26, 2021. We used multivariable logistic regression to estimate the effectiveness of 2 or 3 COVID-19 vaccine doses by time since the latest dose, compared to unvaccinated individuals.

ResultsWe included 16,087 Omicron-positive cases, 4,261 Delta-positive cases, and 114,087 test-negative controls. VE against symptomatic Delta infection declined from 89% (95%CI, 86-92%) 7-59 days after a second dose to 80% (95%CI, 74-84%) after [≥]240 days, but increased to 97% (95%CI, 96-98%) [≥]7 days after a third dose. VE against symptomatic Omicron infection was only 36% (95%CI, 24-45%) 7-59 days after a second dose and provided no protection after [≥]180 days, but increased to 61% (95%CI, 56-65%) [≥]7 days after a third dose. VE against severe outcomes was very high following a third dose for both Delta and Omicron (99% [95%CI, 98-99%] and 95% [95%CI, 87-98%], respectively).

ConclusionsIn contrast to high levels of protection against both symptomatic infection and severe outcomes caused by Delta, our results suggest that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for both variants.


title: Effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes


title: Global Perspective of COVID-19 Vaccine Nationalism

abstract: This study aimed to explore the global perspective of the association between GDP of various countries and progress of COVID-19 vaccinations; to explore how the global pattern holds in the continents, and investigate the spatial distribution pattern of COVID-19 vaccination progress for all countries. We have used consolidated data on COVID-19 vaccination and GDP from Our World in Data, an open-access data source. Data analysis and visualization were performed in R-Studio. There was a strong linear association between per capita income and the proportion of people vaccinated in countries with one million or more populations. GDP per capita accounts for a 50% variation in the vaccination rate across the nations. Our assessments revealed that the global pattern holds in every continent. Rich European and North-American countries are most protected against COVID-19. Less developed African countries barely initiated the vaccination program. There is a significant disparity among Asian countries. The security of wealthier nations (vaccinated their citizens) cannot be guaranteed unless adequate vaccination covers the less-endowed countries. Therefore, the global community should take initiatives to speed up the COVID-19 vaccination program in all countries of the world, irrespective of their wealth.


title: Predicting the impact of COVID-19 vaccination campaigns - a flexible age-dependent, spatially-stratified predictive model, accounting for multiple viral variants and vaccines

abstract:
BackgroundAfter COVID-19 vaccines received approval, vaccination campaigns were launched worldwide. Initially, these were characterized by a shortage of vaccine supply, and specific risk groups were prioritized. Once supply was guaranteed and vaccination coverage saturated, the focus shifted from risk groups to anti-vaxxers, the underaged population, and regions of low coverage. At the same time, hopes to reach herd immunity by vaccination campaigns were put into perspective by the emergence and spread of more contagious and aggressive viral variants. Particularly, concerns were raised that not all vaccines protect against the new-emerging variants.

Methods and findingsA model designed to predict the effect of vaccination campaigns on the spread of viral variants is introduced. The model is a comprehensive extension of the model underlying the pandemic preparedness tool CovidSim 2.0 (http://covidsim.eu/). The model is age and spatially stratified, incorporates a finite (but arbitrary) number of different viral variants, and incorporates different vaccine products. The vaccines are allowed to differ in their vaccination schedule, vaccination rates, the onset of vaccination campaigns, and their effectiveness. These factors are also age and/or location dependent. Moreover, the effectiveness and the immunizing effect of vaccines are assumed to depend on the interaction of a given vaccine and viral variant. Importantly, vaccines are not assumed to immunize perfectly. Individuals can be immunized completely, only partially, or fail to be immunized against one or many viral variants. Not all individuals in the population are vaccinable. The model is formulated as a high-dimensional system of differential equations, which is implemented efficiently in the programming language Julia.

As an example, the model was parameterized to reflect the epidemic situation in Germany until November 2021 and predicted the future dynamics of the epidemic under different interventions. In particular, without tightening contact reductions, a strong epidemic wave is predicted. At the current state, mandatory vaccination would be too late to have a strong effect on reducing the number of infections. However, it would reduce mortality. An emergency brake, i.e., an incidence-based stepwise lockdown would be efficient to reduce the number of infections and mortality. Furthermore, to specifically account for mobility between regions, the model was applied to two German provinces of particular interest: Saxony, which currently has the lowest vaccine rollout in Germany and high incidence, and Schleswig-Holstein, which has high vaccine rollout and low incidence.

ConclusionsA highly sophisticated and flexible but easy-to-parameterize model for the ongoing COVID-19 pandemic is introduced. The model is capable of providing useful predictions for the COVID-19 pandemic, and hence provides a relevant tool for epidemic decision-making. The model can be adjusted to any country, to derive the demand for hospital and ICU capacities as well as economic collateral damages.


title: Antibody binding and ACE2 binding inhibition is significantly reduced for the Omicron variant compared to all other variants of concern

abstract: The rapid emergence of the Omicron variant and its large number of mutations has led to its classification as a variant of concern (VOC) by the WHO(1). Initial studies on the neutralizing response towards this variant within convalescent and vaccinated individuals have identified substantial reductions(2-8). However many of these sample sets used in these studies were either small, uniform in nature, or were compared only to wild-type (WT) or, at most, a few other VOC. Here, we assessed IgG binding, (Angiotensin-Converting Enzyme 2) ACE2 binding inhibition, and antibody binding dynamics for the omicron variant compared to all other VOC and variants of interest (VOI)(9), in a large cohort of infected, vaccinated, and infected and then vaccinated individuals. While omicron was capable of binding to ACE2 efficiently, antibodies elicited by infection or immunization showed reduced IgG binding and ACE2 binding inhibition compared to WT and all VOC. Among vaccinated samples, antibody binding responses towards omicron were only improved following administration of a third dose. Overall, our results identify that omicron can still bind ACE2 while pre-existing antibodies can bind omicron. The extent of the mutations appear to inhibit the development of a neutralizing response, and as a result, omicron remains capable of evading immune control.


title: Waning of SARS-CoV-2 Antibody levels response to inactivated cellular vaccine over 6 months among healthcare workers

abstract:
BackgroundHealth Care workers (HCW) are an important group affected by this pandemic and COVID-19 has presented substantial challenges for health professionals and health systems in many countries. The Brazilian vaccination plan implemented in October, so that third dose for HCW. However, the persistence of CoronaVac vaccine-induced immunity is unknown, and immunogenicity according to age cohorts may differ among individuals.

ObjectiveEvaluate the post vaccination immune humoral response and the relationship between post-vaccination seropositivity rates and demographic data among Healthcare Workers over 6 months after CoronaVac immunization.

MethodsA cross section study including Healthcare professionals vaccinated with CoronaVac for 6 months or more. The study was carried with the analysis of post-vaccination serological test to assess the levels of humoral response after vaccination.

Results329 participants were included. Among them, 76% were female. Overall, 18.5% were positive quantitative titles (IQR 42.87-125.5) and the negative group was 80%, quantitative titles (IQR 5.50-13.92).

ConclusionIt was possible to identify a group with positive quantitative titles in serological test for IgG antibody against the SARS-CoV-2. Further investigation is required to determine the durability of post-vaccination antibodies and how serological tests can be determine the ideal timing of vaccine booster doses.


title: Preferential expansion of cross-reactive pre-existing switched memory B cells that recognize the SARS-CoV-2 Omicron variant Spike protein

abstract:
In previously unvaccinated and uninfected individuals, non-RBD SARS-CoV-2 spike-specific B cells were prominent in two distinct, durable, resting, cross-reactive, "pre-existing" switched memory B cell compartments. While pre-existing RBD-specific B cells were extremely rare in uninfected and unvaccinated individuals, these two pre-existing switched memory B cell compartments were molded by vaccination and infection to become the primary source of RBD-specific B cells that are triggered by vaccine boosting. The frequency of wild-type RBD-binding memory B cells that cross-react with the Omicron variant RBD did not alter with boosting. In contrast, after a boost, B cells recognizing the full-length Omicron variant spike protein expanded, with pre-existing resting memory B cells differentiating almost quantitatively into effector B cell populations. B cells derived from "ancient" pre-existing memory cells and that recognize the full-length wild-type spike with the highest avidity after boosting are the B cells that also bind the Omicron variant spike protein.

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title: Vaccine Effectiveness against COVID-19 among Symptomatic Persons Aged >=12 Years with Reported Contact with COVID-19 Cases, February - September 2021

abstract: Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19, but protection offered by COVID-19 vaccines in the context of known exposure is unknown. Symptomatic outpatients reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 infection were enrolled. Among 2,229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2 positive. Using the test-negative design, adjusted vaccine effectiveness was 71% (95% confidence interval, 49%-83%) among fully vaccinated participants reporting contact versus 80% (95% CI, 72%-86%) among those without. This study supports COVID-19 vaccination and highlights the importance of efforts to increase vaccination coverage.


title: Protective effect of BNT162b2 vaccination on aerobic capacity following mild to moderate SARS-CoV-2 infection: a cross sectional study, Israel, March-December 2021

abstract: We compared 23 unvaccinated to 15 vaccinated patients previously infected with SARS-CoV-2 in terms of their aerobic capacity measured by a cardio pulmonary exercise test (CPET). Compared with unvaccinated individuals, those vaccinated had a higher heart rate, higher VO2. Our results suggest objective limitations to exercise capacity in the months following acute COVID19 illness, mitigated by vaccination


title: From Delta to Omicron: analysing the SARS-CoV-2 epidemic in France using variant-specific screening tests (September 1 to December 18, 2021)

abstract: We analysed 131,478 SARS-CoV-2 variant screening tests performed in France from September 1st to December 18, 2021. Tests consistent with the presence of the Omicron variant exhibit significantly higher cycle threshold Ct values, which could indicate lower amounts of virus genetic material. We estimate that the transmission advantage of the Omicron variant over the Delta variant is +105% (95% confidence interval: 96-114%). Based on these data, we use mechanistic mathematical modelling to explore scenarios for early 2022.


title: Depression, diabetes, their comorbidity and all-cause and cause-specific mortality: a prospective cohort study

abstract:
Aims/hypothesisTo investigate the risk of all-cause and cause-specific mortality among participants with neither, one, or both of diabetes and depression in a large prospective cohort study in the United Kingdom.

MethodsOur study population included 499,830 UK Biobank participants without schizophrenia and bipolar disorder at baseline. Type 1 or type 2 diabetes and depression were identified using self-reported diagnoses, prescribed medication and hospital records. Mortality was identified from death records using the primary cause of death to define cause-specific mortality. We performed Cox proportional hazards models to estimate the risk of all-cause mortality and mortality due to cancer, circulatory disease and causes of death other than circulatory disease or cancer among participants with either depression (n=41,791) or diabetes alone (n=22,677) and with comorbid diabetes and depression (n=3,597), compared to the group with neither condition (n=431,765) adjusting for sociodemographic and lifestyle factors, comorbidities, and history of CVD or cancer. We investigated for interaction between diabetes and depression.

ResultsDuring a median of 6.8 (IQR: 6.1 - 7.5) years of follow-up, there were 13,724 deaths (cancer (n=7,976), circulatory disease (n=2,827), and other causes (n=2,921)). Adjusted hazard ratios of all-cause mortality and mortality due to cancer, circulatory disease and other causes were highest among people with comorbid depression and diabetes (HRs 2.16, 95% CI 1.94 - 2.42; 1.62, 95% CI 1.35 - 1.93; 2.22 95% CI 1.80 - 2.73 and 3.60, 95% CI 2.93 - 4.42, respectively). Among those with comorbid diabetes and depression, the risks of all-cause, cancer and other mortality exceeded the sum of the risks due to diabetes and depression alone.

Conclusions/interpretationWe confirmed the negative impact of depression and diabetes on mortality outcomes, and also identified that comorbid depression and diabetes had synergistic effects on all-cause mortality which was largely driven by deaths due to cancer and causes other than circulatory disease and cancer.

RESEARCH IN CONTEXT

What is already known about this subject?- Comorbid depression is common in individuals with diabetes and associated with increased risks of all-cause and cardiovascular mortality
- The mortality risk among people with comorbid diabetes and depression might exceed the sum of the risks associated with each disorder alone
- There is limited knowledge about the individual and joint effects of depression and diabetes on risk of death from specific causes.

What is the key question?- What is the risk of all-cause and cause-specific mortality associated with neither, one, or both of diabetes (of any type) and depression?

What are the new findings?- In a large prospective cohort study in the United Kingdom, comorbid depression and diabetes had synergistic effects on all-cause mortality which was largely driven by deaths due to cancer and causes other than circulatory disease and cancer

How might this impact on clinical practice in the foreseeable future?- These findings help identify individuals at high risk of adverse events, and suggest a need for cost-effective interventions to support psychological well-being and risk reduction in people with diabetes


title: Social isolation and psychological distress among southern US college students in the era of COVID-19

abstract:
ObjectiveTo examine the prevalence of psychological distress and its association with social isolation among University of North Carolina Chapel Hill (UNC-CH) students.

MethodsA cross-sectional survey was emailed to all students in June 2020. Students reported self-isolating none, some, most, or all of the time and were screened for clinically significant symptoms of depression (CSSD). Data were weighted to the UNC-CH population.

Results7,012 students completed surveys-64% reported self-isolating most or all of the time and 64% reported CSSD. Compared to those self-isolating none of the time, students self-isolating some of the time were 1.78 (95% CI 1.37-2.30) times as likely to report CSSD, and students self-isolating most and all of the time were 2.12 (95% CI 1.64-2.74) and 2.27 (95% CI 1.75-2.94) times as likely to report CSSD, respectively.

ConclusionsUniversities should prioritize student mental health and prepare support services to mitigate mental health consequences of the pandemic.

category: psychiatry and clinical psychology


title: Improving air quality and health in Northern Italy: limits and perspectives

abstract:
A better air quality has led to a significant reduction of premature deaths over the past decade in Europe, as emissions of many pollutants declined considerably in the EU-27 Member States: SOx emissions by 76%, NOx by 42%, NMVOCs by 29% and PM2.5 by 29%. The present paper reports an in-depth analysis of the reasons why the regions of the Po valley, Northern Italy, still have difficulties to comply with EU air quality standards, in particular for PM10 and NO2, in spite of strong emission reductions carried out through careful Air Quality Plans put in practice during the last 2 decades. The analysis includes a consistent comparison of emission inventories for different European regions in Italy, Germany and Poland, the measured air quality trends and PM source apportionment in these areas, and, most of all, a thorough investigation of meteorological parameters influencing atmospheric pollutant dispersion and transport. The study reports that in the colder seasons, wind speed, PBL height and atmospheric pressure occurring in the Po basin are three to five times less efficient in diluting and dispersing pollutant if compared to regions north of the Alps. Due to the extremely disadvantageous orographic and climatic configuration of the Po Valley, only radical emission reductions could bring air quality into EU limit values with a questionable cost-benefit ratio of due policies. Provided that air quality standards (particularly for PM10 and PM2.5) aim at protecting people from adverse health effects arising from air pollution, it is however necessary to also consider the toxicity of atmospheric particulate in addition to PM10/PM2.5 mass concentration as a limit value. Based on existing toxicological studies and reports, a discussion is reported about PM toxicity factor depending on toxicity scores for source-specific aerosols and PM composition determined by Source Apportionment. Provided that PM components profiles are strongly different across Europe, the obtained PM toxicity factors range from 0.3 (for areas where the main PM contribution is referable to sea salts or inorganic matter) to 3.5 (where Elemental and Organic Carbon prevail), suggesting that, even at the same mass concentration, the effects of PM10/2.5 on human health are significantly variable and limit values should take into account differential toxicity.

Modern PM Source Apportionment techniques, along with reliable toxicity and epidemiological analyses, represent the right tools to overcome the shortcomings of the current regulation standard and build a new consistent health metric for ambient PM in the future, helping policy makers impose effective air quality measures to protect people health.

category: health policy