title: Racism as a Leading Cause of Death: Measuring Excess Deaths in the US

abstract:
BackgroundExcess death for Black people compared with White people is a measure of health equity. We sought to determine the excess deaths under the age of 65 (<65) for Black people in the United States (US) over the most recent 20-year period. We also compared the excess deaths for Black people with a cause of death that is traditionally reported.

MethodsWe used the Center of Disease Control (CDC) WONDERs Multiple Cause of Death 1999-2019 dataset to report age-adjusted mortality rates among non-Hispanic Black (Black) and non-Hispanic White (White) people and to calculate annual age-adjusted <65 excess deaths for Black people from 1999-2019. We measured the difference in mortality rates between Black and White people and the 20-year and 5-year trends using linear regression. We compared age-adjusted <65 excess deaths for Black people to the primary causes of death among <65 Black people in the US.

ResultsFrom 1999 to 2019, the age-adjusted mortality rate for Black men was 1,186 per 100,000 and for White men was 921 per 100,000, for a difference of 265 per 100,000. The age-adjusted mortality rate for Black women was 802 per 100,000 and for White women was 664 per 100,000, for a difference of 138 per 100,000. While the gap for men and women is less than it was in 1999, it has been increasing among men since 2014. These differences have led to many Black people dying before age 65. In 1999, there were 22,945 age-adjusted excess deaths among Black women <65 and in 2019 there were 14,444--deaths that would not have occurred had their risks been the same as those of White women. Among Black men, 38,882 age-adjusted excess <65 deaths occurred in 1999 and 25,850 in 2019. When compared to the top 5 causes of deaths among <65 Black people, death related to disparities would be the highest mortality rate among both <65 Black men and women.

CommentIn the US, over the recent 20-year period, disparities in mortality rates resulted in between 61,827 excess deaths in 1999 and 40,294 excess deaths in 2019 among <65 Black people. The race-based disparity in the US was the leading cause of death among <65 Black people. Societal commitment and investment in eliminating disparities should be on par with those focused on other leading causes of death such as heart disease and cancer.

category: public and global health


title: Definition of a new blood cell count (BCT) score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of 4 multicenter clinical trials

abstract:
IntroductionImmune checkpoint inhibitor (ICI) therapy is a major breakthrough in non-small cell lung cancer (NSCLC) treatment. However, valid predictive biomarkers are lacking. Blood cell count test (BCT) provides a direct quantification of various types of immune cells (ICs) to reveal the immune landscape to predict ICI treatment.

MethodsThis study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment (n = 1,479) or docetaxel single-agent treatment (n = 707). BCT was conducted at three timepoints: pre-treatment (T1), the first day of treatment cycle 3 (T2), and first day of treatment cycle 5 (T3). Univariate and multivariate Cox regression analyses were conducted to identify early BCT biomarkers to predict atezolizumab treatment outcomes in NSCLC patients.

ResultsThe BCT biomarkers of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at timepoint T3 and neutrophil-to-monocyte ratio (NMR) at timepoint T2 were identified as strong predictive biomarkers for atezolizumab (Ate)-treated NSCLC patients in comparison to docetaxel (Dtx)-treated patients regarding overall survival (OS) (BCTscore low-risk: HR Ate vs Dtx = 1.54 (95% CI: 1.04-2.27), P = 0.036; high-risk: HR Ate vs Dtx = 0.84 (95% CI: 0.62-1.12), P = 0.236). This identified BCTscore model showed better OS AUC in the OAK (AUC12month=0.696), BIRCH (AUC12month=0.672) and POPLAR+FIR studies (AUC12month=0.727) than that of each of the three single BCT biomarkers.

ConclusionThe BCTscore model is a valid predictive and prognostic biomarker for atezolizumab-treated NSCLC patients.

category: oncology


title: The impact of pausing the Oxford-AstraZeneca COVID-19 vaccine on uptake in Europe: a difference-in-differences analysis

abstract:
BackgroundSeveral countries paused their rollouts of the Oxford-AstraZeneca COVID-19 vaccine in mid-March 2021 due to concerns about vaccine-induced thrombosis and thrombocytopenia. Many warned that this risked damaging public confidence during a critical period of pandemic response. This study investigated whether the pause in the use of the Oxford-AstraZeneca vaccine had an impact on subsequent vaccine uptake in European countries.

MethodsWe used a difference-in-differences approach capitalizing on the fact that some countries halted their rollouts whilst others did not. A longitudinal panel was constructed for European Economic Area countries spanning 15 weeks in early 2021. Media reports were used to identify countries that paused the Oxford-AstraZeneca vaccine and the timing of this. Data on vaccine uptake were available through the European Centre for Disease Control and Prevention COVID-19 Vaccine Tracker. Difference-in-differences linear regression models controlled for key confounders that could influence vaccine uptake, and country and week fixed effects. Further models and robustness checks were performed.

ResultsThe panel included 28 countries, with 19 in the intervention group and 9 in the control group. Pausing the Oxford-AstraZeneca vaccine was associated with a 0.52% decrease in uptake for the first dose of a COVID-19 vaccine and a 1.49% decrease in the uptake for both doses, comparing countries that paused to those that did not. These estimates are not statistically significant (p=0.86 and 0.39 respectively). For the Oxford-AstraZeneca vaccine only, the pause was associated with a 0.56% increase in uptake for the first dose and a 0.07% decrease in uptake for both doses. These estimates are also not statistically significant (p= 0.56 and 0.51 respectively). All our findings are robust to sensitivity analyses.

ConclusionAs new COVID-19 vaccines emerge, regulators should be cautious to deviate from usual protocols if further investigation on clinical or epidemiological grounds is warranted.

category: health policy


title: Single-cell transcriptomic atlas of individuals receiving inactivated COVID-19 vaccines reveals distinct immunological responses between vaccine and natural SARS-CoV-2 infection

abstract: To control the ongoing COVID-19 pandemic, CoronaVac (Sinovac), an inactivated vaccine, has been granted emergency use authorization by many countries. However, the underlying mechanisms of the inactivated COVID-19 vaccine-induced immune response remain unclear, and little is known about its features compared to SARS-CoV-2 infection. Here, we implemented single-cell RNA sequencing (scRNA-seq) to profile longitudinally collected PBMCs (peripheral blood mononuclear cells) in six individuals immunized with CoronaVac and compared these to the profiles of COVID-19 infected patients from a Single Cell Consortium. Both inactivated vaccines and SARS-CoV-2 infection drove changes in immune cell type proportions, caused B cell activation and differentiation, and induced the expression of genes associated with antibody production in the plasma. The inactivated vaccine and SARS-COV-2 infection also caused alterations in peripheral immune activity such as interferon response, inflammatory cytokine expression, innate immune cell apoptosis and migration, effector T cell exhaustion and cytotoxicity, however, the magnitude of change was greater in COVID-19 patients, especially those with severe disease, than in immunized individuals. Further analyses revealed a distinct peripheral immune cell phenotype associated with CoronaVac immunization (HLA class II upregulation and IL21R upregulation in naive B cells) versus SARS-CoV-2 infection (HLA class II downregulation and IL21R downregulation in naive B cells severe disease). There were also differences in the expression of important genes associated with proinflammatory cytokines and thrombosis. In conclusion, this study provides a single-cell atlas of the systemic immune response to CoronaVac immunization and reveals distinct immune responses between inactivated vaccines and SARS-CoV-2 infection.

category: infectious diseases


title: Trajectory of viral load in a prospective population-based cohort with incident SARS-CoV-2 G614 infection

abstract:
ImportanceSARS-CoV-2 viral trajectory has not been well-characterized in documented incident infections. These data will inform SARS-CoV-2 natural history, transmission dynamics, prevention practices, and therapeutic development.

ObjectiveTo prospectively characterize early SARS-CoV-2 viral shedding in persons with incident infection.

DesignProspective cohort study.

SettingSecondary data analysis from a multicenter study in the U.S.

ParticipantsThe samples derived from a randomized controlled trial of 829 community-based asymptomatic participants recently exposed (<96 hours) to persons with SARS-CoV-2. Participants collected daily mid-turbinate swabs for SARS-CoV-2 detection by polymerase-chain-reaction and symptom diaries for 14-days. Persons with negative swab for SARS-CoV-2 at baseline who developed infection during the study were included in the analysis.

ExposureLaboratory-confirmed SARS-CoV-2 infection.

Main outcomes and measuresThe observed SARS-CoV-2 viral shedding characteristics were summarized and shedding trajectories were examined using a piece-wise linear mixed-effects modeling. Whole viral genome sequencing was performed on samples with cycle threshold (Ct)<34.

ResultsNinety-seven persons (57% women, median age 37-years) developed incident infections during 14-days of follow-up. Two-hundred fifteen sequenced samples were assigned to 15 lineages that belonged to the G614 variant. Forty-two (43%), 18(19%), and 31(32%) participants had viral shedding for 1 day, 2-6 days, and [≥]7 days, with median peak viral load Ct of 38.5, 36.7, and 18.3, respectively. Six (6%) participants had 1-6 days of observed viral shedding with censored duration. The peak average viral load was observed on day 3 of viral shedding. The average Ct value was lower, indicating higher viral load, in persons reporting COVID-19 symptoms than asymptomatic. Using the statistical model, the median time from shedding onset to peak viral load was 1.4 days followed by a median of 9.7 days before clearance.

Conclusions and RelevanceIncident SARS-CoV-2 G614 infection resulted in a rapid viral load peak followed by slower decay and positive correlation between peak viral load and shedding duration; duration of shedding was heterogeneous. This longitudinal evaluation of the SARS-CoV-2 G614 variant with frequent molecular testing may serve as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are the early SARS-CoV-2 G614 viral shedding characteristics in persons with incident infection?

FindingsIn this prospective cohort of 97 community-based participants who collected daily mid-turbinate swabs for SARS-CoV-2 detection after recent exposure to SARS-CoV-2, viral trajectory was characterized by a rapid peak followed by slower decay. Peak viral load correlated positively with symptoms. The duration of shedding was heterogeneous.

MeaningA detailed description of the SARS-CoV-2 G614 viral shedding trajectory serves as baseline for comparison to new viral variants of concern and inform models for the planning of clinical trials and transmission dynamics to end this pandemic.


title: AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans

abstract: Despite the success of SARS-CoV-2 vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of COVID-19. Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19, and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct non-overlapping epitopes on the spike protein receptor binding domain to potently neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and abrogate effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry. Together, these two mAbs create a higher barrier to viral escape and a wider breadth of coverage, neutralizing all known SARS-CoV-2 variants of concern. In a non-human primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, while therapeutic administration accelerated virus clearance from lung. In an ongoing Phase I study in healthy participants (NCT04507256), 300 mg intramuscular AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers >10-fold above those of convalescent sera for [≥]3 months, which remained 3-fold above those of convalescent sera 9 months post-AZD7442 administration. Approximately 1-2% of serum AZD7442 levels were detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentrations suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.


title: Discrepancies in the detection of SARS-CoV-2 by qRT-PCR are dependent on the target gene used for its amplification: Implications in the diagnosis of clinical infection

abstract: Discrepancies exist in Cycle threshold (Ct) values during detection of SARS-CoV-2 by qRT-PCR. We demonstrate that Ct values depend on the position of the target gene in the viral genome. Simultaneous detection of five genes in positive samples revealed lower Ct values as we move further to the 3 end (orf1AB/RdRp>E>M>orf7a>N). These findings were confirmed in a retrospective analysis with 363 positive clinical samples. Our findings have key implications in clinical diagnostics of SARS-CoV-2, patient management and public health interventions.


title: Genomic epidemiology of early SARS-CoV-2 transmission dynamics in Gujarat, India

abstract: Genomic surveillance of SARS-CoV-2 has played a decisive role in understanding the transmission and evolution of the virus during its emergence and continued circulation. However, limited genomic sampling in many high-incidence countries has impeded detailed studies of SARS-CoV-2 genomic epidemiology. Consequently, critical questions remain about the generation and global distribution of virus genetic diversity. To address this gap, we investigated SARS-CoV-2 transmission dynamics in Gujarat, India, during its first epidemic wave and shed light on virus spread in one of the pandemics hardest-hit regions. By integrating regional case data and 434 whole virus genome sequences sampled across 20 districts from March to July 2020, we reconstructed the epidemic dynamics and spatial spread of SARS-CoV-2 in Gujarat, India. Our findings revealed that global and regional connectivity, along with population density, were significant drivers of the Gujarat SARS-CoV-2 outbreak. The three most populous districts in Gujarat accounted [~]84% of total cases during the first wave. Moreover, we detected over 100 virus lineage introductions, which were primarily associated with international travel. Within Gujarat, virus dissemination occurred predominantly from densely populated regions to geographically proximate locations with low-population density. Our findings suggest SARS-CoV-2 transmission follows a gravity model in India, with urban centres contributing disproportionately to onward virus spread.


title: BNT162b2 vaccine booster dose protection: A nationwide study from Israel

abstract:
BackgroundOn July 30, 2021, a third (booster) dose of the Pfizer BNT162b2 vaccine was approved in Israel for individuals 60 years or older who had been fully vaccinated (i.e., received two doses) at least five months previously. Here, we estimate the reduction in relative risk for confirmed infection and severe COVID-19 provided by the booster dose.

Methods1,144,690 individuals aged 60y and older who were eligible for a booster dose were followed between July 30 and August 22, 2021. We defined dynamic cohorts where individuals initially belong to the  non-booster cohort, leave it when receiving the booster dose and join the  booster cohort 12 days later. Rates of infection and severe COVID-19 outcomes per person-days at risk were compared between the cohorts using Poisson regression, adjusting for possible confounding factors.

ResultsTwelve days or more after the booster dose we found an 11.4-fold (95% CI: [10.0, 12.9]) decrease in the relative risk of confirmed infection, and a >10-fold decrease in the relative risk of severe illness. Under a conservative sensitivity analysis, we find {approx}5-fold protection against confirmed infection.

ConclusionsIn conjunction with safety reports, this study demonstrates the effectiveness of a third vaccine dose in both reducing transmission and severe disease and indicates the great potential of curtailing the Delta variant resurgence by administering booster shots.

category: epidemiology


title: Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

abstract: Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 6,361 PC patients who initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 single nucleotide polymorphisms (SNPs) associated with conversion, 15 of which were not previously associated with PC risk. We found two genes associated with conversion (MAST3, p = 6.9x10-7 and GAB2, p = 2.0x10-6). Moreover, increasing values of a previously validated 269-SNP genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS--or the intensity of monitoring on AS--versus treatment for the initial management of patients with low-risk PC.


title: Genomic diversity and antimicrobial resistance of Prevotella spp. isolated from chronic lung disease airways

abstract:
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are characterised by increasingly frequent acute pulmonary exacerbations that reduce life quality and length. Human airways are home to a rich polymicrobial environment, including members of the obligately anaerobic genus, Prevotella. Despite their commonness, surprisingly little is known about the prevalence, role, genomic diversity, and antimicrobial resistance (AMR) potential of Prevotella species/strains in healthy and diseased airways. Here, we used comparative genomics to develop a real-time PCR assay to permit rapid Prevotella spp. quantification from cultures and clinical specimens. Assay specificity was validated across a panel of Prevotella and non-Prevotella species, followed by PCR screening of CF and COPD respiratory-derived cultures. Next, 35 PCR-positive isolates were subjected to whole-genome sequencing. Of eight identified species, P. histicola, P. melaninogenica, P. nanceiensis, P. salivae and P. denticola overlapped between participant cohorts. Phylogenomic analysis revealed considerable interhost but limited intrahost diversity, suggesting patient-specific lineages in the lower airways, probably from oral cavity aspirations. Correlation of phenotypic AMR profiles with AMR gene presence identified excellent correlation between tetQ presence and decreased doxycycline susceptibility, and ermF presence and decreased azithromycin susceptibility and clindamycin resistance. AMR rates were higher in the CF isolates, reflecting greater antibiotic use in this cohort. All tested Prevotella isolates were tobramycin-resistant, providing a potential selection method to improve Prevotella culture retrieval rates. Our addition of 35 airway-derived Prevotella genomes to public databases will enhance ongoing efforts to unravel the role of this diverse and enigmatic genus in both chronic respiratory diseases and healthy lungs.

Data summaryThirty-five Prevotella spp. genomes generated in this study are available in the Sequence Read Archive (SRA) and GenBank databases under BioProject accession PRJNA742126.


title: Total Infectomes Characterization of Respiratory Infections in pre-COVID-19 Wuhan, China

abstract: At the end of 2019 Wuhan witnessed an outbreak of "atypical pneumonia" that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus - SARS-CoV-2. Herein, to provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their "total infectome", including viruses, bacteria and fungi. Consequently, we identified 37 pathogen species, comprising 15 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (12.8%). However, SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen - Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.


title: Correlation between times to SARS-CoV-2 symptom onset and secondary transmission undermines epidemic control efforts

abstract: Severe acute respiratory coronavirus 2 (SARS-CoV-2) infections have been associated with substantial presymptomatic transmission, which occurs when the generation interval--the time between infection of an individual with a pathogen and transmission of the pathogen to another individual--is shorter than the incubation period--the time between infection and symptom onset. We collected a dataset of 257 SARS-CoV-2 transmission pairs in Japan and jointly estimated the mean generation interval (3.7-5.1 days) and mean incubation period (4.4-5.7 days) as well as measured their dependence (Kendalls tau of 0.4-0.6), taking into consideration demographic and epidemiological characteristics of the pairs. The positive correlation between the two parameters demonstrates that reliance on isolation of symptomatic COVID-19 cases as a focal point of control efforts is insufficient to address the challenges posed by SARS-CoV-2 transmission dynamics. Accounting for this dependence within SARS-CoV-2 epidemic models can also improve model estimates.


title: Increasing incidence of parosmia and phantosmia in patients recovering from COVID-19 smell loss

abstract:
ImportanceSudden smell loss is a specific early symptom of COVID-19, with an estimated prevalence of ~40% to 75%. Smell impairment affects physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery.

ObjectiveTo characterize smell function and recovery up to 11 months post COVID-19 infection.

Settings, ParticipantsThis longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial respiratory symptoms, chemosensory function and COVID-19 diagnosis survey (S1) between April and September 2020 and completed a follow-up survey (S2) between September 2020 and February 2021; 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness.

Main Outcomes & MeasuresPrimary outcomes are ratings of smell and taste function on a visual analog scale, and self-report of parosmia (smell distortions) and phantosmia (unexplained smells). Secondary outcomes include a checklist of other COVID-19 symptoms.

ResultsOn follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID. During COVID-19 illness, the ability to smell was slightly lower among those who did not recover their pre-illness ability to smell at S2.

Conclusions and RelevanceWhile smell loss improves for many individuals who lost it due to COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is also associated with wider COVID-19 symptoms and may persist for many months after COVID-19 onset. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long term sequelae; more research into treatment options is strongly warranted given that conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.

Trial registrationThis project was pre-registered at OSF: https://osf.io/3e6zc.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/21262763v2_ufig1.gif" ALT="Figure 1">
View larger version (22K):
org.highwire.dtl.DTLVardef@b2aceforg.highwire.dtl.DTLVardef@77a539org.highwire.dtl.DTLVardef@1004dbborg.highwire.dtl.DTLVardef@ef5c9c_HPS_FORMAT_FIGEXP  M_FIG C_FIG Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the characteristics of smell and taste recovery of COVID-19 patients?

FindingsIn this preregistered observational study of 1,468 participants, smell loss is associated with a higher number of COVID-19 symptoms, and may persist for at least 11 months following disease onset. While a majority of participants report quantitative improvement in their ability to smell, the prevalence of parosmia and phantosmia increases substantially at follow-up. Taste recovers faster than smell, suggesting taste and smell recover separately and can be distinguished by the respondents.

MeaningOlfactory dysfunction appears to be a component of long-COVID, with parosmia as a prominent symptom in almost half of those with smell loss. More research into treatment is needed, especially given that olfactory dysfunction is associated with depression and loss of appetite. Health professionals should be aware of these common and long lasting effects.


title: Past dynamics of HIV transmission among men who have sex with men in Montreal, Canada: a mathematical modelling study

abstract:
BackgroundGay, bisexual, and other men who have sex with men (gbMSM) experience disproportionate risks of HIV acquisition/transmission. In 2017, Montreal became the first Canadian Fast-Track city, setting the 2030 goal of zero new HIV infections. To inform local elimination efforts, we estimate the evolving role of prevention/risk behaviours and HIV transmission dynamics among gbMSM in Montreal between 1975-2019.

MethodsData from local bio-behavioural surveys were analyzed to develop, parameterize, and calibrate an agent-based model of sexual HIV transmission. Partnership dynamics, the HIV natural history, and treatment and prevention strategies were considered. The model simulations were analyzed to estimate the fraction of HIV acquisitions/transmissions attributable to specific age-groups and unmet prevention needs.

ResultsThe model-estimated HIV incidence peaked in 1985 (2.2%; 90%CrI: 1.3-2.8%) and decreased to 0.1% (90%CrI: 0.04-0.3%) in 2019. Between 1990-2017, the majority of HIV acquisitions/transmissions occurred among men aged 25-44 years, and men aged 35-44 thereafter. The unmet prevention needs of men with >10 annual anal sex partners contributed 92-94% of transmissions and 63-73% of acquisitions annually. The primary stage of HIV played an increasing role over time, contributing to 12%-27% of annual transmissions over 1990-2019. In 2019, approximately 75% of transmission events occurred from men who had discontinued, or never initiated ART.

ConclusionsThe evolving HIV landscape has contributed to the recent low HIV incidence among MSM in Montreal. The shifting dynamics identified in this study highlight the need for continued population-level surveillance to identify unmet prevention needs and core groups on which to prioritize elimination efforts.


title: Viral loads of Delta-variant SARS-CoV2 breakthrough infections following vaccination and booster with the BNT162b2 vaccine

abstract: The BNT162b2 vaccine showed high real-life effectiveness both at preventing disease and in reducing viral loads of breakthrough infections, but coincidental with the rise of the Delta-variant SARS-CoV2, these protective effects have been decreasing, prompting a third, booster, vaccine inoculation. Here, analyzing viral loads of over 11,000 infections during the current wave in Israel, we find that even though this wave is dominated by the Delta-variant, breakthrough infections in recently vaccinated patients, still within 2 months post their second vaccine inoculation, do have lower viral loads compared to unvaccinated patients, with the extent of viral load reduction similar to pre-Delta breakthrough observations. Yet, this infectiousness protection starts diminishing for patients two months post vaccination and ultimately vanishes for patients 6 months or longer post vaccination. Encouragingly, we find that this diminishing vaccine effectiveness on breakthrough infection viral loads is restored following the booster vaccine. These results suggest that the vaccine is initially effective in reducing infectiousness of breakthrough infections even with the Delta variant, and that while this protectiveness effect declines with time it can be restored, at least temporarily, with a booster vaccine.


title: Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study): Trial Protocol

abstract:
BackgroundThe Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patients physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.

MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.

DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic), could change the outcome of mechanically ventilated patients during the course of this and future pandemics.

Trial registrationClinicalTrials.gov identifier (NCT number): NCT04115709

Administrative informationNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

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category: intensive care and critical care medicine


title: Nanomechanical and molecular characterization of aging in dentinal collagen

abstract: Methylglyoxal (MGO) is an important molecule derived from glucose metabolism with the capacity of attaching to collagen and generating advanced glycation end-products (AGEs), which accumulate in tissues over time and are associated to aging and diseases. However, the accumulation of MGO-derived AGEs in dentin and their effect on the nanomechanical properties of dentinal collagen remain unknown. Thus, the aim of the present study was to quantify MGO-based AGEs in the organic matrix of human dentin as a function of age and associate these changes with alterations in the nanomechanical and ultrastructural properties of dentinal collagen. For this, twelve healthy teeth from <26 year-old and >50 year-old patients were collected and prepared to obtain crown and root dentin discs. Following demineralization, MGO-derived AGEs were quantified with a competitive ELISA assay. In addition, atomic force microscopy (AFM) nano-indentation was utilized to measure changes in elastic modulus in both peritubular (PT) and intertubular (IT) collagen fibrils. Finally, principal component analysis (PCA) was carried out to determine aging profiles for both crown and root dentin. Results showed increased presence of MGO AGEs in the organic matrix of dentin in the >50 year-old compared to <26 year-old samples in both crown and root. Furthermore, an overall increase in PT and IT collagen elasticity was observed in the >50 year-old group associated to ultrastructural changes in the organic matrix determined by AFM analysis. Furthermore, PCA loading plots suggested different  aging profiles in both crown and root dentin, which could potentially have important therapeutic implications in restorative and adhesive dentistry approaches. Overall, these results demonstrate that the organic matrix of human dentin undergoes aging-related changes due to MGO-derived AGEs with important changes in nanomechanical behavior of collagen that may impact diagnostic and restorative procedures in the elderly.

category: dentistry and oral medicine


title: Sex-associated differences between body mass index and SARS-CoV-2 antibody titers following the BNT162b2 vaccine among 2,435 healthcare workers in Japan

abstract: Obesity may downregulate vaccine-induced immunogenicity, but the epidemiological evidence for the COVID-19 vaccine is limited, and the sex-associated difference is unknown. It was observed that a higher body mass index was associated with lower titers of spike IgG antibodies against SARS-CoV-2 in men but not in women.


title: Effects of 105 biological, socioeconomic, behavioural, and environmental factors on the risk of SARS-CoV-2 infection and a severe course of Covid-19: A prospective longitudinal study

abstract: The confirmed number of SARS-CoV-2 infections up to 30 August 2021 is 217 mil. worldwide but information about factors affecting the probability of infection or of a severe course of Covid-19 remains insufficient and often speculative. Only a small number of factors have been rigorously examined, mostly by retrospective or cross-sectional studies. We ran a preregistered study on 5,164 internet users who shared with us information about their exposure to 105 risk factors and reported being Covid negative before the beginning of the fourth wave of Covid-19 in the Czech Republic. After the fourth wave, in which 709 (13.7%) of participants were infected, we used a partial Kendall test controlled for sex, age, and urbanisation to compare the risk of infection and of a severe course of the disease in subjects who originally did and did not report exposure to particular risk factors. After the correction for multiple tests, we identified 13 factors - including male sex, lower age, blood group B, and the larger household size - that increased the risk of infection and 16 factors - including mask wearing, borreliosis in the past, use of vitamin D supplements, or rooibos drinking - that decreased it. We also identified 23 factors that increased the risk of a severe course of Covid-19 and 12 factors that decreased the risk.


title: Health impact and cost of COVID-19 prophylaxis with monoclonal antibodies

abstract:
BackgroundThe COVID-19 pandemic has led to over 600,000 deaths in the United States and continues to disrupt lives even as effective vaccines are available. We aimed to estimate the impact and health system cost of implementing post-exposure prophylaxis against household exposure to COVID-19 with monoclonal antibodies.

MethodsWe developed a decision-analytical model analysis of results from a recent randomized controlled trial with complementary data on household demographic structure, vaccine coverage, and COVID-19 confirmed case counts for the representative month of May, 2021. The model population includes individuals of all ages in the United States by sex and race/ethnicity.

ResultsIn a month of similar intensity to May, 2021, in the USA, a monoclonal antibody post-exposure prophylaxis program reaching 50% of exposed unvaccinated household members aged 50+, would avert 1,813 (1,171 - 2,456) symptomatic infections, 526 (343 - 716) hospitalizations, and 83 (56 - 116) deaths. Assuming the unit cost of administering the intervention was US$ 1,264, this program would save the health system US$ 3,055,202 (-14,034,632 - 18,787,692).

ConclusionsCurrently in the United States, health system and public health actors have an opportunity to improve health and reduce costs through COVID-19 post-exposure prophylaxis with monoclonal antibodies.


title: PERCOVID: A Model to Describe COVID Percolation on a Network of Social Relationships

abstract: We develop a site-bond percolation model, called PERCOVID, in order to describe the time evolution of COVID epidemics and more generally all epidemics propagating through respiratory tract in human populations. This model is based on a network of social relationships representing interconnected households experiencing governmental non-pharmaceutical interventions. The model successfully accounts for the COVID-19 epidemiological data in metropolitan France from December 2019 up to July 2021. Our model shows the impact of lockdowns and curfews, as well as the influence of the progressive vaccination campaign in order to keep COVID-19 pandemic under the percolation threshold. We illustrate the role played by the social interactions by comparing a typical scenario for the epidemic evolution in France, Germany and Italy during the first wave from January to May 2020. We investigate finally the role played by the  and {delta} variants in the evolution of the epidemic in France till autumn 2021, paying particular attention to the essential role played by the vaccination. Our model predicts that the rise of the epidemic observed in July 2021 will not result in a fourth major epidemic wave in France.


title: Temporal stability and state-dependence of retrospective self-reports of childhood maltreatment in major depression: a two-year longitudinal analysis of the childhood trauma questionnaire

abstract:
BackgroundRetrospective self-reports of childhood maltreatment are widely used in research and clinical practice. However, their validity has been questioned due to potential depressive bias. Yet, systematic investigations of this matter are sparse. Thus, we investigate if and to what extent retrospective maltreatment reports vary in relation to longitudinal changes in depressive symptomatology.

MethodsTwo-year temporal stability of maltreatment reports was assessed via the Childhood Trauma Questionnaire (CTQ). Diagnosis and depressive symptoms were assessed using clinical interview and the Beck Depression Inventory. From two independent cohorts (MACS and MNC) we included a total of n=347 major depressive disorder (MDD) patients, n=419 healthy controls (HC), and a subsample with a lifetime first depressive episode between both assessments (n=27). Analysis plan and hypotheses were preregistered prior to data sighting.

ResultsMaltreatment reports were highly stable in HC and MDD patients across both cohorts (ICC=.956; 95%-CI[.949, .963] and ICC=.950; 95%-CI[.933, .963]) and temporal stability did not differ between groups. Stability was lower for cutoff-based maltreatment categorization (K=.551; 95%-CI[.479, .622] and K=.507; 95%-CI[.371, .640]). Baseline maltreatment reports were associated with concurrent and future depression severity. However, longitudinal changes in depression severity predicted variability in CTQ scores only to a small extent across cohorts (b=0.101, p=.009, R2=.021 and b=0.292, p=.320), with the effect being driven by emotional maltreatment subscales.

ConclusionsFindings suggest that the CTQ provides temporally stable self-reports of childhood maltreatment in healthy and depressed populations, and are only marginally biased by depressive symptomatology. Gradual rather than categorical conceptualization of maltreatment is advised for improving psychometric quality.

category: psychiatry and clinical psychology


title: Attitude and Behavior of People Towards Visiting the Hospital During the Pandemic

abstract:
IntroductionVisiting the hospital is important as a part of check-up in avoiding the major risks of unknown and serious diseases irrespective of any pandemic. Our study aims to understand the attitude and behaviour of common people towards visiting the hospital during COVID-19 pandemic in two major hotspot states of India namely Maharashtra and Karnataka.

MethodologyA cross-sectional study was conducted between July-august 2021 among the population of two states. A total of 636 respondents completed the survey and returned electronically. Data were analysed using suitable statistical tools to achieve the objective of the study.

Results74.8% of the respondents were not ready to visit the hospitals during the COVID-19 pandemic unless the symptoms were serious. On the other hand, 25.2% of the of respondents were willing to go to the hospitals. The top three reasons for the reduction in visits are fear of getting infected in the hospitals by COVID-19 patients (72.6%), fear of stepping out of home (31.1%) and fear of COVID-19 infection by the lab equipment (24.5%).

ConclusionOverall the study revealed that there was a reduction in number of visits to the hospitals for common diseases in people after the pandemic started. But the people were still willing to go to the hospitals if they noticed any major symptoms or symptoms related to COVID-19. Our findings may be useful to develop strategies to address concerns in order to ensure that people dont get any serious illness because of the fear of COVID-19.


title: Assessing the validity of dual-minima algorithm for heel-strike and toe-off prediction for the amputee population

abstract: Assessment of gait deficits relies on accurate gait segmentation based on the key gait events of heel strike (HS) and toe-off (TO). Kinematics-based estimation of gait events has shown promise in this regard especially using the leg velocity signal and gyroscopic sensors. However, its validation for the amputee population is not established in the literature. The goal of this study is to assess the accuracy of lower-leg angular velocity signal in determining the TO and HS instants for the amputee population. An open data set containing marker data of 10 subjects with unilateral transfemoral amputation during treadmill walking was used. A rule-based dual-minima algorithm was developed to detect the landmarks in the shank velocity signal indicating TO and HS events. The predictions were compared against the force platform data for 2595 walking cycles from 239 walking trials. Results showed considerable accuracy for the HS with a median error of -1ms. The TO prediction error was larger with the median ranging from 35-84ms. The algorithm consistently predicted the TO earlier than the actual event. Significant differences were found between the prediction accuracy for the sound and prosthetic legs. The prediction accuracy was also affected by the subjects mobility level (K-level) but was largely unaffected by gait speed. In conclusion, the leg velocity profile during walking can predict the heel-strike and toe-off events for the transfemoral amputee population with varying degrees of accuracy depending upon the leg side and amputees functional ability level.

category: rehabilitation medicine and physical therapy


title: Evaluation of patient experience for a computationally-guided intranasal spray protocol to augment therapeutic penetration

abstract: The global respiratory outbreak in the form of COVID-19 has underlined the necessity to devise more effective and reproducible intranasal drug delivery modalities, that would also be user-friendly for adoption compliance. In this study, we have collected evaluation feedback from a cohort of 13 healthy volunteers, who assessed two different nasal spray administration techniques, namely the vertical placement protocol (or, VP), wherein the nozzle is held vertically upright at a shallow insertion depth of 0.5 cm inside the nasal vestibule; and the shallow angle protocol (or, SA), wherein the spray axis is angled at 45{degrees} to the vertical, with a vestibular insertion depth of 1.5 cm. The SA protocol is derived from published findings on alternate spray orientations that have been shown to enhance targeted delivery at posterior infection sites, e.g., the ostiomeatal complex and the nasopharynx. All study participants reported that the SA protocol offered a more gentle and soothing delivery experience, with less impact pressure. Additionally, 60% participants opined that the VP technique caused painful irritation. We also tracked the drug transport processes for the two spray techniques in a computed tomography-based nasal reconstruction; the SA protocol marked a distinct improvement in therapeutic penetration when compared to the VP protocol.

category: respiratory medicine


title: Adolescent-led sexual and reproductive health and rights research: qualitative evaluation of an innovative participatory action research project in Senegal

abstract: Participatory approaches are increasingly popular in public health, but remain little used to address adolescent health issues. However, adolescent participation in research has enormous potential for identifying solutions to health issues that concern them. In Senegal, a youth-led participatory action research project was implemented to evaluate the potential of the approach to address adolescent sexual and reproductive health and rights issues. A qualitative evaluation was conducted in four Senegalese communities, where teams of adolescents were trained to conduct a research project and identify solutions relevant for their communities. Observations and interviews were carried out during results dissemination meetings in each of the communities. Based on participatory action research principles and expected adolescent participation outcomes, the evaluation of the project demonstrated the potential of the approach to identify relevant solutions, while promoting positive and meaningful adolescent participation. Despite some difficulties, such as community resistance, the youth researchers were able to successfully complete their research project, while developing their confidence and self-esteem. The adolescents were convinced that they could act as agents of positive social change. This project has shown that it is possible and relevant to involve adolescents in research projects, and that this approach has significant potential in global health.

category: sexual and reproductive health


title: High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

abstract: Possession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman {rho}=0.25, p=0.008) and coagulation (Spearman {rho}=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

category: genetic and genomic medicine


title: Childhood Socioeconomic Status and Polygenic Scores for Cognition Have Independent Associations with Cognitive Performance in Childhood

abstract: Childhood cognitive abilities are heritable and influenced by malleable environmental factors such as socioeconomic status (SES). As cognition and SES share genetic architecture, it is critical to understand the extent to which SES is associated with cognition beyond genetic propensity to inform the potential benefit of SES-based interventions. Previous investigations conducted in small samples have suggested that SES is linked with cognitive ability independent of polygenic prediction for educational attainment. Here, we extend this work to a large sample (total n = 4,650) of children (ages 9-10) of genomically-confirmed European ancestry. We find that an SES composite (i.e., family income-to-needs, caregiver education, and neighborhood median income) and a polygenic cognition score composite created using genomic structural equation modeling (COG PGS; Educational Attainment, Intelligence, and Executive Function) are associated with cognitive performance indices (i.e., general ability, executive function, learning/memory, fluid intelligence) that are largely independent of one another. SES x COG PGS interactions are not associated with cognition. These findings provide further evidence for the significant role of modifiable environmental factors in the development of cognitive abilities in youth.


title: Clinical autism subscales have common genetic liability that is heritable, pleiotropic, and generalizable to the general population

abstract: The complexity of autisms phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is unclear whether clinical autism instruments such as the Social Communication Questionnaire (SCQ), Repetitive Behavior Scale-Revised (RBS-R), and Developmental Coordination Disorder Questionnaire (DCDQ) are more genetically informative than case-control. In N = 6,134 autistic children in the SPARK cohort, we investigated the common genetic properties of the 12 subscales from these instruments. Educational attainment polygenic scores (PGS) were significantly negatively correlated with 11 subscales, while major depression and ADHD PGS were positively correlated with many subscales. Surprisingly, the autism case-control PGS was negatively correlated in females and had no strong correlation in males. In comparison to the SNP-heritability of autism case-control at 0.13 (N = 46,350), five RBS-R subscales were increased, ranging from 0.19 - 0.22 (p < 0.05). SNP-heritability of the DCDQ subscales ranged from 0.04 - 0.09, and SCQ subscales from 0 - 0.11. We also found evidence for genetic correlations among the RBS-R, SCQ, and DCDQ subscales. GWAS followed by estimation of polygenic scores (PGS) in the typically-developing ABCD cohort (N = 6,718), revealed significant associations of RBS-R and SCQ PGS with autism-related behavior traits, with several subscale PGS more strongly correlated than the autism case-control PGS. Overall, our analyses suggest that clinical subscales are more genetically powerful than case-control, and that of the three instruments investigated, the RBS-R shows the greatest evidence of common genetic signal in both autistic and general population samples.


title: Inferring causal pathways between metabolic processes and liver fat accumulation: an IMI DIRECT study

abstract:
Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) often co-occur. Defining causal pathways underlying this relationship may help optimize the prevention and treatment of both diseases. Thus, we assessed the strength and magnitude of the putative causal pathways linking dysglycemia and fatty liver, using a combination of causal inference methods.

Measures of glycemia, insulin dynamics, magnetic resonance imaging (MRI)-derived abdominal and liver fat content, serological biomarkers, lifestyle, and anthropometry were obtained in participants from the IMI DIRECT cohorts (n=795 with new onset T2D and 2234 individuals free from diabetes). UK Biobank (n=3641) was used for modelling and replication purposes. Bayesian networks were employed to infer causal pathways, with causal validation using two-sample Mendelian randomization.

Bayesian networks fitted to IMI DIRECT data identified higher basal insulin secretion rate (BasalISR) and MRI-derived excess visceral fat (VAT) accumulation as the features of dysmetabolism most likely to cause liver fat accumulation; the unconditional probability of fatty liver (>5%) increased significantly when conditioning on high levels of BasalISR and VAT (by 23%, 32% respectively; 40% for both). Analyses in UK Biobank yielded comparable results. MR confirmed most causal pathways predicted by the Bayesian networks.

Here, BasalISR had the highest causal effect on fatty liver predisposition, providing mechanistic evidence underpinning the established association of NAFLD and T2D. BasalISR may represent a pragmatic biomarker for NAFLD prediction in clinical practice.


title: COVID-19 scenarios for comparing the effectiveness of age-specific vaccination regimes, exemplified for the city of Aschaffenburg (Germany)

abstract:
Purpose of this reportThe purpose of this rapid communication is to illustrate the effectiveness of different vaccination regimes for controlling the number of severe and critical COVID-19 cases in the city of Aschaffenburg, Germany. Our results show that, despite numerous vaccinations in the past, further vaccinations are necessary to immunize the population and to keep the number of severe and critical cases low in the coming months. Considering that not all people can or want to receive vaccination, we compare different age-specific vaccination approaches.

Applied MethodsWe use the agent-based epidemiological simulator Covasim for discussing the impact of different vaccination strategies. We calibrate it to reproduce the historical course of the COVID-19 pandemic in the city of Aschaffenburg, Germany; for this, we model and integrate numerous public health interventions imposed on the local population. As for some of the political actions rigorous quantification is currently not available, we fit those unknown (free) model parameters to published data on the measured epidemiological dynamics. Then we calculate the state of immunization of the population, gained through infections and vaccinations, at any time in the past, including models for time-dependent immunity decay that have been made available in Covasim. Finally, we define and compare scenarios of different vaccination regimes, especially with regard to vaccinating adolescents and providing booster vaccinations to the elderly.

Key messageWithout further vaccinations, we expect a strong increase in severe and critical cases. In order to restrict their growth our simulations suggest that in all considered cases vaccinations of unvaccinated people is more effective than booster vaccinations for already fully vaccinated people. This applies even to vaccinations of young people who are not themselves at high risk of developing severe or critical illness. We attribute this observation to the fact that immunization of adolescents indirectly protects vulnerable age groups by preventing the spread of the virus more effectively than further immunizing other age groups. This indicates that with the pandemic ongoing, strategies focussed on minimizing individual health risks by vaccinations may no longer coincide with those needed to minimize the number of severe and critical cases.


title: SARS-CoV-2 Variant Tracking and Mitigation: Strategies and Results from In-Person Learning at a Midwestern University in the 2020/2021 School Year

abstract:
ImportanceThe COVID-19 pandemic led many higher education institutions to close campuses during the 2020-21 academic year. As campuses prepared for a return to in-person education, many institutions were mandating vaccines for students and considering the same for faculty and staff. This paper demonstrates the effectiveness of such a strategy based on evidence from a mid-sized midwestern university.

ObjectiveTo determine whether high vaccination coverage can mitigate the spread of SARS-CoV-2, even in the presence of highly-transmissible variants and congregate living.

SettingThis study was conducted at a mid-sized midwestern university during the spring 2021 semester.

DesignThe university developed a saliva-based surveillance program capable of high-throughput SARS-CoV-2 polymerase chain reaction testing and genomic sequencing with the capacity to deliver results in less than 24 hours. On April 7, 2021, the university announced a vaccine requirement for all students for the fall 2021 semester and announced the same requirement for faculty and staff on May 20, 2021. The university hosted an onsite mass vaccination clinic using the two-dose Pfizer-BioNTech vaccine April 8-15 and April 29 - May 6, 2021. Data from January 6 - May 20, 2021 were analyzed.

ParticipantsThis study includes 14,894 individuals from the university population who tested on campus for COVID-19 during the spring 2021 semester.

Main Outcomes and MeasuresPositive SARS-CoV-2 diagnosis was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of saliva specimens and variant identity was assessed by qRT-PCR and next-generation sequencing (NGS) of viral genomes.

ResultsBetween January and May 2021, the university conducted 196,185 COVID-19 tests and identified 1,603 positives - [~]89% students - with 687 identified via PCR of saliva specimens. The Alpha (B.1.1.7) variant constituted 44% of total positives sequenced. By May 20, 2021, 91% (10,068) of students, 92% (814) of faculty, and 72% (2,081) of staff were vaccinated. The 7-day rolling average of positive cases peaked at 37 cases on February 17 but declined to zero by May 14, 2021. The 7-day moving average of positive cases was inversely associated with the cumulative vaccination rate.

Conclusions and RelevanceThis study demonstrates the high effectiveness of robust vaccination programs even in the presence of highly-transmissible variants and congregate living.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow is the spread of COVID-19 affected by increasing rates of vaccination?

FindingsWe leverage 190,000+ COVID-19 surveillance tests including 1,603 positives for COVID-19 at a mid-sized midwestern university from January 6 - May 20, 2021. Genomic sequencing indicates that the Alpha (B.1.1.7) variant was first identified in early February and became the dominant variant by early March and the only variant resulting in positive cases by April. An increase in vaccination was associated with a dramatic decrease in COVID-19 cases in the campus population.

MeaningMass vaccination efforts can effectively control the spread of SARS-CoV-2 even as highly-transmissible variants are introduced.


title: Too many yet too few caesarean section deliveries in Bangladesh: an ongoing public health challenge to improve maternal and child health

abstract:
BackgroundCaesarean section (CS) use is on the rise in Bangladesh, particularly among women in improved socio-economic condition. However, the deficit use of CS remains common among disadvantage women in terms of employment, education, wealth quintile, and place of residence. This increases risks of long-term obstetric complications as well as maternal and child deaths. We aimed to determine the interaction effects of womens disadvantage characteristics on CS use in Bangladesh.

MethodsTotal of 27,093 women data analysed extracted from five rounds of Bangladesh Demographic and Health Survey, conducted between 2004 and 2017/18. The inclusion criteria used to select these women were: (i) having at least one child within three prior to the survey, (ii) reported delivery methods and place, and (iii) do not have twin or more ordered pregnancy for the most recent live birth. The major exposure variables were type of health facilities, divisions, place of residence, economic status, and maternal education. Other factors considered were factors at the individual and household level. The outcome variable was CS use, coded as use (1) and non-use (0). Multilevel logistic regression model was used to determine association of CS with socio-demographic characteristics and the interactions of the working status and wealth quintile with place of residence.

ResultsWe reported a 751% increase of CS use over the last 13 years -- from 3.88% in 2004 to 33% in 2017/18. Nearly, 80% of these occurred in the private health facilities followed by the government health facilities (15%). Rural women with no engagement of formal income generating activity showed 11% (OR, 0.89, 95% CI, 0.71-0.99) lower use of CS in 2004. This association was further strengthened with the year passes, and a 51% (OR, 0.49, 0.03-0.65) lower in CS use was reported in 2017/18. Similarly, around 12%-83% lower likelihoods of CS use were found among rural poor and poorer women.

ConclusionBangladesh is facing a double burden of CS, that is a group of women with improved socio-economic condition using this life saving procedure without medical necessity while their counterpart of disadvantage characteristics could not access this service. Improved monitoring from the government along with support to use CS services for the disadvantage groups on necessity are important.


title: Visible light optical coherence tomography of peripapillary retinal nerve fiber layer reflectivity in glaucoma

abstract:
PurposeTo evaluate the clinical utility of visible light optical coherence tomography (VIS-OCT) and to test whether VIS-OCT reflectivity and spectroscopy of peripapillary retinal nerve fiber layer (pRNFL) are correlated with severity of glaucoma, compared with standard-of-care OCT thickness measurements.

DesignCross-sectional study.

MethodFifty-four eyes from three groups of subjects (normal, glaucoma suspect, and glaucoma) were scanned by a custom-designed dual-channel device that simultaneously acquired visible (VIS-OCT) and near-infrared OCT (NIR-OCT) images. A 5x5 mm2 scan was taken of the peripapillary nerve fiber layer (pRNFL).

The pRNFL reflectivity was calculated for both channels and the spectroscopic marker was quantified by pVN, defined by the ratio of VIS-OCT to NIR-OCT pRNFL reflectivity. The results were compared with ophthalmic exams and clinical Zeiss OCT measurements. Mixed linear model was used to evaluate the association of imaging markers with glaucoma severity.

ResultsVIS-OCT pRNFL reflectivity significantly, se uentially declined from normal to suspect to glaucoma (3.42 {+/-} 0.35, 2.58 {+/-} 0.37, 2.16 {+/-} 0.39, mean {+/-} SD), as did NIR-OCT pRNFL reflectivity (2.46 {+/-} 0.24, 2.27 {+/-} 0.24, 1.96 {+/-} 0.25). The pVN also had the same decreasing trend among three groups (1.39 {+/-} 0.08, 1.14 {+/-} 0.08, 1.08 {+/-} 0.10). Normal and suspect eyes were significantly different in VIS-OCT pRNFL reflectivity (p=0.002), pVN (p<0.001) but not in NIR-OCT pRNFL reflectivity (p=0.14), circumpapillary RNFL (cpRNFL) thickness (p=0.17), or macular ganglion cell layer and inner plexiform layer (GCL+IPL) thickness (p=0.07) in the mixed linear model.

ConclusionVIS-OCT pRNFL reflectivity and pVN was more sensitive in separating suspect eyes from normal ones than clinical OCT thickness measurements. VIS-OCT pRNFL reflectivity and pVN could be a useful metric in early detection of glaucoma upon further longitudinal validation.

category: ophthalmology


title: Vascular risk is not associated with Alzheimer's disease neuropathology among cognitively normal older adults

abstract:
Cardiovascular disease (CVD) is associated with a higher risk of developing dementia. Studies have found that vascular risk factors are associated with greater amyloid-{beta} (A{beta}) and tau burden, which are hallmark neuropathologies of Alzheimers disease (AD). Evidence for these associations during the preclinical stages of AD, when A{beta} and tau pathologies first become detectable, is mixed. Quantifying the effect of vascular risk among cognitively normal individuals can help focus the efforts to develop therapeutic approaches aimed at modifying the course of preclinical AD.

Using Bayesian analysis, we examined the relationship of A{beta} and tau pathology with concurrent vascular risk among 87 cognitively normal individuals (median age 77, interquartile range 70- 83) in the Baltimore Longitudinal Study of Aging. We quantified vascular risk as the probability of developing CVD within 10 years using published equations from the Framingham Heart Study. A{beta} and tau pathologies were measured using positron emission tomography.

As expected, A{beta} positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG) (difference in means = 0.09, p < 0.05 for each region), and 10-year CVD risk was positively correlated with white matter lesion burden (r = 0.24, p = 0.03). However, we did not find any associations between CVD risk and A{beta} or tau. The data provided over two- and four-fold evidence towards the lack of a correlation between CVD risk and tau in the EC (Bayes factor BF = 2.4) and ITG (BF = 4.0), respectively. We found over three-fold evidence towards the lack of a difference in mean CVD risk by A{beta} group (BF = 3.4). These null findings were replicated using a data-driven vascular risk score in the BLSA based on a principal component analysis of eight indicators of vascular health.

Our data provide moderate evidence towards the lack of an association between vascular risk and concurrent AD neuropathology among cognitively normal older adults. This finding suggests that vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia.

HighlightsO_LIVascular risk is associated with white matter lesion load, but not amyloid-{beta} or tau
C_LIO_LIModerate evidence for lack of association between vascular risk & early AD pathology
C_LIO_LIVascular risk and Alzheimers neuropathology may constitute independent pathways
C_LI

category: neurology


title: Vascular risk is not associated with PET measures of Alzheimer's disease neuropathology among cognitively normal older adults


title: Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

abstract:
Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. We used 380 post-mortem tissue RNA-seq transcriptomes from 154 ALS cases and 49 control individuals from cervical, thoracic, and lumbar spinal cord segments to investigate the gene expression response to ALS. We observed an increase in microglia and astrocyte expression, accompanied by a decrease in oligodendrocytes. By creating a gene co-expression network in the ALS samples, we identify several activated microglia modules that negatively correlate with retrospective disease duration.

We map molecular quantitative trait loci and find several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell-types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how repeat expansions that alter splicing of C9orf72 are tagged by common variants, and use this to suggest ATXN3 as a putative risk gene.


title: A deep transcriptome meta-analysis reveals sex-based molecular differences in Multiple Sclerosis

abstract:
BackgroundMultiple Sclerosis (MS) is a chronic autoimmune, inflammatory, and degenerative disease of the central nervous system that affects both women and men but the risk of developing MS is higher in women (2-3:1 ratio compared to men). Current knowledge does not allow a precise definition of the sex-related factors intervening in MS. Here, we explore the role of sex in this neurodenegerative disease to identify molecular mechanisms underlying sex-based diferences that can guide novel therapeutics approaches aimed for men and women.

MethodsWe performed a rigorous and systematic review of MS whole transcriptome studies that included sex patient information in Gene Expression Omnibus and ArrayExpress databases, following PRISMA statment guidelines. A differential gene expression (DGE) was performed for each selected study. Then, three meta-analyses based on genes and different contrasts were addressed to evaluate common features and sex bias in all scenarios: one meta-analysis in nervous tissue studies (4), another in blood studies (5), and a third that integrated the studies from both tissues, blood and nervous system (9). Finally, a gene set analysis (GSA) was performed on the meta-analyzed differential transcriptomic profile between women and men, to study their involvement in biological pathways and phenotypes (physiological and pathological states) sex related.

ResultsAfter screening 122 publications, the systematic review provided a selection of nine studies (5 in blood and 4 in nervous tissue) with a total of 653 samples (269 MS women, 152 control women, 116 MS men, 116 control men). The blood sex-differences gene meta-analysis identified 1 gene overexpressed in women (KIR2DL3) while gene meta-analysis in the nervous tissue resulted in 5 genes differentially expressed (4 overexpressed in women: C7orf73, CECR7, TRAF3IP2-AS1, ZNF117; and 1 overexpressed in men: HIST1H2AE). In the global meta-analysis (blood and nervous tissue), 1 gene involved in sex differences were detected (more expressed in women: LOC102723701). 9 MS biomarkers were also identified in both sexes (4 overexpressed genes in MS patients: HIST1H2BC, SMEK2, STBD1, TMEM140) and 5 down-regulated in MS patients: C16orf59, C20orf177, C9orf23, FAM65B, PKI55). Additionally, the GSA related to gene meta-analysis revealed a set of functions differentially enriched in men and women, in the different analysed tissues.

ConclusionThese findings provide valuable opportunities for better understanding of MS related sex differences and develop effective and sex-specific interventions down further studies.


title: Aberrant transcript usage induces homologous recombination deficiency and predicts therapeutic responses

abstract: BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors causing low precision in predicting samples that will respond to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA damaging agents. Here, we present molecular evidence and clinical utility of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Our functional assays validated its association with impaired HR activity. Remarkably, tHRD detection based on the TU pattern of key genes was superior to gHRD or BRCA1/2 screening in accuracy for predicting the responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. In particular, this approach demonstrated the capability to reflect functional HR status, particularly when applied to our cohort of olaparib users with acquired platinum resistance in ovarian cancer. Hence, the tHRD-based diagnostic tests are expected to broaden the clinical utility of PARP inhibitors.


title: Combined PD-L1 and TIM-3 blockade improves the expansion of fit human CD8+ antigen-specific T cells for adoptive immunotherapy

abstract:
BackgroundThe stimulation and expansion of antigen-specific T cells ex vivo enables the targeting of a multitude of cancer antigens. However, clinical scale T-cell expansion from rare precursors requires repeated stimulations ex vivo leading to T-cell terminal effector differentiation and exhaustion that adversely impact therapeutic potential. We leveraged immune checkpoint blockade relevant to antigen-specific CD8+ human T cells to improve the expansion and function of T cells targeting clinically relevant antigens.

MethodsA clinically-compliant protocol relying on peptide-pulsed monocyte-derived dendritic cells and cytokines was used to expand antigen-specific CD8+ targeting the oncogenic Epstein-Barr virus (EBV) and the tumor associated antigen (TAA) Wilms Tumor 1 (WT1) protein. The effects of antibody-mediated blockade of immune checkpoints applied to the cultures (T-cell expansion, phenotypes and function) were assessed at various time points. Genomic studies including single cell RNA (scRNA) sequencing and T-cell receptor sequencing were performed on EBV-specific T cells to inform about the impact of immune checkpoint blockade on the clonal distribution and gene expression of the expanded T cells.

ResultsSeveral immune checkpoints were expressed early by ex vivo expanded antigen-specific CD8+ T cells, including PD-1 and TIM-3 with co-expression matching evidence of T-cell dysfunction as the cultures progressed. The introduction of anti-PD-L1 (expressed by the dendritic cells) and anti-TIM-3 antibodies in combination (but not individually) to the culture led to markedly improved antigen-specific T-cell expansion based on cell counts, fluorescent multimer staining and functional tests. This was not associated with evidence of T-cell dysfunction when compared to T cells expanded without immune checkpoint blockade. Genomics studies largely confirmed these results, showing that double blockade does not impart specific transcriptional programs or patterns on TCR repertoires. However, our data indicate that combined blockade may nonetheless alter gene expression in a minority of clonotypes and have donor-specific impacts.

ConclusionsThe manufacturing of antigen-specific CD8+ T cells can be improved in terms of yield and functionality using blockade of TIM-3 and the PD-L1/PD-1 axis in combination. Overcoming the deleterious effects of multiple antigenic stimulations through PD-L1/TIM-3 blockade is a readily applicable approach for several adoptive-immunotherapy strategies.

category: hematology


title: Elastomeric Harnesses Decrease Aerosol Particles Leak and Improve the Fit of Surgical Masks

abstract:
ImportanceThe outbreak of Coronavirus diseases 2019 (COVID-19) disease has increased demand for N95 respirators, surgical masks, and other facial coverings to stop the spread of SARS-CoV-2. Research shows that N95 respirators perform the best at filtering viral droplets and aerosols, however these masks are much more difficult to manufacture and expensive to distribute on a large scale, which led to shortages during the pandemic. Surgical masks, on the other hand, were more widely available and have been previously used to mitigate the spread of tuberculosis and influenza.

ObjectivesTo evaluate the filter filtration efficiency (FFE) of three elastomeric harness designs in hospital and research settings in order to improve facemask seal.

Design, setting and participantsA multi-institutional collaboration between engineers and health professionals, conducted between November 2020 and March 2021, was set up to design an elastomeric harness to improve the face seal of a surgical mask. Three elastomeric harness designs were created with harness designs 1 and 2 tested in a research laboratory setting and harness design 2.1 tested in a hospital setting. The initial harness design 1 was laser cut for testing and design 2 was developed to improve the detected particle leakage around the nose bridge area by introducing more material in that region. Design 2.1 is developed for hospital settings with less material around the nose bridge to reduce vision disruption. The designs were tested on mannequins and human volunteers using IR imaging and standard fit testing equipment.

Main Outcomes and MeasuresOur elastomeric harness can improve the seal of a surgical mask allowing it to pass the fit test used to evaluate N95 respirators. 24/39 participants achieved a passing score of 100 or more while wearing the second harness design. IR imaging determined that the nasal sidewalls region of the mask is most prone to leakage when using our first elastomeric harness.

Conclusions and RelevanceOverall, these results confirm that elastomeric harnesses combined with surgical masks improve their ability to filter aerosolized particles, which is especially important when in close proximity to individuals who are infectious or while performing aerosol-generating medical procedures.


title: Early versus late third trimester maternal SARS-CoV-2 BNT162b2 mRNA immunization maximizes transplacental antibody transfer and neonatal neutralizing antibody levels

abstract:
ObjectiveWe aimed to assess the impact of early versus late third trimester maternal SARS-CoV-2 vaccination on transplacental transfer and neonatal levels of SARS-CoV-2 antibodies.

MethodsMaternal and cord blood sera were collected following term delivery after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination, with the first vaccine dose administered during 27-36 weeks gestation. SARS-CoV-2 spike protein (S) and receptor binding domain (RBD)- specific, IgG levels and neutralizing potency were evaluated in maternal and cord blood samples.

ResultsThe study cohort consisted of 171 parturients (median age, 31 years; median gestational age, 39.7 weeks): 83 (48.5%) immunized at early 3rd trimester (1st dose at 27-31 weeks), and 88 (51.5%) immunized at late 3rd trimester (1st dose at 32-36 weeks). All mother-infant paired sera were positive for anti S- and anti-RBD-specific IgG. Anti-RBD-specific IgG concentrations in neonatal sera were higher following early versus late 3rd trimester vaccination and were positively correlated with increasing time since vaccination (r={square}0.26; P=0.001). The median placental transfer ratios of anti-S and anti-RBD specific IgG were increased following early versus late 3rd trimester immunization (anti-S ratio:1.3 vs. 0.9, anti-RBD-specific ratio:2.3 vs. 0.7, P<0.001). Neutralizing antibodies placental transfer ratio was greater following early versus late 3rd trimester immunization (1.9 vs. 0.8, P<0.001), and was positively associated with longer duration from vaccination (r={square}0.77; P<0.001).

ConclusionsEarly- as compared to late third trimester maternal SARS-CoV-2 immunization enhanced transplacental antibody transfer and increased neonatal neutralizing antibody levels. Our findings highlight that vaccination of pregnant women early in the third trimester may optimize neonatal seroprotection.


title: Estimation of Vaccine Efficacy for Variants that Emerge After the Placebo Group Is Vaccinated

abstract: SARS-CoV-2 continues to evolve and the vaccine efficacy against variants is challenging to estimate. It is now common in phase III vaccine trials to provide vaccine to those randomized to placebo once efficacy has been demonstrated, precluding a direct assessment of placebo controlled vaccine efficacy after placebo vaccination. In this work we extend methods developed for estimating vaccine efficacy post placebo vaccination to allow variant specific time varying vaccine efficacy, where time is measured since vaccination. The key idea is to infer counterfactual strain specific placebo case counts by using surveillance data that provide the proportions of the different strains. This blending of clinical trial and observational data allows estimation of strain-specific time varying vaccine efficacy, or sieve effects, including for strains that emergent after placebo vaccination. The key requirements are that surveillance strain distribution accurately reflect the strain distribution for a placebo group, throughout follow-up after placebo group vaccination and that at least one strain is present before and after placebo vaccination. For illustration, we develop a Poisson approach for an idealized design under a rare disease assumption and then use a proportional hazards modeling to better reflect the complexities of field trials with staggered entry, crossover, and smoothly varying strain specific vaccine efficacy We evaluate these by theoretical work and simulations, and demonstrate that useful estimation of the efficacy profile is possible for strains that emerge after vaccination of the placebo group. An important principle is to incorporate sensitivity analyses to guard against mis-specfication of the strain distribution. We also provide an approach for use when genotyping of the infecting strains of the trial participants has not been done.


title: Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

abstract: Tocilizumab is one of few treatments that have been shown to improve mortality in patients with COVID-19, but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters which likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, though weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/PD insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.


title: Fine analysis of lymphocyte subpopulations in SARS-CoV-2 infected patients: toward a differential profiling of patients with severe outcome

abstract: COVID-19 is caused by the human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in widespread morbidity and mortality. CD4+ T cells, CD8+ T cells and neutralizing antibodies all contribute to control SARS-CoV-2 infection. However, heterogeneity is a major factor in disease severity and in immune innate and adaptive responses to SARS-CoV-2. We performed a deep analysis by flow cytometry of lymphocyte populations of 125 hospitalized SARS-CoV-2 infected patients on the day of hospital admission. Five clusters of patients were identified using hierarchical classification on the basis of their immunophenotypic profile, with different mortality outcomes. Some characteristics were observed in all the clusters of patients, such as lymphopenia and an elevated level of effector CD8+CCR7- T cells. However, low levels of T cell activation are associated to a better disease outcome; on the other hand, profound CD8+ T-cell lymphopenia, a high level of CD4+ and CD8+ T-cell activation and a high level of CD8+ T-cell senescence are associated with a higher mortality outcome. Furthermore, a cluster of patient was characterized by high B-cell responses with an extremely high level of plasmablasts. Our study points out the prognostic value of lymphocyte parameters such as T-cell activation and senescence and strengthen the interest in treating the patients early in course of the disease with targeted immunomodulatory therapies based on the type of adaptive response of each patient.

category: allergy and immunology


title: Unique plasma metabolite signature for adolescents with Klinefelter syndrome reveals altered fatty acid metabolism

abstract: Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS).The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 {+/-} 2 yrs), pubertal stage, and body mass index z-score (0.1 {+/-} 1.2), and then between testosterone treated (n=16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (AUC>0.9, p<0.0001). Multiple saturated free fatty acids were higher in KS while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial {beta}-oxidation of long-chain saturated fatty acids (enrichment ratio 16, p<0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from males without KS independent of age, obesity, pubertal development, or testosterone treatment status, and is suggestive of differences in mitochondrial {beta}-oxidation.

category: endocrinology


title: How control and relaxation interventions and virus mutations influence the resurgence of COVID-19

abstract: After a year of the unprecedented COVID-19 pandemic in 2020, the world has been overwhelmed by COVID-19 resurgences in 2021. Resurgences usually cause longer, broader and higher waves of infection, with greater threat to societies and economies compared to first waves. They may be caused by late implementation or early relaxation of non-pharmaceutical interventions (NPIs) such as social restrictions, ineffective interventions, or virus mutations. Here we provide quantitative evidence to characterize epidemiological differences between waves, evaluate possible causes, and predict potential trends under virus mutations. We use an event-driven dynamic epidemiological model embedded with time-dependent intervention interactions to compare two waves of COVID-19 outbreaks, and we quantify the impacts of control or relaxation interventions (called events) on wave patterns. We show the second waves in late 2020 in Germany, France and Italy could have been better contained by either carrying forward the effective interventions from their first waves or implementing better controls and timing. We also obtain the quantitative effects of enforcing or relaxing interventions on various transmissibility levels of coronavirus mutants (like delta or lambda) in the second waves and in the next 30 days. Comprehensive analyses at four levels - vertical (between waves), horizontal (across countries), what-if (scenario simulations on second waves) and future (30-day trend) - in the two 2020 waves in Germany, France and Italy show that (1) intervention fatigue (government and community reluctance to interventions), early relaxations and lagging interventions may be common reasons for the resurgences observed in many countries; (2) timely strong interventions such as full lockdown will contain resurgence; and (3) in the absence of sufficient vaccination, herd immunity and effective antiviral pharmaceutical treatments and with more infectious mutations, the widespread early or fast relaxation of interventions including public activity restrictions will result in a COVID-19 resurgence.


title: Psychological antecedents towards COVID-19 vaccination using the Arabic 5C validated tool: An online study in 13 Arab countries

abstract:
Background and aimFollowing emergency approval of vaccines, the amount of scientific literature investigating population hesitancy towards vaccination against the novel coronavirus disease (COVID-19) has increased exponentially. Nevertheless, the associated psychological behaviors with this phenomenon are still not clearly understood. This study aims to assess the psychological antecedents of the Arab population toward COVID-19 vaccines.

MethodsA cross-sectional, online study using a validated Arabic version of the 5C questionnaire was conducted through different media platforms in different Arabic-speaking countries. The questionnaire included three sections: socio-demographics, COVID-19 related questions, and the 5C scale of vaccine psychological antecedents, namely confidence, complacency, constraints, calculation, and collective responsibility.

ResultsA total of 4,474 participants, 40.8% males from 13 Arab countries were included in the study. About 26.7% of participants had confidence in COVID-19 vaccination, 10.7% had complacency, 96.5% had no constraints, 48.8% had calculation and 40.4% had collective responsibility. The 5C antecedents showed variation among countries with confidence and collective responsibility being higher in the United Arab Emirates (UAE) (59% and 58%, respectively), complacency and constraints were higher in Morocco (21% and 7%, respectively) and calculation was higher in Sudan (60%). Regression analysis revealed that sex, age, educational degrees, being a health care professional, getting a COVID-19 infection, having a relative infected or died from COVID-19 can affect the 5C psychological antecedents by different degrees.

Conclusion and recommendationsWide variations of psychological antecedents between Arab countries exist. Different determinants can affect vaccine psychological antecedents.


title: Variant abundance estimation for SARS-CoV-2 in wastewater using RNA-Seq quantification

abstract: Effectively monitoring the spread of SARS-CoV-2 variants is essential to efforts to counter the ongoing pandemic. Wastewater monitoring of SARS-CoV-2 RNA has proven an effective and efficient technique to approximate COVID-19 case rates in the population. Predicting variant abundances from wastewater, however, is technically challenging. Here we show that by sequencing SARS-CoV-2 RNA in wastewater and applying computational techniques initially used for RNA-Seq quantification, we can estimate the abundance of variants in wastewater samples. We show by sequencing samples from wastewater and clinical isolates in Connecticut U.S.A. between January and April 2021 that the temporal dynamics of variant strains broadly correspond. We further show that this technique can be used with other wastewater sequencing techniques by expanding to samples taken across the United States in a similar timeframe. We find high variability in signal among individual samples, and limited ability to detect the presence of variants with clinical frequencies <10%; nevertheless, the overall trends match what we observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in variant prevalence in situations where clinical sequencing is unavailable or impractical.


title: High-Throughput Adaptable SARS-CoV-2 Screening for Rapid Identification of Dominant and Emerging Regional Variants

abstract:
ObjectivesEmerging SARS-CoV-2 variant strains can be associated with increased transmissibility, more severe disease, and reduced effectiveness of treatments. To improve the availability of regional variant surveillance, we describe a variant genotyping system that is rapid, accurate, adaptable, and able to detect new low-level variants built with existing hospital infrastructure.

MethodsWe use a tiered high-throughput SARS-CoV-2 screening program to characterizes variants in a supra-regional health system over 76 days. Combining targeted qPCR and selective sequencing, we screen positive SARS-CoV-2 samples from all hospitals within our health care system for genotyping dominant and emerging variants.

ResultsThe median turnaround for genotyping was two days using the high-throughput qPCR-based screen, allowing us to rapidly characterize the emerging Delta variant. In our population, the Delta variant is associated with a lower CT value, lower age at infection, and increased vaccine breakthrough cases. Detection of low-level and potentially emerging variants highlights the utility of a tiered approach.

ConclusionsThese findings underscore the need for fast, low-cost, high-throughput monitoring of regional viral sequences as the pandemic unfolds and the emergence of SARS-CoV-2 variants increases. Combing qPCR-based screening with selective sequencing allows for rapid genotyping of variants and dynamic system improvement.

Key messagesO_LIA tiered approach that uses qPCR-based screening to identify dominant variants and sequencing for unique variants maximizes throughput, turnaround time, and information gleaned from each sample.
C_LIO_LIIn our population, the Delta variant became dominant in less than a month and is associated with lower CT, lower age at infection, and increased breakthrough cases.
C_LIO_LIWe identified low-level variants, including the variant of interest B.1.621 and a Delta variant with an E484K mutation in our population using existing hospital infrastructure.
C_LI

category: pathology