id
stringlengths 16
27
| title
stringlengths 18
339
| abstract
stringlengths 95
38.7k
| category
stringlengths 7
44
|
|---|---|---|---|
10.1101/2021.01.26.21250580 | THE AIRBORNE CONTAGIOUSNESS OF RESPIRATORY VIRUSES: A COMPARATIVE ANALYSIS AND IMPLICATIONS FOR MITIGATION | BackgroundThe infectious emission rate is a critical input parameter for airborne contagion models, but data are limited due to reliance on estimates from chance superspreading events. A predictive estimation approach for the quanta emission rate (ERq) was recently proposed for SARS-CoV-2 using the droplet volume concentration of various expiratory activities. This study assesses the strength of the approach and uses novel predictive estimates of ERq to compare the contagiousness of respiratory pathogens.
MethodsWe applied the predictive approach to SARS-CoV-1, SARS-CoV-2, MERS, measles virus, adenovirus, rhinovirus, coxsackievirus, seasonal influenza virus and Mycobacterium tuberculosis (TB) and compared ERq estimates to values reported in literature. We calculated infection risk in a prototypical classroom and barracks to assess the relative ability of ventilation to mitigate airborne transmission.
ResultsOur median standing and speaking ERq estimate for SARS-CoV-2 (2.6 quanta hour (h)-1) is similar to active, untreated TB (3.1 h-1), higher than seasonal influenza (0.17 quanta h-1), and lower than measles virus (15 quanta h-1). We calculated event reproduction numbers above 1 for SARS-CoV-2, measles virus, and untreated TB in both the classroom and barracks for an activity level of standing and speaking at low, medium and high ventilation rates of 2.3, 6.6 and 14 liters per second per person, respectively.
ConclusionsOur predictive ERq estimates are consistent with the range of values reported over decades of research. In congregate settings, current ventilation standards are unlikely to control the spread of viruses with upper quartile ERq values above 10 quanta h-1, such as SARS-CoV-2, indicating the need for additional control measures. | infectious diseases |
10.1101/2021.01.27.21250605 | Multidimensional analysis of immune response identified biomarkers of recent Mycobacterium tuberculosis infection | The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to my-cobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing (vast) scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the single datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical validation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC)=0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC=0.91), while the innate data EN model performed poorly (average AUROC=0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test{chi} 2=6.09, p=0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models.
A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection. | infectious diseases |
10.1101/2021.01.27.21250382 | Evaluation of spike protein antigens for SARS-CoV-2 serology | BackgroundSpike protein domains are being used in various serology-based assays to detect prior exposure to SARS-CoV-2 virus. However, there has been limited comparison of human antibody titers against various spike protein antigens among COVID-19 infected patients.
MethodsWe compared four spike proteins (RBD, S1, S2 and a stabilized spike trimer (ST)) representing commonly used antigens for their reactivity to human IgG antibodies using indirect ELISA in serum from COVID-19 patients and pre-2020 samples. ST ELISA was also compared against the EUROIMMUN IgG ELISA test. Further, we estimated time appropriate IgG and IgA seropositivity rates in COVID-19 patients using a panel of sera samples collected longitudinally from the day ofonset of symptoms (DOS).
ResultsAmong the four spike antigens tested, the ST demonstrated the highest sensitivity (86.2%; 95% CI: 77.8-91.7%), while all four antigens showed high specificity to COVID-19 sera (94.7-96.8%). 13.8% (13/94) of the samples did not show seroconversion in any of the four antigen-based assays. In a double-blinded head-to-head comparison, ST based IgG ELISA displayed a better sensitivity (87.5%, 95%CI: 76.4-93.8%) than the EUROIMMUN IgG ELISA (67.9%, 95% CI: 54.8-78.6%). Further, in ST-based assays, we found 48% and 50% seroconversion in the first six days (from DOS) for IgG and IgA antibodies, respectively, which increased to 84% (IgG) and 85% (IgA) for samples collected [≥]22 days DOS.
ConclusionsComparison of spike antigens demonstrates that spike trimer protein is a superior option as an ELISA antigen for COVID-19 serology.
HighlightsO_LISpike trimer displays the highest antibody titer in SARS-CoV-2 infections among spike protein antigens.
C_LIO_LISpike trimer IgG ELISA displays a sensitivity of 50% within six days and 86.2% after 14 days from onset of symptoms.
C_LIO_LIIgA and IgG responses to spike trimer antigen were comparable and concomitant in time after infection.
C_LIO_LI16% (IgG) and 15% (IgA) of COVID-19 RT-PCR positive patients did not seroconvert even after 21 days from onset of symptoms.
C_LI | infectious diseases |
10.1101/2021.01.27.21250517 | SARS-CoV-2 infection and transmission in school settings during the second wave in Berlin, Germany: a cross-sectional study | BackgroundSchool attendance during the SARS-CoV-2 pandemic is intensely debated. Modelling studies suggest that school closures contribute to community transmission reduction. However, data among school-attending students and staff are scarce. In November 2020, we examined SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.
MethodsStudents and school staff were examined, oro-nasopharyngeal swabs and blood samples collected, and SARS-CoV-2 infection and IgG antibodies detected by RT-PCR and ELISA. Household members performed self-swabs. Individual and institutional infection prevention and control measures were assessed. Classes with SARS-CoV-2 infection and connected household members were re-tested after one week.
Findings1119 participants were examined, including 177 primary and 175 secondary school students, 142 staff, and 625 household members. Participants reported mainly cold symptoms (19{middle dot}4%). SARS-CoV-2 infection occurred in eight of 24 classes affecting each 1-2 individuals. Infection prevalence was 2{middle dot}7% (95%CI; 1{middle dot}2-5{middle dot}0%; 9/338), 1{middle dot}4% (0{middle dot}2-5{middle dot}1%; 2/140), and 2{middle dot}3% (1{middle dot}3-3{middle dot}8%; 14/611) among students, staff and household members, respectively, including quarantined persons. Six of nine infected students were asymptomatic. Prevalence increased with inconsistent facemask use in school, way to school on foot, and case-contacts outside school. IgG antibodies were detected in 2{middle dot}0% (0{middle dot}8-4{middle dot}1%; 7/347), 1{middle dot}4% (0{middle dot}2-5{middle dot}0%; 2/141) and 1{middle dot}4% (0{middle dot}6-2{middle dot}7%; 8/576), respectively. For three of nine households with infection(s) detected at cross-sectional assessment, origin in school seemed possible. After one week, no school-related, secondary infections appeared in affected classes; the attack rate in connected households was 1{middle dot}1%.
InterpretationThese data suggest that school attendance under preventive measures is feasible, provided their rigorous implementation. In balancing threats and benefits of open versus closed schools during the pandemic, parents and society need to consider possible spill-overs into their households. Deeper insight is needed into the infection risks due to being a schoolchild as compared to attending school.
FundingSenate of Berlin. | infectious diseases |
10.1101/2021.01.26.21250543 | The E484K mutation in the SARS-CoV-2 spike protein reduces but does not abolish neutralizing activity of human convalescent and post-vaccination sera. | One year in the coronavirus disease 2019 (COVID-19) pandemic, the first vaccines are being rolled out under emergency use authorizations. It is of great concern that newly emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can escape antibody-mediated protection induced by previous infection or vaccination through mutations in the spike protein. The glutamate (E) to Lysine (K) substitution at position 484 (E484K) in the receptor binding domain (RBD) of the spike protein is present in the rapidly spreading variants of concern belonging to the B.1.351 and P.1 lineages. We performed in vitro microneutralization assays with both the USA-WA1/2020 virus and a recombinant (r)SARS-CoV-2 virus that is identical to USA-WA1/2020 except for the E484K mutation introduced in the spike RBD. We selected 34 sera from study participants based on their SARS-CoV-2 spike ELISA antibody titer (negative [N=4] versus weak [N=8], moderate [N=11] or strong positive [N=11]). In addition, we included sera from five individuals who received two doses of the Pfizer SARS-CoV-2 vaccine BNT162b2. Serum neutralization efficiency was lower against the E484K rSARS-CoV-2 (vaccination samples: 3.4 fold; convalescent low IgG: 2.4 fold, moderate IgG: 4.2 fold and high IgG: 2.6 fold) compared to USA-WA1/2020. For some of the convalescent donor sera with low or moderate IgG against the SARS-CoV-2 spike, the drop in neutralization efficiency resulted in neutralization ID50 values similar to negative control samples, with low or even absence of neutralization of the E484K rSARS-CoV-2. However, human sera with high neutralization titers against the USA-WA1/2020 strain were still able to neutralize the E484K rSARS-CoV-2. Therefore, it is important to aim for the highest titers possible induced by vaccination to enhance protection against newly emerging SARS-CoV-2 variants. Two vaccine doses may be needed for induction of high antibody titers against SARS-CoV-2. Postponing the second vaccination is suggested by some public health authorities in order to provide more individuals with a primer vaccination. Our data suggests that this may leave vaccinees less protected against newly emerging variants. | infectious diseases |
10.1101/2021.01.26.21250557 | Covid-19 positive test cycle threshold trends predict covid-19 mortality in Rhode Island | The cycle thresholds (Cts) at which reverse transcriptase polymerase chain reaction (rtPCR) tests for covid-19 become positive are intimately associated with both viral load, and covid-19 infectiousness (i.e., ability to culture live virus). Clinical data indicate lower Cts--and hence larger viral loads--independently predict greater covid-19 mortality when patients are hospitalized for symptomatic covid-19 pneumonia. We merged public covid-19 mortality data from the Rhode Island Department of Health with a de-identified dataset of n=5036 positive rtPCR test Cts from the Rhode Island Department of Health State Laboratory to explore the potential relationship between positive covid-19 test Ct distribution trends, and covid-19 mortality in the state of Rhode Island, from March through early to mid-June, 2020. Mean daily covid-19 positive test Ct data were compiled, and 7-day rolling average covid-19 mortality was offset by 21-days, given the lag between infection and death. We divided the Ct data into three strata, >32, 28-32, and <28, which were operationally defined as "not infectious," "maybe infectious," and "infectious," respectively. Between late March and June, mean daily Ct values rose linearly (R-squared=0.789) so that by early June, as the covid-19 pandemic ebbed in severity, all means reached the noninfectious (Ct >32) range. Most notably, this May-June trend for Cts was accompanied by a marked, steady decline in Rhode Islands daily covid-19 mortality. Our results suggest that monitoring, and public reporting of mean population covid-19 test Cts over time is warranted to gauge the vacillations of covid-19 outbreak severity, including covid-19 mortality trends. | infectious diseases |
10.1101/2021.01.26.21250535 | SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study | BackgroundThe risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent infection among seropositive young adults was studied prospectively.
MethodsThe study population comprised 3,249 predominantly male, 18-20-year-old Marine recruits. Upon arrival at a Marine-supervised two-week quarantine, participants were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent (ELISA) assays. SARS-CoV-2 infection was assessed by PCR at initiation, middle and end of the quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, we performed three biweekly PCR tests in both seropositive and in seronegative groups once recruits left quarantine and entered basic training and baseline neutralizing antibody titers on all subsequently infected seropositive and selected seropositive uninfected participants.
FindingsAmong 189 seropositive participants, 19 (10.1%) had at least one positive PCR test for SARS-CoV-2 during the six-week follow-up (1.1 cases per person-year). In contrast, 1,079 (48.0%) of the 2,247 seronegative participants tested positive (6.2 cases per person-year). The incidence rate ratio was 0.18 (95% CI 0.11-0.28, p<0.00001). Among seropositive recruits, infection was associated with lower baseline full-length spike protein IgG titers (p<0.0001). Compared with seronegative recruits, seropositive recruits had about 10-fold lower viral loads (ORF1ab gene, p<0.005), and trended towards shorter duration of PCR positivity (p=0.18) and more frequent asymptomatic infections (p=0.13). Among seropositive participants, baseline neutralizing titers were detected in 45 of 54 (83.3%) uninfected and in 6 of 19 (31.6%) infected participants during the 6 weeks of observation (ID50 difference p<.0001).
InterpretationSeropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection. These findings may be relevant for optimization of mass vaccination strategies.
FundingDefense Health Agency and Defense Advanced Research Projects Agency | infectious diseases |
10.1101/2021.01.26.21250532 | Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts | BackgroundAlthough deubiquitinating enzymes (DUBs) such as CYLD, A20 and OTULIN are expressed in multiple tissues and thought to be linked with inflammatory diseases, their expression in periodontal tissues remains to be determined. This research was designed to assess the expression of CYLD, A20 and OTULIN in human gingiva, and to evaluate the regulation of these DUBs in human gingival fibroblasts (HGFs) upon different stimuli.
MethodsImmunohistochemistry assay was conducted to determine the expression of CYLD, A20 and OTULIN in human gingiva. Immunofluorescence assay was employed to observe the protein expression of CYLD, A20 and OTULIN in HGFs. RT-PCR and western blots were carried out to assess gene and protein expression changes of these DUBs in HGFs upon LPS or TNF-.
ResultsCYLD, A20 and OTULIN were found to be expressed in human gingiva and HGFs. Further, the expression of CYLD, A20 and OTULIN in HGFs exhibited distinct regulation by different stimuli.
ConclusionsOur findings suggest that CYLD, A20 and OTULIN might play a role in the progression of periodontitis. | dentistry and oral medicine |
10.1101/2021.01.26.21250532 | Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts | BackgroundAlthough deubiquitinating enzymes (DUBs) such as CYLD, A20 and OTULIN are expressed in multiple tissues and thought to be linked with inflammatory diseases, their expression in periodontal tissues remains to be determined. This research was designed to assess the expression of CYLD, A20 and OTULIN in human gingiva, and to evaluate the regulation of these DUBs in human gingival fibroblasts (HGFs) upon different stimuli.
MethodsImmunohistochemistry assay was conducted to determine the expression of CYLD, A20 and OTULIN in human gingiva. Immunofluorescence assay was employed to observe the protein expression of CYLD, A20 and OTULIN in HGFs. RT-PCR and western blots were carried out to assess gene and protein expression changes of these DUBs in HGFs upon LPS or TNF-.
ResultsCYLD, A20 and OTULIN were found to be expressed in human gingiva and HGFs. Further, the expression of CYLD, A20 and OTULIN in HGFs exhibited distinct regulation by different stimuli.
ConclusionsOur findings suggest that CYLD, A20 and OTULIN might play a role in the progression of periodontitis. | dentistry and oral medicine |
10.1101/2021.01.27.21250590 | RNA sequencing of a large number of psoriatic patients identifies 131 novel miRNAs and 11 miRNAs associated with disease severity | BackgroundMicroRNAs are small regulatory molecules that are dysregulated in psoriasis. Despite previous efforts, much is unknown about the regulatory mechanisms of psoriasis genetics and their contributions to disease development and activity.
ObjectivesTo globally characterize the miRNAome of psoriatic skin in a large sample of psoriatic cases and controls for increased understanding of psoriasis pathophysiology.
MethodsSkin biopsies from psoriatic cases (n=75) and non-psoriatic controls (n=57) were RNA sequenced. Count data was meta-analyzed with a previously published dataset (cases, n=24, controls, n=20), increasing the number of psoriatic cases four-fold from previously published studies. Differential expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell specific analyses were performed.
ResultsWe identified 439 significantly differentially expressed miRNAs (DEMs), of which 131 were novel and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in all psoriatic skin. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including thyroid hormone signaling, insulin resistance and various infectious diseases. Cell specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells.
ConclusionsWe have provided the most comprehensive overview of the miRNome in psoriatic skin to date and identified a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets. | dermatology |
10.1101/2021.01.27.21250484 | Machine learning approaches to calibrate individual-based infectious disease models | Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose a using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability. | epidemiology |
10.1101/2021.01.27.21250484 | Machine learning approaches to calibrate individual-based infectious disease models | Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose a using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability. | epidemiology |
10.1101/2021.01.27.21250484 | Machine learning approaches to calibrate individual-based infectious disease models | Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose a using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability. | epidemiology |
10.1101/2021.01.27.21250484 | Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria | Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose a using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability. | epidemiology |
10.1101/2021.01.26.21250501 | Stringency of the containment measures in response to COVID-19 inversely correlates with the overall disease occurrence over the epidemic wave | Non-pharmaceutical interventions (NPIs) were the only viable choice to mitigate or suppress transmission of COVID-19 in the absence of efficient and safe vaccines. Moreover, the importance of some NPIs is likely to remain in the future, at least in specific settings, in which the limited vaccination coverage and the high rate of contacts would enable further disease transmission. Nonetheless, the benefits of NPIs have been questioned with respect to their effectiveness and societal costs. In this study of 28 European countries during the first wave of epidemic we demonstrate a significant inverse correlation between the stringency of adopted containment measures and cumulative incidences of the confirmed COVID-19 cases. Our results indicate that early implementation of the stringent containment measures prior to detection of the first confirmed case, and rapid ramp-up of containment stringency after the first case was diagnosed, were instrumental for lowering the number of COVID-19 cases during the epidemic wave. The impact of delayed adoption of containment measures could not be fully attenuated by later adoption of even more stringent community containment. | epidemiology |
10.1101/2021.01.27.21250656 | Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations in cancer diagnoses | IntroductionRanitidine is a member of the H2-blocker class of medications, commonly used in the treatment gastroesophageal reflux and peptic ulcer disease. Recent laboratory analyses have demonstrated that ranitidine may yield the probable carcinogen, N-Nitrosodimethylamine (NDMA). Here, we characterized the kinetics of NDMA production from ranitidine under various simulated gastric conditions. Moreover, we conducted a cross-sectional epidemiologic analysis to evaluate potential associations between ranitidine use and various cancer presentations.
MethodsThe formation of NDMA in the presence of ranitidine was studied in a series of experiments conducted in simulated gastric fluid (SGF), while varying pH, nitrite concentration, and time of reaction. Chemical analyses of NDMA yield were performed by liquid chromatography-high resolution mass spectrometry per FDA guidelines on the detection of NDMA from ranitidine drug products.
To evaluate potential associations between ranitidine use and cancer diagnoses, we conducted a cross-sectional analysis among a population of oncology patients, following institutional review board approval. Analyses were limited to those reporting use of ranitidine or an active comparator (i.e. proton-pump inhibitor [PPI] or other H2-blocker) to partially mitigate potential confounding. Multivariable logistic regression was employed to identify associations between ranitidine and certain cancers, adjusted for age, sex, race, ethnicity, and body-mass index.
ResultsIncreasing sodium nitrite concentrations in SGF at pH 1.2 were associated with increasing NDMA yield. At a pH of 2.5, previously identified as the optimal reaction condition, samples collected at incubation times of 1, 2 and 4 hours (approximating typical gastric emptying conditions) showed a continued increase in NDMA over time. Notably, the reaction trajectory suggests NDMA may have continued to form beyond the last observed timepoint of 4 hours.
On cross-sectional analysis of an oncology population, use of ranitidine (versus active comparators) was associated with increased odds of presenting with cancers of the breast (OR=1.58; 95%CI: 1.23-2.01) as compared to presentation with another cancer. Similar positive associations were observed for cancers of the thyroid (OR=1.89; 95%CI: 1.18-2.92), bladder (OR=1.58; 95%CI: 1.10-2.21), and prostate (OR=1.80; 95%CI: 1.34-2.39). Conversely, ranitidine was inversely associated with cancers of the colorectum (OR=0.48; 95%CI: 0.30-0.74) and brain (OR=0.56; 95%CI: 0.33-0.89).
ConclusionUnder simulated gastric conditions, ranitidine yields increasing amounts of NDMA over time (up to, and likely beyond 4 hours) and with increasing concentrations of sodium nitrite. In addition, among a cohort of cancer patients reporting use of H2-blockers or PPIs at the time of diagnosis, we found an association between ranitidine use and cancers of the breast, thyroid, bladder and prostate. We further observed unexplained inverse associations with cancers of the brain and colorectum. These associations reflect the odds of presenting with different cancers exclusively among an oncology population, and do not directly represent risk in a general population (as there were no cancer-free individuals in this study). Moreover, these exploratory analyses are to be viewed as hypothesis generating and should prompt analyses of larger cohorts with longer follow-up. | pharmacology and therapeutics |
10.1101/2021.01.26.21250125 | Prospective and detailed behavioral phenotyping in DDX3X syndrome | BackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay (DD) and/or intellectual disability (ID) in females and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.
MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures; three participants in this cohort have been previously reported. We compared results against population norms and contrasted phenotypes between individuals harboring either (i) protein-truncating variants or (ii) missense variants and in-frame deletions.
ResultsEighty percent of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.
LimitationsSample size is modest, however, DDX3X is a rare and underdiagnosed disorder.
ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions yielding a more severe phenotype. | psychiatry and clinical psychology |
10.1101/2021.01.27.21250654 | Risk perception of COVID-19 and its socioeconomic correlates in the United States: A social media analysis | Social media analysis provides a new approach to monitoring and understanding risk perceptions regarding COVID-19 over time. Our current understandings of risk perceptions regarding COVID-19 do not disentangle the three dimensions of risk perceptions (perceived susceptibility, perceived severity, and negative emotion) over a long enough timeframe to cover different pandemic phases. The impact of social determinants of health factors on COVID-19-related risk perceptions over time is also not clear. To address these two knowledge gaps, we extracted tweets regarding COVID-19-related risk perceptions and developed index indicators for three dimensions of risk perceptions based on over 297 million geotagged tweets posted by over 3.5 million Twitter users from January to October 2020 in the United States. We also examined correlations between index indicator scores and county-level social determinants of health factors. The three domains of risk perceptions demonstrate different trajectories. Perceived severity kept climbing throughout the whole study period. Perceived susceptibility and negative emotion declined and remained stable at a lower level after peaking on March 11 (WHO named COVID-19 a global pandemic). Attention on risk perceptions was not exactly in accordance with epidemic trends of COVID-19 (cases, deaths). Users from socioeconomically vulnerable counties showed lower attention on perceived severity and susceptibility of COVID-19 than those from wealthier counties. Examination of trends in tweets regarding the multiple domains of risk perceptions throughout stages of the COVID-19 pandemic can help policy makers frame in-time, tailored, and appropriate responses to prevent viral spread and encourage preventive behavior uptake in United States. | public and global health |
10.1101/2021.01.26.21250558 | Depression Symptoms during the COVID-19 Pandemic among Well-Educated, Employed Adults with Low Infection Risks | Levels and distributions of depression symptoms 8-10 months after the onset of the COVID-19 pandemic are reported in a population of faculty, staff, and students at Duke University who faced minimal infection and economic disruption due to the pandemic. Almost 5,000 respondents age 18-81 years who completed the 20-item Center for Epidemiological Studies-Depression (CES-D) battery reported high rates of depression symptoms with more than 40% reporting levels that indicate risk of moderate depression and 25% indicating risk of severe depression. There is a very steep age gradient with the highest levels reported by the youngest respondents of whom over 40% are at risk of severe depression. Symptoms are worse among those who report the demands of work often interfere with family responsibilities but these pressures neither explain the high reported rates nor the steep age gradient. Severe depression risks are highest among students. High levels of depression symptoms during the pandemic appear to be persistent and not confined to those at greatest risk of infection or economic insecurity. | public and global health |
10.1101/2021.01.27.21250595 | The therapeutic effect of intra-articular facet joint injection with normal saline as a comparator for chronic low back pain: a systematic review and meta-analysis | BackgroundIntra-articular facet joint injection (FJI) has been increasingly used as a treatment for chronic low back pain (LBP). Choice of the substance has been based on clinical experience with unclear evidence on marginal effectiveness of active substance over normal saline as a placebo control. This systematic review investigates the comparative effectiveness between normal saline and active substances on patient-reported outcomes (PROs).
MethodsSystematic search was conducted in five databases: PubMed, Embase, Scopus, Web of Science, and CENTRAL for randomized controlled trials and observational studies of evaluating the PROs of FJI comparing active injected substances with normal saline as placebo in chronic LBP patients in the English language without publication date restriction. Quality assessment was performed using ROB2 and ROBINS-I. The meta-analysis was done using a random-effects model. Mean difference with 95% CIs of efficacy outcomes including pain, numbness, disability, quality of life were measured.
ResultsOf 2,467 potential studies, three were included in the systematic review and meta-analysis (247 patients). Compared to other active substances, normal saline provided similar therapeutic effects on pain outcome within one hour (MD 2.43, 95% CI -11.61 to 16.50), at 1-1.5 months follow up (MD -0.63, 95% CI -7.97 to 6.72), and at 3 to 6 months (MD 1.90, 95% CI -16.03 to 19.83) as well as the quality of life at one and six months follow-up.
ConclusionsThe short-term and long-term clinical improvements of intra-articular FJI using normal saline are comparable to the other active substances in LBP patients.
PROSPEROregistration number CRD42020216426 | rehabilitation medicine and physical therapy |
10.1101/2021.01.28.21250529 | Linking objective measures of physical activity and capability with brain structure in healthy community dwelling older adults | Maintaining high levels of daily activity and physical capability have been proposed as important constituents to promote healthy brain and cognitive aging. Studies investigating the associations between brain health and physical activity in late life have, however, mainly been based on self-reported data or measures designed for clinical populations. In the current study, we examined cross-sectional associations between physical activity, recorded by an ankle-positioned accelerometer for seven days, physical capability (grip strength, postural control, and walking speed), and neuroimaging based surrogate markers of brain health in 122 healthy older adults aged 65-88 years. We used a multimodal brain imaging approach offering two complementary structural MRI based indicators of brain health: white matter diffusivity and coherence based on diffusion tensor imaging and subcortical and global brain age based on brain morphology inferred from T1-weighted MRI data. The analyses revealed a significant association between global white matter fractional anisotropy (FA) and walking speed, indicating higher white matter coherence in people with higher pace. We also found a significant interaction between sex and brain age on number of daily steps, indicating younger-appearing brains in more physically active women, with no significant associations among men. These results provide insight into the intricate associations between different measures of brain and physical health in old age, and corroborate established public health advice promoting physical activity. | neurology |
10.1101/2021.01.27.21249817 | Multinational Prevalence of Neurological Phenotypes in Patients Hospitalized with COVID-19 | OBJECTIVENeurological complications can worsen outcomes in COVID-19. We defined the prevalence of a wide range of neurological conditions among patients hospitalized with COVID-19 in geographically diverse multinational populations.
METHODSUsing electronic health record (EHR) data from 348 participating hospitals across 6 countries and 3 continents between January and September 2020, we performed a cross-sectional study of hospitalized adult and pediatric patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test, both with and without severe COVID-19. We assessed the frequency of each disease category and 3-character International Classification of Disease (ICD) code of neurological diseases by countries, sites, time before and after admission for COVID-19, and COVID-19 severity.
RESULTSAmong the 35,177 hospitalized patients with SARS-CoV-2 infection, there was increased prevalence of disorders of consciousness (5.8%, 95% confidence interval [CI]: 3.7%-7.8%, pFDR<.001) and unspecified disorders of the brain (8.1%, 95%CI: 5.7%-10.5%, pFDR<.001), compared to pre-admission prevalence. During hospitalization, patients who experienced severe COVID-19 status had 22% (95%CI: 19%-25%) increase in the relative risk (RR) of disorders of consciousness, 24% (95%CI: 13%-35%) increase in other cerebrovascular diseases, 34% (95%CI: 20%-50%) increase in nontraumatic intracranial hemorrhage, 37% (95%CI: 17%-60%) increase in encephalitis and/or myelitis, and 72% (95%CI: 67%-77%) increase in myopathy compared to those who never experienced severe disease.
INTERPRETATIONUsing an international network and common EHR data elements, we highlight an increase in the prevalence of central and peripheral neurological phenotypes in patients hospitalized with SARS-CoV-2 infection, particularly among those with severe disease. | neurology |
10.1101/2021.01.27.21249807 | Population Pharmacokinetics of Oxcarbazepine: A Systematic Review | IntroductionOxcarbazepine is commonly used as a first-line drug in the treatment of partial seizures. Due to the high pharmacokinetic variability of oxcarbazepine, many population pharmacokinetic models have been developed to optimise the dosing regimen of oxcarbazepine.
Areas coveredThis review summarize the published population pharmacokinetic studies of oxcarbazepine in children and adults. The quality of the identified reports from the PubMed and Embase databases was also evaluated. We also explored the significant covariates that may have an impact on the dosage regimen and clinical use of oxcarbazepine.
Expert OpinionThe oxcarbazepine dose regimen was dependent on weight and co-administration with enzyme-inducing medications. In order to achieve more accurate treatment, we should establish PK / PD model of OXC to evaluate the effectiveness of dose adjustment from pharmacodynamic indicators. Furthermore, exploring the pharmacokinetic in specifical patients, such as infants is essential to improve its safety.
Article highlightsO_LIIn this review, we identified weight, renal function, and co-administered medications as covariates that most likely to influence oxcarbazepine pharmacokinetics.
C_LIO_LIComparing to adult patients, paediatric patients show a higher clearance per kilogramme weigh which lead to higher doses per kilogramme; they may also require therapeutic drug monitoring owing to a larger variation in clearance.
C_LIO_LIFurther studies are essential to evaluate oxcarbazepine pharmacokinetics in special populations such as infants.
C_LI | neurology |
10.1101/2021.01.27.21250608 | Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in Alzheimer's disease and possible clinical implications | Study ObjectivesThe lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH neurons in Alzheimers disease (AD) and progressive supranuclear palsy (PSP), and relate the new findings to our previously reported pattern of degeneration of wake-promoting orexinergic neurons
MethodsPost-mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH- and tau-antibodies on formalin-fixed, celloidin embedded tissue was performed.
ResultsThere was no difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non-MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non-MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (p<0.001).
ConclusionsMCH neurons are more vulnerable to AD than PSP pathology. High burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD, contributing to wake-sleep disorders in AD. Further experimental research is needed to understand why MCH neurons are more resistant to tau-toxicity compared to orexinergic neurons.
STATEMENT OF SIGNIFICANCEThis is the first study to investigate the involvement of melanin-concentrating hormone (MCH) neurons in patients with Alzheimers disease and progressive supranuclear palsy. MCH neurons are key regulators of sleep and metabolic functions, and one of the major neuronal populations of the lateral hypothalamic area (LHA), but still underexplored in humans. Uncovering the pathology of this neuronal population in neurodegenerative disorders will improve our understanding of the complex neurobiology of the LHA and the interaction between MCH and orexinergic neurons. This new knowledge may open new strategies for treatment interventions. Further, this study represents a fundament for future research on MCH neurons and the LHA in tauopathies. | neurology |
10.1101/2021.01.28.21250673 | Is vitamin D deficiency associated with the COVID-19 epidemic in Europe? | The authors have withdrawn this manuscript because, following comments received during the review process, they have updated the number of countries included in their study (and also changed from 5 to 10 years the limit for Vit-D information studies that they included), which led to non-significant correlations between mortality and infections and Vit D deficiency prevalence. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. | nutrition |
10.1101/2021.01.28.21250673 | Is vitamin D deficiency associated with the COVID-19 epidemic in Europe? | The authors have withdrawn this manuscript because, following comments received during the review process, they have updated the number of countries included in their study (and also changed from 5 to 10 years the limit for Vit-D information studies that they included), which led to non-significant correlations between mortality and infections and Vit D deficiency prevalence. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. | nutrition |
10.1101/2021.01.27.21250464 | A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes | PurposeA subset of primary prostate cancer (PCa) expresses programmed death-ligand 1 (PD-L1), but whether they have unique tumor immune microenvironment (TIME) or genomic features is unclear.
Experimental DesignWe selected PD-L1-positive high-grade and/or high-risk primary PCa, characterized tumor-infiltrating lymphocytes (TILS) with multiplex immunofluorescence, and identified genomic alterations in immunogenic and non-immunogenic tumor foci.
ResultsOne-quarter of aggressive localized PCa cases (29/115) had tumor PD-L1 expression >5%. This correlated with increased density of CD8+ T cells, a large fraction co-expressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM-3 or LAG-3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting-cell niches in close proximity to MHC II+ cells. CD8 T cell density in immunogenic PCa and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent; the latter being strongly associated with a dendritic cell gene set in TCGA. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.
ConclusionsA subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8+ T cell content comparable to RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients.
Statement of Translational RelevanceProstate cancer (PCa) is generally considered poorly immunogenic, with low expression of programmed death-ligand 1 (PD-L1) and low density of tumor-infiltrating immune cells. Accordingly, response rates to PD(L)-1 inhibition in unselected patients with advanced prostate cancer have been low. Here, we find that a substantial subset of aggressive primary PCa exhibits tumor PD-L1 expression and contains a high density of tumor-infiltrating lymphocytes. These lymphocytes contain sub-populations of exhausted progenitor CD8+ T cells and differentiated effector T cells, the hallmarks of ongoing anti-tumor immune response and a prerequisite for response to checkpoint inhibition. Furthermore, we identify genomic alterations that may be contributing to immunogenicity in these cases. These findings point to immune responses elicited in a subset of primary PCa, supporting the development of immune checkpoint blockade clinical trials in early-stage disease, such as biochemically recurrent PCa, that are driven by genomic features of the tumor or the immune microenvironment. | oncology |
10.1101/2021.01.28.21250547 | Ownership and COVID-19 in care homes for older people: A living systematic review of outbreaks, infections, and mortalities | BackgroundThe adult social care sector is increasingly outsourced to for-profit providers, who constitute the largest provider of care homes in many developed countries. During the COVID-19 pandemic, for-profit providers have been accused of failing their residents by prioritising profits over care, prevention, and caution, which has been reported to result in a higher prevalence of COVID-19 infections and deaths in for-profit care homes. Although many of these reports are anecdotal or based on news reports, there is a growing body of academic research investigating ownership variation across COVID-19 outcomes, which has not been systematically appraised and synthesised.
ObjectivesTo identify, appraise, and synthesise the available research on ownership variation in COVID-19 outcomes (outbreaks, infections, deaths, shortage of personal protective equipment (PPE) and staff) across for-profit, public, and non-profit care homes for older people, and to update our findings as new research becomes available.
DesignLiving systematic review.
MethodsThis review was prospectively registered with Prospero (CRD42020218673). We searched 17 databases and performed forward and backward citation tracking of all included studies. Search results were screened and reviewed in duplicate. Risk of bias (RoB) was assessed in duplicate according to the COSMOS-E guidance. Data was extracted by ABM and independently validated. The results were synthesised by country, RoB, and model adjustments, and visualised using harvest plots.
ResultsTwenty-nine studies across five countries were included, with 75% of included studies conducted in the Unites States. For-profit ownership was not consistently associated with a higher probability of a COVID-19 outbreak. However, there was compelling evidence of worse COVID-19 outcomes following an outbreak, with for-profit care homes having higher rates of accumulative infections and deaths. For-profit providers were also associated with shortages in PPE, which may have contributed to the higher incidence of infections and deaths in the early stages of the pandemic. Chain affiliation was often correlated with an increased risk of outbreak but was usually not reported to be associated with higher rates of deaths and infections.
ConclusionFor-profit ownership was a consistent risk factor for higher cumulative COVID-19 infections and deaths in the first wave of the pandemic. Thus, ownership and the characteristics associated with FP care home providers may present key regulatable factors that can be addressed to improve health outcomes in vulnerable populations and reduce health disparities. This review will be updated as new research becomes published, which may change the conclusion of our synthesis. | health policy |
10.1101/2021.01.28.21250547 | Ownership and COVID-19 in care homes for older people: A living systematic review of outbreaks, infections, and mortalities | BackgroundThe adult social care sector is increasingly outsourced to for-profit providers, who constitute the largest provider of care homes in many developed countries. During the COVID-19 pandemic, for-profit providers have been accused of failing their residents by prioritising profits over care, prevention, and caution, which has been reported to result in a higher prevalence of COVID-19 infections and deaths in for-profit care homes. Although many of these reports are anecdotal or based on news reports, there is a growing body of academic research investigating ownership variation across COVID-19 outcomes, which has not been systematically appraised and synthesised.
ObjectivesTo identify, appraise, and synthesise the available research on ownership variation in COVID-19 outcomes (outbreaks, infections, deaths, shortage of personal protective equipment (PPE) and staff) across for-profit, public, and non-profit care homes for older people, and to update our findings as new research becomes available.
DesignLiving systematic review.
MethodsThis review was prospectively registered with Prospero (CRD42020218673). We searched 17 databases and performed forward and backward citation tracking of all included studies. Search results were screened and reviewed in duplicate. Risk of bias (RoB) was assessed in duplicate according to the COSMOS-E guidance. Data was extracted by ABM and independently validated. The results were synthesised by country, RoB, and model adjustments, and visualised using harvest plots.
ResultsTwenty-nine studies across five countries were included, with 75% of included studies conducted in the Unites States. For-profit ownership was not consistently associated with a higher probability of a COVID-19 outbreak. However, there was compelling evidence of worse COVID-19 outcomes following an outbreak, with for-profit care homes having higher rates of accumulative infections and deaths. For-profit providers were also associated with shortages in PPE, which may have contributed to the higher incidence of infections and deaths in the early stages of the pandemic. Chain affiliation was often correlated with an increased risk of outbreak but was usually not reported to be associated with higher rates of deaths and infections.
ConclusionFor-profit ownership was a consistent risk factor for higher cumulative COVID-19 infections and deaths in the first wave of the pandemic. Thus, ownership and the characteristics associated with FP care home providers may present key regulatable factors that can be addressed to improve health outcomes in vulnerable populations and reduce health disparities. This review will be updated as new research becomes published, which may change the conclusion of our synthesis. | health policy |
10.1101/2021.01.27.21250617 | More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis | COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. This systematic review followed Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines, although the study protocol was not registered. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 14 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care. | infectious diseases |
10.1101/2021.01.27.21250617 | More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis | COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. This systematic review followed Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines, although the study protocol was not registered. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 14 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care. | infectious diseases |
10.1101/2021.01.27.21250428 | Diagnostic accuracy and utility of SARS-CoV-2 antigen lateral flow assays in medical admissions with possible COVID-19 | We evaluated diagnostic accuracy of the Innova SARS-CoV-2 Antigen Rapid Qualitative Test compared to SARS-CoV-2 RT-PCR from nasopharyngeal swabs in adult admissions who met the COVID-19 case definition at a busy acute hospital in the UK. We found the Innova SARS-CoV-2 Antigen Rapid Qualitative Test had a good specificity in patients with symptoms of COVID-19 presenting to hospital. The Innova LFA can be used to rapidly identify COVID-19 cases amongst hospital admissions meeting the COVID-19 case definition, allowing patients to be allocated to COVID-19 cohort areas. | infectious diseases |
10.1101/2021.01.26.21250584 | First detection and report of SARS-CoV-2 Spike protein N501Y mutations in Oklahoma USA | We describe the detection of SARS-CoV-2 (VOC)B.1.1.7 lineage in Oklahoma, USA. Various mutations in the S gene and ORF8 with similarity to the genome of B.1.1.7 lineage were detected in 4 of the 6 genomes sequenced and reported here. The sequences have been made available in GISAID. Presence of novel lineages indicate the need for frequent whole genome sequencing to better understand pathogen dynamics in different geographical locations. | infectious diseases |
10.1101/2021.01.27.21250599 | A systematic review and meta-analysis on the safety and efficacy of tocilizumab in the management of COVID-19 | BackgroundThis systematic review and meta-analysis was aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19).
MethodsThe electronic search was performed using PubMed, Scopus, CENTRAL, and Google scholar to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo/standard of care. The comparison will be between TCZ versus standard of care (SOC)/placebo. Inconsistency between the studies was evaluated with I2 and quality of the evidences were evaluated by Newcastle-Ottawa scale.
ResultsBased on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (M-H,RE-OR -0.11(-0.18 to -0.04) 95% CI, p =0.001, I2 =88%) and increased the incidences of super-infections (M-H, RE-OR 1.49(1.13 to 1.96) 95% CI, p=0.004, I2=47%). However, there is no significant difference in ICU admissions rate (M-H, RE-OR -0.06(-0.23 to 0.12), I2=93%), need of MV (M-H, RE-OR of 0.00(-0.06 to 0.07), I = 74%), LOS (IV -2.86(-0.91 to 3.38), I2=100%), LOS-ICU (IV: -3.93(-12.35 to 4.48), I2=100%), and incidences of pulmonary thrombosis (M-H, RE-OR 1.01 (0.45 to 2.26), I2=0%) compared to SOC/control.
ConclusionBased on cumulative low to moderate certainty evidence shows that TCZ could reduce the risk of mortality in hospitalized patients. However, there is no statistically significant difference observed between the TCZ and SOC/control groups in other parameters. | infectious diseases |
10.1101/2021.01.27.21250599 | A systematic review and meta-analysis on the safety and efficacy of tocilizumab in the management of COVID-19 | BackgroundThis systematic review and meta-analysis was aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19).
MethodsThe electronic search was performed using PubMed, Scopus, CENTRAL, and Google scholar to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo/standard of care. The comparison will be between TCZ versus standard of care (SOC)/placebo. Inconsistency between the studies was evaluated with I2 and quality of the evidences were evaluated by Newcastle-Ottawa scale.
ResultsBased on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (M-H,RE-OR -0.11(-0.18 to -0.04) 95% CI, p =0.001, I2 =88%) and increased the incidences of super-infections (M-H, RE-OR 1.49(1.13 to 1.96) 95% CI, p=0.004, I2=47%). However, there is no significant difference in ICU admissions rate (M-H, RE-OR -0.06(-0.23 to 0.12), I2=93%), need of MV (M-H, RE-OR of 0.00(-0.06 to 0.07), I = 74%), LOS (IV -2.86(-0.91 to 3.38), I2=100%), LOS-ICU (IV: -3.93(-12.35 to 4.48), I2=100%), and incidences of pulmonary thrombosis (M-H, RE-OR 1.01 (0.45 to 2.26), I2=0%) compared to SOC/control.
ConclusionBased on cumulative low to moderate certainty evidence shows that TCZ could reduce the risk of mortality in hospitalized patients. However, there is no statistically significant difference observed between the TCZ and SOC/control groups in other parameters. | infectious diseases |
10.1101/2021.01.27.21250599 | Efficacy and safety of tocilizumab in the management of COVID-19: A systematic review and meta-analysis of observational studies | BackgroundThis systematic review and meta-analysis was aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19).
MethodsThe electronic search was performed using PubMed, Scopus, CENTRAL, and Google scholar to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo/standard of care. The comparison will be between TCZ versus standard of care (SOC)/placebo. Inconsistency between the studies was evaluated with I2 and quality of the evidences were evaluated by Newcastle-Ottawa scale.
ResultsBased on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (M-H,RE-OR -0.11(-0.18 to -0.04) 95% CI, p =0.001, I2 =88%) and increased the incidences of super-infections (M-H, RE-OR 1.49(1.13 to 1.96) 95% CI, p=0.004, I2=47%). However, there is no significant difference in ICU admissions rate (M-H, RE-OR -0.06(-0.23 to 0.12), I2=93%), need of MV (M-H, RE-OR of 0.00(-0.06 to 0.07), I = 74%), LOS (IV -2.86(-0.91 to 3.38), I2=100%), LOS-ICU (IV: -3.93(-12.35 to 4.48), I2=100%), and incidences of pulmonary thrombosis (M-H, RE-OR 1.01 (0.45 to 2.26), I2=0%) compared to SOC/control.
ConclusionBased on cumulative low to moderate certainty evidence shows that TCZ could reduce the risk of mortality in hospitalized patients. However, there is no statistically significant difference observed between the TCZ and SOC/control groups in other parameters. | infectious diseases |
10.1101/2021.01.27.21250615 | Duration of SARS-CoV-2 Sero-Positivity in a Large Longitudinal Sero-Surveillance Cohort: The COVID-19 Community Research Partnership | BackgroundEstimating population prevalence and incidence of prior SARS-CoV-2 infection is essential to formulate public health recommendations concerning the COVID-19 pandemic. However, interpreting estimates based on sero-surveillance requires an understanding of the duration of elevated antibodies following SARS-CoV-2 infection, especially in the large number of people with pauci-symptomatic or asymptomatic disease.
MethodsWe examined >30,000 serology assays for SARS-CoV-2 specific IgG and IgM assays acquired longitudinally in 11,468 adults between April and November 2020 in the COVID-19 Community Research Partnership.
FindingsAmong participants with serologic evidence for infection but few or no symptoms or clinical disease, roughly 50% sero-reverted in 30 days of their initial positive test. Sero-reversion occurred more quickly for IgM than IgG and for antibodies targeting nucleocapsid protein compared with spike proteins, but was not associated with age, sex, race/ethnicity, or healthcare worker status.
InterpretationThe short duration of antibody response suggests that the true population prevalence of prior SARS-CoV-2 infection may be significantly higher than presumed based on earlier sero-surveillance studies. The impact of the large number of minimally symptomatic COVID-19 cases with only a brief antibody response on population immunity remains to be determined.
FundingThis publication is supported by the CARES Act, of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling $20,000,000. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HHS, or the U.S. Government.
O_TEXTBOXResearch in context
Evidence before this studyPrevious longitudinal studies of the humoral response to SARS-CoV-2 suggest that people with less severe disease have a more rapid decline of SARS-CoV-2 specific antibodies than people with severe disease. However, these data come from small laboratory-based investigations or studies of convenience samples identified based on symptomatic disease.
Added value of this studyThis study provides extensive longitudinal serologic follow-up in a large number of people with serologic evidence of prior infection who had little or no symptoms based on active daily symptom surveillance.
Implications of the available evidenceThe data indicate that serologic evidence of prior infection in minimally symptomatic people is fleeting, suggesting that cross-sectional sero-surveys have under-estimated the true prevalence of prior infection in populations. The data highlight the challenge of determining transmission dynamics and long-term immunity in asymptomatic cases which likely represents an even larger fraction of all cases of prior SARS-CoV-2 infection than previously presumed.
C_TEXTBOX | infectious diseases |
10.1101/2021.01.27.21249186 | SARS-CoV-2 in Ivory Coast: serosurveillance survey among mines workers | BackgroundEight months after the detection of the first COVID-19 case in Africa, 1,262,476 cases have been reported in African countries compared to 72 million worldwide. The real burden of SARS-CoV-2 infection in West Africa is not clearly defined. The aim of the study was to evaluate the seroprevalence of SARS-CoV-2 in half of the 3,380 workers of several mining companies operating in two mines in the Ivory Coast and having its headquarters in the economic capital Abidjan.
MethodsFrom 15th July to 13th October 2020, a voluntary serological test campaign was performed in the 3 sites where the companies operate: two mines, and the headquarters in Abidjan.We performed a COVID-PRESTO rapid test for the detection of IgG and IgM on capillary blood. A multivariate analysis was performed to identify independent sociodemographic characteristics associated with a higher SARS-CoV-2 seroprevalence rate.
ResultsA total of 1,687 subjects were tested. 91% were male (n= 1,536) and mean age was 37 years old. The overall crude seroprevalence rate was 25.1% (n=422), but differing significantly between different sites, rising from 13.6% (11.2%-16.1%) in mine A to 34.4% (31.1%-37.7%) in mine B and 34.7% (26.2%-43.2%) in Abidjan. Non-resident workers in mines had a significantly lower prevalence rate than those living full-time in mines. Seroprevalence was 26.5% in natives of the Ivory Coast, while people coming from countries other than Africa were less likely to be SARS-CoV-2 seropositive. Among the 422 positive subjects, 74 reported mild symptoms in the three previous months and one was hospitalized for a severe COVID-19 infection.
ConclusionThe prevalence of SARS-CoV-2 infection among mine workers in Ivory Coast is high. The low morbidity observed has probably led to an underestimation of the burden of this infection in West Africa. The high prevalence reported in subjects living in Abidjan, who have not any close contact with mine workers, may be indicative of the real seroprevalence in the Ivory Coast capital. | infectious diseases |
10.1101/2021.01.28.21250664 | Risk of SARS-CoV-2 exposure among hospital healthcare workers in relation to patient contact and type of care | AimWe aimed to assess the risk for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a large cohort of healthcare workers (HCWs).
MethodsFrom May 11 until June 11, 2020, 3,981 HCWs at a large Swedish Emergency Care hospital provided serum samples and questionnaire data. Exposure was measured by assaying IgG antibodies to SARS-CoV-2.
ResultsThe total seroprevalence was 17.7% and increased during the study period. Among the seropositive HCWs, 10.5% had been entirely asymptomatic. Participants who worked with COVID-19 patients had higher odds for seropositivity: ORadj 1.96 (95% CI 1.59 - 2.42). HCWs from three of the departments managing COVID-19 patients had significantly higher seroprevalences, whereas the prevalence among HCWs from the Intensive Care Unit (also managing COVID-19 patients) was significantly lower.
ConclusionHCWs in contact with SARS-CoV-2 infected patients had a variable, but on average higher, likelihood for SARS-CoV-2 infections. | infectious diseases |
10.1101/2021.01.26.21250349 | HLA-A*11:01:01:01, HLA*C*12:02:02:01-HLA-B*52:01:02:02, age and sex are associated with severity of Japanese COVID-19 with respiratory failure | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19. | infectious diseases |
10.1101/2021.01.27.21250048 | A Rapid and Low-Cost protocol for the detection of B.1.1.7 lineage of SARS-CoV-2 by using SYBR Green-Based RT-qPCR | BackgroundThe new SARS-CoV-2 variant VUI (202012/01), identified recently in the United Kingdom (UK), exhibits a higher transmissibility rate compared to other variants, and a reproductive number 0.4 higher. In the UK, scientists were able to identify the increase of this new variant through the rise of false negative results for the spike (S) target using a three-target RT-PCR assay (TaqPath kit).
MethodsTo control and study the current coronavirus pandemic, it is important to develop a rapid and low-cost molecular test to identify the aforementioned variant. In this work, we designed primer sets specific to SARS-CoV-2 variant VUI (202012/01) to be used by SYBR Green-based RT-PCR. These primers were specifically designed to confirm the deletion mutations {Delta}69/{Delta}70 in the spike and the {Delta}106/{Delta}107/{Delta}108 in the NSP6 gene. We studied 20 samples from positive patients, 16 samples displayed an S-negative profile (negative for S target and positive for N and ORF1ab targets) and four samples with S, N and ORF1ab positive profile.
ResultsOur results emphasized that all S-negative samples harbored the mutations {Delta}69/{Delta}70 and {Delta}106/{Delta}107/{Delta}108. This protocol could be used as a second test to confirm the diagnosis in patients who were already positive to COVID-19 but showed false negative results for S-gene.
ConclusionsThis technique may allow to identify patients carrying the VUI (202012/01) variant or a closely related variant, in case of shortage in sequencing. | infectious diseases |
10.1101/2021.01.27.21250620 | Safety and efficacy of long-acting insulins (degludec and glargine) among type 2 diabetic Asian Population: A Systematic Review and Meta-Analysis. | BackgroundAccording to IDF Diabetes Atlas 2019, globally, 463 million people live with Diabetes mellitus. Out of that, 88 million people are in South East Asia. By 2045, it is expected to increase by 51% globally and 74% in South East Asia. Global variation in susceptibility to diabetes, insulin sensitivity, and regimen intensity due to race and ethnic differences pose a challenge regarding the optimal choice of second-line therapy for clinicians. Asian populations are at higher risk of developing diabetes mellitus than the European population. The current study was carried out to see the relative efficacy of currently available long-acting insulins in reducing blood sugar, HbA1c and the occurrence of hypoglycemia as a complication associated with them.
MethodsA systematic literature search was done using various search engines (PubMed, Cochrane, Google Scholar, Scopus, and Embase) and included published RCTs in English before December 2019. Further, a manual search was performed by screening the reference list of the identified articles.
ResultsWe included four RCTs with 534 participants (349 in the insulin degludec group and 185 in the insulin glargine group) with T2DM. Results show that both insulin glargine and degludec are equally efficacious in reducing fasting blood glucose and HbA1c. However, insulin glargine was associated with lower risks of hypoglycemia.
ConclusionsInsulin glargine and degludec are comparable in achieving glycemic control with fewer hypoglycemic episodes in insulin glargine treated group. | endocrinology |
10.1101/2021.01.27.21250604 | The World Mortality Dataset: Tracking excess mortality across countries during the COVID-19 pandemic | Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently-updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 94 countries and territories, openly available as the regularly-updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality. At the same time, in several other countries (Australia, New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), sometimes by two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring. | epidemiology |
10.1101/2021.01.27.21250604 | The World Mortality Dataset: Tracking excess mortality across countries during the COVID-19 pandemic | Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently-updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 94 countries and territories, openly available as the regularly-updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality. At the same time, in several other countries (Australia, New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), sometimes by two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring. | epidemiology |
10.1101/2021.01.27.21250604 | The World Mortality Dataset: Tracking excess mortality across countries during the COVID-19 pandemic | Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently-updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 94 countries and territories, openly available as the regularly-updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality. At the same time, in several other countries (Australia, New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), sometimes by two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring. | epidemiology |
10.1101/2021.01.27.20240309 | Beyond the new normal: assessing the feasibility of vaccine-based elimination of SARS-CoV-2 | As the COVID-19 pandemic drags into its second year, there is hope on the horizon, in the form of SARS-CoV-2 vaccines which promise disease elimination and a return to pre-pandemic normalcy. In this study we critically examine the basis for that hope, using an epidemiological modeling framework to establish the link between vaccine characteristics and effectiveness in bringing an end to this unprecedented public health crisis. Our findings suggest that vaccines that do not prevent infection will allow extensive endemic SARS-CoV-2 spread upon a return to pre-pandemic social and economic conditions. Vaccines that only reduce symptomatic COVID-19 or mortality will fail to mitigate serious COVID-19 mortality risks, particularly in the over-65 population, likely resulting in hundreds of thousands of US deaths on a yearly basis. Our modeling points to the possibility of complete SARS-CoV-2 elimination with high population-level compliance and a vaccine that is highly effective at reducing SARS-CoV-2 infection. Notably, vaccine-mediated reduction of transmission is critical for elimination, and in order for partially-effective vaccines to play a positive role in SARS-CoV-2 elimination, other stackable (complementary) interventions must be deployed simultaneously. | epidemiology |
10.1101/2021.01.27.21250619 | Evaluation of COVID-19 vaccination strategies with a delayed second dose | Two of the COVID-19 vaccines currently approved in the United States require two doses, administered three to four weeks apart. Constraints in vaccine supply and distribution capacity, together with a deadly wave of COVID-19 from November 2020 to January 2021 and the emergence of highly contagious SARS-CoV-2 variants, sparked a policy debate on whether to vaccinate more individuals with the first dose of available vaccines and delay the second dose, or to continue with the recommended two-dose series as tested in clinical trials. We developed an agent-based model of COVID-19 transmission to compare the impact of these two vaccination strategies, while varying the temporal waning of vaccine efficacy following the first dose and the level of pre-existing immunity in the population. Our results show that for Moderna vaccines, a delay of at least 9 weeks could maximize vaccination program effectiveness and avert at least an additional 17.3 (95% CrI: 7.8 - 29.7) infections, 0.71 (95% CrI: 0.52 - 0.97) hospitalizations, and 0.34 (95% CrI: 0.25 - 0.44) deaths per 10,000 population compared to the recommended 4-week interval between the two doses. Pfizer-BioNTech vaccines also averted an additional 0.61 (95% CrI: 0.37 - 0.89) hospitalizations and 0.31 (95% CrI: 0.23 - 0.45) deaths per 10,000 population in a 9-week delayed second dose strategy compared to the 3-week recommended schedule between doses. However, there was no clear advantage of delaying the second dose with Pfizer-BioNTech vaccines in reducing infections, unless the efficacy of the first dose did not wane over time. Our findings underscore the importance of quantifying the characteristics and durability of vaccine-induced protection after the first dose in order to determine the optimal time interval between the two doses. | epidemiology |
10.1101/2021.01.27.21250619 | Evaluation of COVID-19 vaccination strategies with a delayed second dose | Two of the COVID-19 vaccines currently approved in the United States require two doses, administered three to four weeks apart. Constraints in vaccine supply and distribution capacity, together with a deadly wave of COVID-19 from November 2020 to January 2021 and the emergence of highly contagious SARS-CoV-2 variants, sparked a policy debate on whether to vaccinate more individuals with the first dose of available vaccines and delay the second dose, or to continue with the recommended two-dose series as tested in clinical trials. We developed an agent-based model of COVID-19 transmission to compare the impact of these two vaccination strategies, while varying the temporal waning of vaccine efficacy following the first dose and the level of pre-existing immunity in the population. Our results show that for Moderna vaccines, a delay of at least 9 weeks could maximize vaccination program effectiveness and avert at least an additional 17.3 (95% CrI: 7.8 - 29.7) infections, 0.71 (95% CrI: 0.52 - 0.97) hospitalizations, and 0.34 (95% CrI: 0.25 - 0.44) deaths per 10,000 population compared to the recommended 4-week interval between the two doses. Pfizer-BioNTech vaccines also averted an additional 0.61 (95% CrI: 0.37 - 0.89) hospitalizations and 0.31 (95% CrI: 0.23 - 0.45) deaths per 10,000 population in a 9-week delayed second dose strategy compared to the 3-week recommended schedule between doses. However, there was no clear advantage of delaying the second dose with Pfizer-BioNTech vaccines in reducing infections, unless the efficacy of the first dose did not wane over time. Our findings underscore the importance of quantifying the characteristics and durability of vaccine-induced protection after the first dose in order to determine the optimal time interval between the two doses. | epidemiology |
10.1101/2021.01.27.21250619 | Evaluation of COVID-19 vaccination strategies with a delayed second dose | Two of the COVID-19 vaccines currently approved in the United States require two doses, administered three to four weeks apart. Constraints in vaccine supply and distribution capacity, together with a deadly wave of COVID-19 from November 2020 to January 2021 and the emergence of highly contagious SARS-CoV-2 variants, sparked a policy debate on whether to vaccinate more individuals with the first dose of available vaccines and delay the second dose, or to continue with the recommended two-dose series as tested in clinical trials. We developed an agent-based model of COVID-19 transmission to compare the impact of these two vaccination strategies, while varying the temporal waning of vaccine efficacy following the first dose and the level of pre-existing immunity in the population. Our results show that for Moderna vaccines, a delay of at least 9 weeks could maximize vaccination program effectiveness and avert at least an additional 17.3 (95% CrI: 7.8 - 29.7) infections, 0.71 (95% CrI: 0.52 - 0.97) hospitalizations, and 0.34 (95% CrI: 0.25 - 0.44) deaths per 10,000 population compared to the recommended 4-week interval between the two doses. Pfizer-BioNTech vaccines also averted an additional 0.61 (95% CrI: 0.37 - 0.89) hospitalizations and 0.31 (95% CrI: 0.23 - 0.45) deaths per 10,000 population in a 9-week delayed second dose strategy compared to the 3-week recommended schedule between doses. However, there was no clear advantage of delaying the second dose with Pfizer-BioNTech vaccines in reducing infections, unless the efficacy of the first dose did not wane over time. Our findings underscore the importance of quantifying the characteristics and durability of vaccine-induced protection after the first dose in order to determine the optimal time interval between the two doses. | epidemiology |
10.1101/2021.01.27.21250611 | Operational response simulation tool for epidemics within refugee and IDP settlements | The spread of infectious diseases such as COVID-19 presents many challenges to healthcare systems and infrastructures across the world, exacerbating inequalities and leaving the worlds most vulnerable populations most affected. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to disease spread. Non-pharmaceutical public health interventions can be used to mitigate transmission, and modeling efforts can provide crucial insights on the potential effectiveness of such interventions to help inform decision making processes. In this paper we present an agent-based modeling approach to simulating the spread of disease in refugee and IDP settlements. The model, based on the JUNE open-source framework, is informed by data on geography, demographics, comorbidities, physical infrastructure and other parameters obtained from real-world observations and previous literature. Furthermore, we present a visual analytics tool which allows decision makers to distill insights by comparing the results of different simulations and scenarios. Through simulating their effects on the epidemiological development of COVID-19, we evaluate several public health interventions ranging from increasing mask wearing compliance to the reopening of learning institutions. The development and testing of this approach focuses on the Coxs Bazar refugee settlement in Bangladesh, although our model is designed to be generalizable to other informal settings. | epidemiology |
10.1101/2021.01.27.21250611 | Operational response simulation tool for epidemics within refugee and IDP settlements | The spread of infectious diseases such as COVID-19 presents many challenges to healthcare systems and infrastructures across the world, exacerbating inequalities and leaving the worlds most vulnerable populations most affected. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to disease spread. Non-pharmaceutical public health interventions can be used to mitigate transmission, and modeling efforts can provide crucial insights on the potential effectiveness of such interventions to help inform decision making processes. In this paper we present an agent-based modeling approach to simulating the spread of disease in refugee and IDP settlements. The model, based on the JUNE open-source framework, is informed by data on geography, demographics, comorbidities, physical infrastructure and other parameters obtained from real-world observations and previous literature. Furthermore, we present a visual analytics tool which allows decision makers to distill insights by comparing the results of different simulations and scenarios. Through simulating their effects on the epidemiological development of COVID-19, we evaluate several public health interventions ranging from increasing mask wearing compliance to the reopening of learning institutions. The development and testing of this approach focuses on the Coxs Bazar refugee settlement in Bangladesh, although our model is designed to be generalizable to other informal settings. | epidemiology |
10.1101/2021.01.28.21250680 | The effect of SARS-CoV-2 variant B.1.1.7 on symptomatology, re-infection and transmissibility | BackgroundSARS-CoV-2 variant B.1.1.7 was first identified in December 2020 in England. It is not known if the new variant presents with variation in symptoms or disease course, if previously infected individuals may become reinfected with the new variant, or how the variants increased transmissibility affects measures to reduce its spread.
MethodsUsing longitudinal symptom reports from 36,920 users of the COVID Symptom Study app testing positive for Covid-19 between 28 September and 27 December 2020, we performed an ecological study to examine the association between the regional proportion of B.1.1.7 and reported symptoms, disease course, rates of reinfection, and transmissibility.
FindingsWe found no evidence for changes in reported symptoms or disease duration associated with B.1.1.7. We found a likely reinfection rate of 0.7% (95% CI 0.6-0.8), but no evidence that this was higher compared to older strains. We found an increase in R(t) by a factor of 1.35 (95% CI 1.02-1.69). Despite this, we found that R(t) fell below 1 during regional and national lockdowns, even in regions with high proportions of B.1.1.7.
InterpretationThe lack of change in symptoms indicates existing testing and surveillance infrastructure do not need to change specifically for the new variant, and the reinfection findings suggest that vaccines are likely to remain effective against the new variant.
FundingZoe Global Limited, Department of Health, Wellcome Trust, EPSRC, NIHR, MRC, Alzheimers Society.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence on SARS-CoV-2 variant B.1.1.7 we searched PubMed and Google Scholar for articles between 1 December 2020 and 1 February 2021 using the keywords Covid-19 AND B.1.1.7, finding 281 results. We did not find any studies that investigated B.1.1.7-associated changes in the symptoms experienced, their severity and duration, but found one study showing B.1.1.7 did not change the ratio of symptomatic to asymptomatic infections. We found six articles describing laboratory-based investigations of the responses of B.1.1.7 to vaccine-induced immunity to B.1.1.7, but no work investigating what this means for natural immunity and the likelihood of reinfection outside of the lab. We found five articles demonstrating the increased transmissibility of B.1.1.7.
Added value of this studyTo our knowledge, this is the first study to explore changes in symptom type and duration, as well as community reinfection rates, associated with B.1.1.7. The work uses self-reported symptom logs from 36,920 users of the COVID Symptom Study app reporting positive test results between 28 September and 27 December 2020. We find that B.1.1.7 is not associated with changes in the symptoms experienced in Covid-19, nor their duration. Building on existing lab studies, our work suggests that natural immunity developed from previous infection provides similar levels of protection to B.1.1.7. We add to the emerging consensus that B.1.1.7 exhibits increased transmissibility.
Implications of all the available evidenceOur findings suggest that existing criteria for obtaining a Covid-19 test in the community need not change for the rise of B.1.1.7. The fact that immunity developed from infection by wild type variants protects against B.1.1.7 provides an indication that vaccines will remain effective against B.1.1.7. R(t) fell below 1 during the UKs national lockdown, even in regions with high levels of B.1.1.7, but further investigation is required to establish the factors that enabled this, to facilitate countries seeking to control the spread of B.1.1.7. | epidemiology |
10.1101/2021.01.28.21250680 | Changes in symptomatology, re-infection and transmissibility associated with SARS-CoV-2 variant B.1.1.7: an ecological study | BackgroundSARS-CoV-2 variant B.1.1.7 was first identified in December 2020 in England. It is not known if the new variant presents with variation in symptoms or disease course, if previously infected individuals may become reinfected with the new variant, or how the variants increased transmissibility affects measures to reduce its spread.
MethodsUsing longitudinal symptom reports from 36,920 users of the COVID Symptom Study app testing positive for Covid-19 between 28 September and 27 December 2020, we performed an ecological study to examine the association between the regional proportion of B.1.1.7 and reported symptoms, disease course, rates of reinfection, and transmissibility.
FindingsWe found no evidence for changes in reported symptoms or disease duration associated with B.1.1.7. We found a likely reinfection rate of 0.7% (95% CI 0.6-0.8), but no evidence that this was higher compared to older strains. We found an increase in R(t) by a factor of 1.35 (95% CI 1.02-1.69). Despite this, we found that R(t) fell below 1 during regional and national lockdowns, even in regions with high proportions of B.1.1.7.
InterpretationThe lack of change in symptoms indicates existing testing and surveillance infrastructure do not need to change specifically for the new variant, and the reinfection findings suggest that vaccines are likely to remain effective against the new variant.
FundingZoe Global Limited, Department of Health, Wellcome Trust, EPSRC, NIHR, MRC, Alzheimers Society.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence on SARS-CoV-2 variant B.1.1.7 we searched PubMed and Google Scholar for articles between 1 December 2020 and 1 February 2021 using the keywords Covid-19 AND B.1.1.7, finding 281 results. We did not find any studies that investigated B.1.1.7-associated changes in the symptoms experienced, their severity and duration, but found one study showing B.1.1.7 did not change the ratio of symptomatic to asymptomatic infections. We found six articles describing laboratory-based investigations of the responses of B.1.1.7 to vaccine-induced immunity to B.1.1.7, but no work investigating what this means for natural immunity and the likelihood of reinfection outside of the lab. We found five articles demonstrating the increased transmissibility of B.1.1.7.
Added value of this studyTo our knowledge, this is the first study to explore changes in symptom type and duration, as well as community reinfection rates, associated with B.1.1.7. The work uses self-reported symptom logs from 36,920 users of the COVID Symptom Study app reporting positive test results between 28 September and 27 December 2020. We find that B.1.1.7 is not associated with changes in the symptoms experienced in Covid-19, nor their duration. Building on existing lab studies, our work suggests that natural immunity developed from previous infection provides similar levels of protection to B.1.1.7. We add to the emerging consensus that B.1.1.7 exhibits increased transmissibility.
Implications of all the available evidenceOur findings suggest that existing criteria for obtaining a Covid-19 test in the community need not change for the rise of B.1.1.7. The fact that immunity developed from infection by wild type variants protects against B.1.1.7 provides an indication that vaccines will remain effective against B.1.1.7. R(t) fell below 1 during the UKs national lockdown, even in regions with high levels of B.1.1.7, but further investigation is required to establish the factors that enabled this, to facilitate countries seeking to control the spread of B.1.1.7. | epidemiology |
10.1101/2021.01.27.21250658 | COVID-19 mortality: positive correlation with cloudiness and sunlight but no correlation with latitude in Europe | We systematically investigated an ongoing debate about the possible correlation between SARS-CoV-2 (COVID-19) epidemiological outcomes and solar exposure in European countries, in the period of March - August 2020. For each country, we correlated its mortality data with solar insolation (watt/square metre) and objective sky cloudiness (as cloud fraction) derived from satellite weather data. We found a positive correlation between the monthly mortality rate and the overall cloudiness in that month (Pearsons r(35)=.779, P<.001; linear model fitting the data, adjusted R2 =0.59). In Europe, in colder months, approximately 34% to 58% of the variance in COVID-19 mortality/million appears to be predicted by the cloudiness fraction of the sky, except in August in which only [~]15% of the variance was explained. The data show a low, negative correlation between the mortality rate with the overall insolation received by the country area in that entire month (Pearsons r(35)=-0.622, P<.001). Additionally, we did not find any statistically significant correlation between the mortality and the latitude of the countries when the "latitude of a country" was precisely defined as the average landmass location (country centroid). The unexpected correlation found between cloudiness and mortality could perhaps be explained by the following: 1) heavy cloudiness is linked with colder outdoor surfaces, which might aid virus survival; 2) reduced evaporation rate; 3) moderate pollution may be linked to both cloudiness and mortality; and 4) large-scale behavioural changes due to cloudiness (which perhaps drives people to spend more time indoors and thus facilitates indoor contamination). | epidemiology |
10.1101/2021.01.27.21250490 | Baseline functional connectivity in resting state networks associated with depression and remission status after 16 weeks of pharmacotherapy: A CAN-BIND Report | Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. While numerous studies have been conducted, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity findings in the default mode, salience and cognitive control networks (DMN, SN, and CCN respectively) associated with MDD and pharmacotherapy outcomes in a large, multi-site sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression (CAN-BIND) initiative. Symptoms were assessed with the Montgomery-[A]sberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior DMN, SN and CCN) and all other brain voxels across participants. Partial least squares, a multivariate statistical technique, was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission early (MADRS [≤] 10 within 8 weeks), late (MADRS [≤] 10 within 16 weeks) or not at all. We replicated previous findings of altered connectivity in the DMN, SN and CCN in patients. In addition, baseline connectivity of the anterior/posterior DMN and SN seeds differentiated patients with different treatment outcomes. Weaker connectivity within the anterior DMN and between the anterior DMN and the SN and CCN characterised early remission; stronger connectivity within the SN and weaker connectivity between the SN and the DMN and CCN was related to late remission, of which the weaker SN - anterior DMN connectivity might specifically be associated with remission to dual pharmacotherapy; and connectivity strength between the posterior DMN and cingulate areas distinguished all three groups, with early remitters showing the strongest connections and non-remitters the weakest. The stability of these baseline patient differences was established in the largest single-site subsample of the data. Our replication and extension of altered connectivity within and between the DMN, SN and CCN highlighted previously reported and new differences between patients with MDD and controls, and revealed features that might predict remission prior to pharmacotherapy.
Trial registrationClinicalTrials.gov: NCT01655706. | psychiatry and clinical psychology |
10.1101/2021.01.26.21250587 | Loneliness and the onset of new mental health problems in the general population: a systematic review | BackgroundLoneliness is associated with poor health including premature mortality. There are cross-sectional associations with depression, anxiety, psychosis and other mental health outcomes. However, the direction of causation is unclear and clarifying the evidence from longitudinal studies is a key step in understanding this relationship.
AimsWe synthesized evidence from longitudinal studies investigating the relationship between loneliness and new onset of mental health problems, in the general population.
MethodWe systematically searched six electronic databases, unpublished sources and hand-searching of references, up to March 2020. We conducted a meta-analysis of eight independent cohorts, and narrative synthesis of the remaining studies.
ResultsWe included 20 studies, of which the majority focused on depression. Our narrative synthesis concluded that loneliness at baseline is associated with subsequent new onset of depression. The few studies on anxiety also showed an association. Our meta-analysis found a pooled adjusted odds ratio of 2.33 (95% C.I. 1.62 - 3.34) for risk of new onset depression in adults who were often lonely compared with people who were not often lonely. This should be interpreted with caution given evidence of heterogeneity. Most of the studies were in older adults.
ConclusionLoneliness is a public mental health issue. There is growing evidence it is associated with the onset of depression and other common mental health problems. Future studies should explore its impact across the age range, look beyond depression, and explore the mechanisms involved. | psychiatry and clinical psychology |
10.1101/2021.01.26.21250587 | Loneliness and the onset of new mental health problems in the general population: a systematic review | BackgroundLoneliness is associated with poor health including premature mortality. There are cross-sectional associations with depression, anxiety, psychosis and other mental health outcomes. However, the direction of causation is unclear and clarifying the evidence from longitudinal studies is a key step in understanding this relationship.
AimsWe synthesized evidence from longitudinal studies investigating the relationship between loneliness and new onset of mental health problems, in the general population.
MethodWe systematically searched six electronic databases, unpublished sources and hand-searching of references, up to March 2020. We conducted a meta-analysis of eight independent cohorts, and narrative synthesis of the remaining studies.
ResultsWe included 20 studies, of which the majority focused on depression. Our narrative synthesis concluded that loneliness at baseline is associated with subsequent new onset of depression. The few studies on anxiety also showed an association. Our meta-analysis found a pooled adjusted odds ratio of 2.33 (95% C.I. 1.62 - 3.34) for risk of new onset depression in adults who were often lonely compared with people who were not often lonely. This should be interpreted with caution given evidence of heterogeneity. Most of the studies were in older adults.
ConclusionLoneliness is a public mental health issue. There is growing evidence it is associated with the onset of depression and other common mental health problems. Future studies should explore its impact across the age range, look beyond depression, and explore the mechanisms involved. | psychiatry and clinical psychology |
10.1101/2021.01.26.21250065 | The Experience of Two Independent Schools with In-Person Learning During the COVID-19 Pandemic | BACKGROUNDIn 2020, U.S schools closed due to SARS-CoV-2 but their role in transmission was unknown. In fall 2020, national guidance for reopening omitted testing or screening recommendations. We report the experience of 2 large independent K-12 schools (School-A and School-B) that implemented an array of SARS-CoV-2 mitigation strategies that included periodic universal testing.
METHODSSARS-CoV-2 was identified through periodic universal PCR testing, self-reporting of tests conducted outside school, and contact tracing. Schools implemented behavioral and structural mitigation measures, including mandatory masks, classroom disinfecting, and social distancing.
RESULTSOver the fall semester, School-A identified 112 cases in 2320 students and staff; School-B identified 25 cases (2.0%) in 1200 students and staff. Most cases were asymptomatic and none required hospitalization. Of 69 traceable introductions, 63(91%) were not associated with school-based transmission, 59 cases (54%) occurred in the 2 weeks post-Thanksgiving. In 6/7 clusters, clear noncompliance with mitigation protocols was found. The largest outbreak had 28 identified cases and was traced to an off-campus party. There was no transmission from students to staff.
CONCLUSIONSAlthough school-age children can contract and transmit SARS-CoV-2, rates of COVID-19 infection related to in-person education were significantly lower than those in the surrounding community. However, social activities among students outside of school undermined those measures and should be discouraged, perhaps with behavioral contracts, to ensure the safety of school communities. In addition, introduction risks were highest following extended school breaks. These risks may be mitigated with voluntary quarantines and surveillance testing prior to re-opening. | public and global health |
10.1101/2021.01.27.21250521 | Induction of labour during the COVID-19 pandemic: a national survey of impact on practice in the UK | BackgroundInduction of labour (IOL) is one of the most commonly performed interventions in maternity care, with outpatient cervical ripening increasingly offered as an option for women undergoing IOL. The COVID-19 pandemic has changed the context of practice and the option of returning home for cervical ripening may now assume greater significance. This work aimed to examine whether and how the COVID-19 pandemic has changed practice around IOL in the UK.
MethodWe used an online questionnaire to survey senior obstetricians and midwives at all 156 UK NHS Trusts and Boards that currently offer maternity services. Responses were analysed to produce descriptive statistics, with free text responses analysed using a conventional content analysis approach.
FindingsResponses were received from 92 of 156 UK Trusts and Boards, a 59% response rate. Many Trusts and Boards reported no change to their IOL practice, however 23% reported change in methods used for cervical ripening; 28% a change in criteria for home cervical ripening; 28% stated that more women were returning home during cervical ripening; and 24% noted changes to womens response to recommendations for IOL. Much of the change was reported as happening in response to attempts to minimise hospital attendance and restrictions on birth partners accompanying women.
ConclusionsThe pandemic has changed practice around induction of labour, although this varied significantly between NHS Trusts and Boards. There is a lack of formal evidence to support decision-making around outpatient cervical ripening: the basis on which changes were implemented and what evidence was used to inform decisions is not clear. | obstetrics and gynecology |
10.1101/2021.01.27.21250294 | Objective adherence to an online FAVAS therapeutic game for treating amblyopia in children | AimThis retrospective study was to evaluate whether an updated version of attention binding digital therapeutic games based on the principle of Focal Ambient Visual Acuity Stimulation (FAVAS) would result in an improved patient adherence of patching in 4- to 12-year-old patients with amblyopia.
MethodsWe analyzed pseudonymised electronically recorded data from patients treated with two different versions of attention binding digital therapeutic games in 2015 and 2020. Two groups of children treated with occlusion therapy and attention binding digital therapeutic games, divided in treatment version, were compared. Patients in Group 2015 used the old version of therapeutic games without tablet computer functionality, while Group 2020 used more attractive therapeutic games with tablet computer functionality. Objective adherence was calculated by comparing the amount of minutes using the therapeutic games as monitored in the automatized logbook versus prescribed minutes of using the games.
ResultsChildren in Group 2015 spent on average 2009.3{+/-}1372.1 (36 to 5472) minutes using FAVAS; children in Group 2020 spent on average 2695.5{+/-}1526.8 (37.5 to 5672) minutes using the improved therapy. Meaning, Group 2020 spent 686.2 more minutes on FAVAS than Group 2015 (t=3.87, P<0.001). Although patient adherence was very variable, it significantly improved up to 78% {+/-} 46% in Group 2020 compared to the 57% {+/-} 34% in Group 2015 (t=4.3, P<0.001).
ConclusionFAVAS 2020 with an improved gamification aspect as well as tablet computer functionality increased adherence significantly compared to the earlier version FAVAS 2015, indicating that FAVAS 2020 could be an effective approach to support patching amblyopia treatment. | ophthalmology |
10.1101/2021.01.27.21250294 | Objective adherence to an online FAVAS therapeutic game for treating amblyopia in children | AimThis retrospective study was to evaluate whether an updated version of attention binding digital therapeutic games based on the principle of Focal Ambient Visual Acuity Stimulation (FAVAS) would result in an improved patient adherence of patching in 4- to 12-year-old patients with amblyopia.
MethodsWe analyzed pseudonymised electronically recorded data from patients treated with two different versions of attention binding digital therapeutic games in 2015 and 2020. Two groups of children treated with occlusion therapy and attention binding digital therapeutic games, divided in treatment version, were compared. Patients in Group 2015 used the old version of therapeutic games without tablet computer functionality, while Group 2020 used more attractive therapeutic games with tablet computer functionality. Objective adherence was calculated by comparing the amount of minutes using the therapeutic games as monitored in the automatized logbook versus prescribed minutes of using the games.
ResultsChildren in Group 2015 spent on average 2009.3{+/-}1372.1 (36 to 5472) minutes using FAVAS; children in Group 2020 spent on average 2695.5{+/-}1526.8 (37.5 to 5672) minutes using the improved therapy. Meaning, Group 2020 spent 686.2 more minutes on FAVAS than Group 2015 (t=3.87, P<0.001). Although patient adherence was very variable, it significantly improved up to 78% {+/-} 46% in Group 2020 compared to the 57% {+/-} 34% in Group 2015 (t=4.3, P<0.001).
ConclusionFAVAS 2020 with an improved gamification aspect as well as tablet computer functionality increased adherence significantly compared to the earlier version FAVAS 2015, indicating that FAVAS 2020 could be an effective approach to support patching amblyopia treatment. | ophthalmology |
10.1101/2021.01.27.21250153 | The prevalence of olfactory dysfunction and its associated factors in patients with COVID-19 infection | ObjectiveTo determine the prevalence of olfactory dysfunctions, mainly, anosmia and to identify its associated factors in patients with COVID-19 infection.
Study designA hospital-based prospective observational cohort study
SettingA COVID dedicated hospital, Square Hospitals Ltd., Dhaka, Bangladesh.
MethodsWe collected patients information including laboratory-confirmed COVID-19 test results. We used Pearson Chi-square test and logistic regression model to assess the associations between demographic and clinical characteristics and olfactory outcomes.
ResultsOut of 600 COVID-19 positive patients, 38.7% were diagnosed with olfactory dysfunction. Our analyses showed that patients age, smoking status, cough, dyspnea, sore throat, asthenia, and nausea or vomiting were significantly associated with the anosmia. We observed the risk of developing anosmia was greater in younger patients than in older patients, and this risk decreased as age increased [odds ratio (OR) range for different age groups: 1.26 to 1.08]. Smoking patients were 1.73 times more likely to experience anosmia than non-smoking patients [OR=1.73, 95% confidence interval (CI) = 1.01-2.98]. In addition, patients complained asthenia had a significantly double risk of developing the anosmia [OR = 1.96, CI = 1.23-3.06].
ConclusionsOur study shows that about 39% of patients diagnosed with olfactory dysfunction. Patients age, smoking status, and asthenia are significantly positively associated with the anosmia. Since anosmia can be a significant marker for the diagnosis of COVID-19, we suggest regular screening of olfactory dysfunction in patients with early symptoms of COVID-19, particularly younger patients, smoker, and complained asthenia. | otolaryngology |
10.1101/2021.01.27.21250487 | Self-Reported Mask Wearing Greatly Exceeds Directly Observed Use: Urgent Need for Policy Intervention in Kenya | BackgroundMany countries in sub-Saharan Africa have so far avoided large outbreaks of COVID-19, perhaps due to the strict lockdown measures that were imposed early in the pandemic. Yet the harsh socio-economic consequences of the lockdowns have led many governments to ease the restrictions in favor of less stringent mitigation strategies. In the absence of concrete plans for widespread vaccination, masks remain one of the few tools available to low-income populations to avoid the spread of SARS-CoV-2 for the foreseeable future.
MethodsWe compare mask use data collected through self-reports from phone surveys and direct observations in public spaces from population-representative samples in Ugunja subcounty, a rural setting in Western Kenya. We examine mask use in different situations and compare mask use by gender, age, location, and the riskiness of the activity
FindingsWe assess mask use data from 1,960 phone survey respondents and 9,549 direct observations. While only 12% of people admitted in phone interviews to not wearing a mask in public, 90% of people we observed did not have a mask visible (77.7% difference, 95% CI 0.742, 0.802). Self-reported mask use was significantly higher than observed mask use in all scenarios (i.e. in the village, in the market, on public transportation).
InterpretationWe find limited compliance with the national government mask mandate in Kenya using directly observed data, but high rates of self-reported mask use. This vast gap suggests that people are aware that mask use is socially desirable, but in practice they do not adopt this behavior.
Focusing public policy efforts on improving adoption of mask use via education and behavioral interventions may be needed to improve compliance.
FundingWeiss Family Foundation, International Growth Centre | health policy |
10.1101/2021.01.26.21250503 | Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia | Malaria diagnostic testing in Africa is threatened by Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes. Among 12,572 subjects enrolled along Ethiopias borders with Eritrea, Sudan, and South Sudan and using multiple assays, we estimate HRP2-based rapid diagnostic tests would miss 9.7% (95% CI 8.5-11.1) of falciparum malaria cases due to pfhrp2 deletion. Established and novel genomic tools reveal distinct subtelomeric deletion patterns, well-established pfhrp3 deletions, and recent expansion of pfhrp2 deletion. Current diagnostic strategies need to be urgently reconsidered in Ethiopia, and expanded surveillance is needed throughout the Horn of Africa. | infectious diseases |
10.1101/2021.01.27.21250388 | Passing the Test: A model-based analysis of safe school-reopening strategies | BackgroundThe COVID-19 pandemic has induced historic educational disruptions. In December 2020, at least two-thirds of US public school students were not attending full-time in-person education. The Biden Administration has expressed that reopening schools is a priority.
ObjectiveTo compare risks of SARS-COV-2 transmission in schools across different school-based prevention strategies and levels of community transmission.
DesignWe developed an agent-based network model to simulate transmission in elementary and high school communities, including home, school, and inter-household interactions.
SettingWe parameterized school structure based on average US classrooms, with elementary schools of 638 students and high schools of 1,451 students. We varied daily community incidence from 1 to 100 cases per 100,000 population.
Patients (or Participants)We simulated students, faculty/staff, and adult household members.
InterventionsWe evaluated isolation of symptomatic individuals, quarantine of an infected individuals contacts, reduced class sizes, alternative schedules, staff vaccination, and weekly asymptomatic screening.
MeasurementsWe projected transmission among students, staff and families during one month following introduction of a single infection into a school. We also calculated the number of infections expected for a typical 8-week quarter, contingent on community incidence rate.
ResultsSchool transmission risk varies according to student age and community incidence and is substantially reduced with effective, consistent mitigation measures. Nevertheless, when transmission occurs, it may be difficult to detect without regular, frequent testing due to the subclinical nature of most infections in children. Teacher vaccination can reduce transmission to staff, while asymptomatic screening both improves understanding of local circumstances and reduces transmission, facilitating five-day schedules at full classroom capacity.
LimitationsThere is uncertainty about susceptibility and infectiousness of children and low precision regarding the effectiveness of specific prevention measures, particularly with emergence of new variants.
ConclusionWith controlled community transmission and moderate school-based prevention measures, elementary schools can open with few in-school transmissions, while high schools require more intensive mitigation. Asymptomatic screening should be a key component of school reopenings, allowing reopening at higher community incidence while still minimizing transmission risk. | infectious diseases |
10.1101/2021.01.27.21250648 | Sequencing Data of North American SARS-CoV-2 Isolates Shows Widespread Complex Variants | Several new variants of the SARS-CoV-2 have been isolated in the United States, Mexico, and Canada. Many of the variants contain single variants of functional significance (e.g. S: N501Y increases transmissibility). To study the occurrence and co-circulation of these variants, we have developed an easy-to-use dashboard at janieslab.github.io/sars-cov-2.
We created a multiple sequence alignment workflow and processing script to generate a variant dataset, which populates this dashboard. We then use the features of the dashboard, such as visualization of the single and complex nucleotide variants geospatially and in a color-coded matrix format. Users also interact with the dashboard to filter the underlying data to regions of interest and or variants of interest. The user can export reports based on the desired filters, which we intend to be used for regionally specific pandemic response. We find in Genbank, an isolate from Massachusetts containing [(S: Q677H), (ORF3a: Q57H), (M: A85S), (N: D377Y)] collected on September 11, 2020.
Moreover, we find that many viral isolates bear a marker of increased transmissibility (S: N501Y) in linkage with at least one variant of concern isolated from Ohio also range across the Untied States and stretch from British Columbia, Canada to Mexico. When we analyze co-circulation of more complex variant constellations with (S: N501Y), we note that the Upper Midwest and Northeast United States contain these isolates.
In summary, the viral variants that have raised concern in a few US States in recent reports are widespread. Based on the increase in the proportion of variant viruses being sampled and some empirical evidence in the United Kingdom, South Africa, and Ohio, these variants are likely to lead to increased transmission of SARS-CoV-2 across North America in the coming months. | infectious diseases |
10.1101/2021.01.27.21250612 | The effectiveness of the first dose of BNT162 b 2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence | BackgroundBNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days.
MethodsWe conducted a retrospective cohort study using data from 2{middle dot}6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models.
FindingsData of 503,875 individuals (mean age 59{middle dot}7 years SD=14{middle dot}7, 47{middle dot}8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0{middle dot}57% (n=2484) during days 1-12 and 0{middle dot}27% (n=614) in days 13-24. A 51{middle dot}4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43{middle dot}41-per-100,000(SE=12{middle dot}07) in days 1-12 to 21{middle dot}08-per-100,000(SE=6{middle dot}16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities.
ConclusionsWe demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for follow-up studies regarding the effectiveness of BNT162b2 mRNA Covid-19 Vaccine without any language restrictions. The search terms were (BNT162b2 OR mRNA Covid-19 Vaccine) AND (effectiveness OR real-world OR phase IV) until Jan 15, 2021. We found no relevant observational studies among humans. We also assessed Phase II and Phase III clinical trials with BNT162b2 mRNA vaccine.
Added value of this studyTo our knowledge, this is the first and largest phase IV study on the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in real-world settings. Our findings showed that the first dose of the vaccine is associated with an approximately 51% reduction in the incidence of PCR-confirmed SARS-CoV-2 infections at 13 to 24 days after immunization compared to the rate during the first 12 days. Similar levels of effectiveness were found across age groups, sex, as well as among individuals residing in Arab or ultra-orthodox Jewish communities that display an increased COVID-19 risk.
Implications of all the available evidenceThe study results indicate that in real life the first dose of the new BNT162b2 mRNA COVID-19 vaccine confers around 50% protection against overall SARS-CoV-2 infections (symptomatic or asymptomatic). Together our findings and the 95% efficacy shown in the phase III trial, suggest that the BNT162b2 vaccine should be administered in two doses to achieve maximum protection and impact in terms of disease burden reduction and possibly reducing SARS-CoV-2 transmission. COVID-19 vaccines should be urgently deployed globally. | infectious diseases |
10.1101/2021.01.26.21250561 | SARS-CoV-2 antigenemia/viremia masks seroconversion in a COVID-19 patient | Immune responses against SARS-CoV-2 have been vigorously analyzed. It has been proposed that a subset of mild or asymptomatic cases with undetectable antibodies may clear the virus in a T-cell cytotoxic-dependent manner, albeit recent data revealed the importance of B-cells in that regard. We hypothesized that underdiagnosed antigenemia/viremia may conceal humoral response possibly through immunocomplex formation. We report the first case of late-onset seroconversion detected following decline in antigenemia/viremia levels. Consequently, classification of at least a subset of COVID-19 cases as non-responders might not represent a true immunobiological phenomenon, rather reflect antibody masking due to prolonged antigenemia/viremia. | infectious diseases |
10.1101/2021.01.28.21250096 | The successful use of volunteers to enhance NHS Test and Trace contact tracing of in-patients with Covid-19: a Pilot Study | Contact tracing in the UK for Covid-19 is performed by NHS Test and Trace (NHSTT) via telephone or email. This study estimates how many patients who have been admitted to hospital are not reached by NHSTT and the number of their contacts who were not advised to self-isolate.
Medical Student volunteers conducted face to face interviews with patients diagnosed with Covid-19 on an infectious diseases ward. Data on their close contacts were sent to NHSTT.
20 cases were enrolled. 13(65%) did not engage with NHSTT, 4(20%) because they had no positive PCR, 9(45%) because of severity of illness, language or intellectual difficulties. 49 close contacts were identified of whom 33(67%) were from cases who had not engaged with NHSTT. "Backwards" contacts tracing information was collected from 11(55%) cases and 8(40%) gave detailed information.
These data suggest that NHSTT fails to engage nearly two thirds of Covid-19 in-patients and fails to advise two thirds of their close contacts to self isolate.Volunteers used face to face interviews to overcome false negative tests, illness and communication problems to identify both close contacts and data on sources of infection. | infectious diseases |
10.1101/2021.01.27.21250559 | New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19 | Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in [~]25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins. | allergy and immunology |
10.1101/2021.01.27.21250527 | Association of COVID-19 incidence with objectively and subjectively measured mental health proxies in the Austrian Football League: an epidemiological study | ObjectiveWe aimed to explore the association of COVID-19 incidence with mental health in 225 team and staff members of five professional Austrian Football clubs captured by objective (location variance) or subjective (self-reported sleep quality, level of recovery, perceived risk of infection) mental health proxies.
MethodsData collected during the implementation of a novel monitoring concept to enable safe continuation of professional Football during the COVID-19 pandemic were matched with Austrian COVID-19 incidence data and smartphone collected location data (time-period June 17th to July 31st, 2020). Multivariable linear regression models explored the association of COVID-19 incidence, defined as daily novel or active cases of COVID-19, with the objective and subjective health proxies while adjusting for the occurrence of one COVID-19 case in a staff member in one of the clubs, team status (i.e. player vs staff) and game days.
ResultsData from 115 participants were analysed. An increasing number of novel COVID-19 cases was significantly associated with deteriorating sleep quality (B 0.48, 95% CI 0.05; 1.00) but with none of the other mental health proxies. An increasing number of active COVID-19 cases was significantly associated with an increase in perceived infection risk (B 0.04, 95% CI 0.00; 0.07) and location variance (B 0.28, 95% CI 0.06; 0.49).
ConclusionThe adverse association of an increasing COVID-19 incidence with mental health in professional Footballers and staff members became obvious particularly in subjectively measured mental health. During the ongoing pandemic, targeted mental care should be included in the daily routines of this population.
O_TEXTBOXSUMMARY BOX
O_LIAn increasing COVID-19 incidence is associated with deterioration of mental health in players and staff members of professional Football teams.
C_LIO_LIThe perceived COVID-19 infection risk is more pronounced in staff members than in players of professional Football clubs.
C_LIO_LISurprisingly, a rise in the number of active COVID-19 cases results in an increasing location variance.
C_LI
C_TEXTBOX | epidemiology |
10.1101/2021.01.28.21250601 | UK osteopathic practice in 2019: a retrospective analysis of practice data. | BackgroundThis study describes osteopathic activity, scope of practice and the osteopathic patient profile in order to understand the role osteopathy plays within the UK health system a decade after our previous survey.
MethodWe used a retrospective questionnaire survey design to ask about osteopathic practice and audit patient case notes. All UK registered osteopaths were invited to participate in the survey.
The survey was conducted using a web-based system. Each participating osteopath was asked about themselves, their practice and asked to randomly select and extract data from up to 8 random new patient health records during 2018. All patient related data were anonymised.
ResultsThe survey response rate was 500 osteopaths (9.4% of the profession) who provided information about 395 patients and 2,215 consultations.
Most osteopaths were self-employed (81.1%; 344/424 responses) working alone either exclusively or often (63.9%; 237/371) and were able to offer 48.6% of patients an appointment within 3 days (184/379).
Patient ages ranged from 1 month to 96 years (mean 44.7 years, Std Dev. 21.5), of these 58.4% (227/389) were female. Infants <1 years old represented 4.8% (18/379) of patients.
The majority of patients presented with musculoskeletal complaints (81.0%; 306/378). Persistent complaints (present for more than 12 weeks before appointment) were the most common (67.9%; 256/377) and 41.7% (156/374) of patients had co-existing medical conditions. The most common treatment approaches used at the first appointment were soft-tissue techniques (73.9%; 292/395), articulatory techniques (69.4%; 274/395) and high velocity low amplitude thrust (34.4%; 136/395). The mean number of treatments per patient was 7 (mode 4).
ConclusionTo better understand the role of osteopathy in UK health service delivery, the profession needs to do more research with patients in order to understand their needs and their expected outcomes of care, and for this to inform osteopathic practice and education. | rehabilitation medicine and physical therapy |
10.1101/2021.01.26.21250366 | Timing and Dose of Pharmacological Thromboprophylaxis in Adult Trauma Patients: Perceptions, Barriers, and Experience of Saudi Arabia Practicing Physicians | BackgroundPharmacological venous thromboembolism prophylaxis (PVTE-Px) in trauma care is challenging and frequently delayed until post injury bleeding risk is perceived to be sufficiently low; yet data for optimal initiation time is lacking. This study assessed practice pattern of PVTE-Px initiation time and dose in traumatic brain injury (TBI), spinal cord injury (SCI), and non-operative (NOR) solid organ injuries.
MethodsMulticenter, cross sectional, observational, survey-based study involving intensivists, trauma surgeons, general surgeons, spine orthopedics, and neurosurgeons practicing in trauma centers. The data of demographics, PVTE-Px timing and dose, and five clinical case scenarios were obtained. Analyses were stratified by early initiators vs. late initiators and logistic regression models were used to identify factors associated with early initiation of PVTE-Px.
ResultsOf 102 physicians (29 % response rate), most respondents were intensivists (63.7%) and surgeons (who are general and trauma surgeons) (22.5%); majority were consultants (58%), practicing at level 1 trauma centers (40.6%) or academic teaching hospitals (45.1%). A third of respondents (34.2%) indicated that decision to initiate PVTE-Px in TBI and SCI was made by a consensus between surgical, critical care, and neurosurgical services. For patients with NOR solid organ injuries, 34.2% of respondents indicated trauma surgeons initiated the decision on PVTE-Px timing. About 53.7% of the respondents considered their PVTE-Px practice as appropriate, half used combined mechanical and PVTE-Px (57.1%), 52% preferred enoxaparin (40 mg once daily), and only 6.5% used anti-Xa level to guide enoxaparin prophylactic dose. Responses to clinical cases varied. For TBI and TBI with intracranial pressure monitor, 40.3% and 45.6% of the respondents were early initiators with stable repeated head computed tomography [CT], respectively. For SCI, most respondents were early initiators without repeated CT spine (36.8%). With regards to NOR solid organ injuries [gunshot wound to the liver and grade IV splenic injuries], 49.1% and 36.4% of respondents were early initiators without a repeat CT abdomen.
ConclusionsVariations were observed in PVTE-Px initiation time influenced by trauma type. Our findings suggested enoxaparin is preferred in a standard prophylactic dose. More robust data from randomized trials are needed and the use of clinicians judgment is recommended.
Key MessagesO_LIIdeal time to initiate therapy, agent selection, dosing, and monitoring of pharmacological venous thromboembolism prophylaxis (PVTE-Px) for trauma patients is challenging.
C_LIO_LIVariations were observed in PVTE-Px initiation time influenced by trauma type.
C_LIO_LIOur study results are relatively in line with the recent evidence-based clinical literature
C_LIO_LIOur findings suggested limited awareness of augmented renal clearance (ARC) and utilization of serum anti-factor-Xa (anti-Xa) level.
C_LI | surgery |
10.1101/2021.01.26.21250550 | Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer PatientsShort title: Comparative Study of Chemotherapy Regimens for Gastric Cancer | PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.
MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.
ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).
ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients. | oncology |
10.1101/2021.01.26.21250550 | Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer PatientsShort title: Comparative Study of Chemotherapy Regimens for Gastric Cancer | PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.
MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.
ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).
ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients. | oncology |
10.1101/2021.01.26.21250550 | Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer Patients | PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.
MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.
ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).
ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients. | oncology |
10.1101/2021.01.25.21250099 | Trans-ethnic eQTL meta-analysis of human brain reveals regulatory architecture and candidate causal variants for brain-related traits | While large-scale genome-wide association studies (GWAS) have identified hundreds of loci associated with neuropsychiatric and neurodegenerative traits, identifying the variants, genes and molecular mechanisms underlying these traits remains challenging. Integrating GWAS results with expression quantitative trait loci (eQTLs) and identifying shared genetic architecture has been widely adopted to nominate genes and candidate causal variants. However, this integrative approach is often limited by the sample size, the statistical power of the eQTL dataset, and the strong linkage disequilibrium between variants. Here we developed the multivariate multiple QTL (mmQTL) approach and applied it to perform a large-scale trans-ethnic eQTL meta-analysis to increase power and fine-mapping resolution. Importantly, this method also increases power to identify conditional eQTLs that are enriched for cell type specific regulatory effects. Analysis of 3,188 RNA-seq samples from 2,029 donors, including 444 non-European individuals, yields an effective sample size of 2,974, which is substantially larger than previous brain eQTL efforts. Joint statistical fine-mapping of eQTL and GWAS identified 301 variant-trait pairs for 23 brain-related traits driven by 189 unique candidate causal variants for 179 unique genes. This integrative analysis identifies novel disease genes and elucidates potential regulatory mechanisms for genes underlying schizophrenia, bipolar disorder and Alzheimers disease. | genetic and genomic medicine |
10.1101/2021.01.25.21250439 | Ranking videolaryngoscopes and direct laryngoscopes by orotracheal intubation performance in children: protocol of a systematic review and network meta-analysis of randomized clinical trials at patient level. | BackgroundVideolaryngoscopy was shown to improve glottic visualization in children as compared to direct laryngoscopy, but at the expenses of delayed time for intubation. As little evidence is available regarding the relative performance of different laryngoscopes at present, we designed this systematic review and network meta-analysis to rank the different videolaryngoscopes (VLs) and direct laryngoscopes (DLs) for orotracheal intubation in children.
MethodsWe will conduct a search in PubMed, LILACS, Scielo, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 1) on 27/01/2021. We will include randomized clinical trials fully reported with patients aged [≤] 18 years, making comparisons between different types of laryngoscopes (any of both VLs and DLs) for failed first intubation attempt, intubation time, number of attempts at intubation or number of unsuccessful intubations, failed intubation, glottic view score, or adverse responses to endotracheal intubation. Pooled effects will be estimated by both fixed and random-effects models and presented according to qualitative and quantitative heterogeneity assessment. Sensitivity analyses will be performed as well as a priori subgroup, meta-regression and multiple meta-regression analyses. Additionally, network meta-analyses will be applied to rank the different VLs and DLs. We will also assess the risk of selective publication by funnel plot asymmetry.
DiscussionThis systematic review and network meta-analysis aim to understand which laryngoscopes perform better than others for orotracheal intubation.
Systematic review registrationThe current protocol was submitted to PROSPERO on 25/01/2021. | anesthesia |
10.1101/2021.01.25.21249942 | Development and external validation of prognostic models for COVID-19 to support risk stratification in secondary care | ObjectivesExisting UK prognostic models for patients admitted to hospital with COVID-19 are limited by reliance on comorbidities, which are under-recorded in secondary care, and lack of imaging data among the candidate predictors. Our aims were to develop and externally validate novel prognostic models for adverse outcomes (death, intensive therapy unit (ITU) admission) in UK secondary care; and externally validate the existing 4C score.
DesignCandidate predictors included demographic variables, symptoms, physiological measures, imaging, laboratory tests. Final models used logistic regression with stepwise selection.
SettingModel development was performed in data from University Hospitals Birmingham (UHB). External validation was performed in the CovidCollab dataset.
ParticipantsPatients with COVID-19 admitted to UHB January-August 2020 were included.
Main outcome measuresDeath and ITU admission within 28 days of admission.
Results1040 patients with COVID-19 were included in the derivation cohort; 288 (28%) died and 183 (18%) were admitted to ITU within 28 days of admission. Area under the receiver operating curve (AUROC) for mortality was 0.791 (95%CI 0.761-0.822) in UHB and 0.767 (95%CI 0.754-0.780) in CovidCollab; AUROC for ITU admission was 0.906 (95%CI 0.883-0.929) in UHB and 0.811 (95%CI 0.795-0.828) in CovidCollab. Models showed good calibration. Addition of comorbidities to candidate predictors did not improve model performance. AUROC for the 4C score in the UHB dataset was 0.754 (95%CI 0.721-0.786).
ConclusionsThe novel prognostic models showed good discrimination and calibration in derivation and external validation datasets, and outperformed the existing 4C score. The models can be integrated into electronic medical records systems to calculate each individual patients probability of death or ITU admission at the time of hospital admission. Implementation of the models and clinical utility should be evaluated.
Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIWe developed novel prognostic models predicting mortality and ITU admission within 28 days of admission for patients hospitalised with COVID-19, using a large routinely collected dataset gathered at admission with a wide range of possible predictors (demographic variables, symptoms, physiological measures, imaging, laboratory test results).
C_LIO_LIThese novel models showed good discrimination and calibration in both derivation and external validation cohorts, and outperformed the existing ISARIC model and 4C score in the derivation dataset. We found that addition of comorbidities to the set of candidate predictors included in model derivation did not improve model performance.
C_LIO_LIIf integrated into hospital electronic medical records systems, the model algorithms will provide a predicted probability of mortality or ITU admission for each patient based on their individual data at, or close to, the time of admission, which will support clinicians decision making with regard to appropriate patient care pathways and triage. This information might also assist clinicians in explaining complex prognostic assessments and decisions to patients and their relatives.
C_LIO_LIA limitation of the study was that in the external validation cohort we were unable to examine all of the predictors included in the original full UHB model due to only a reduced set of candidate predictors being available in CovidCollab. Nevertheless, the reduced model performed well and the results suggest it may be applicable in a wide range of datasets where only a reduced set of predictor variables is available.
C_LIO_LIFurthermore, it was not possible to carry out stratified analysis by ethnicity as the UHB dataset contained too few patients in most of the strata, and no ethnicity data was available in the CovidCollab dataset.
C_LI | public and global health |
10.1101/2021.01.23.21250364 | What does 16S rRNA gene-targeted next generation sequencing contribute to the study of infective endocarditis in valve tissue? | Infective endocarditis (IE) is a severe and life-threatening disease. Identification of infectious etiology is essential for establishing the appropriate antimicrobial treatment and decreasing mortality. The aim of this study was to explore potential utility of metagenomics for improving microbiological diagnosis of IE. In this work, next-generation sequencing (NGS) of V3-V4 region of the 16S rRNA gene was performed in 27 heart-valve tissues (18 natives, 5 intravascular devices, and 4 prosthetics) of patients diagnosed by IE. Initial microbiological diagnosis, blood culture (BC) and/or PCR, was compared with NGS-based diagnosis. Metagenomics matched with conventional techniques diagnosis in 24/27 cases (88.9%). The same bacterial family was assigned to 24 cases, the same genus to 23 cases, and the same specie for 13 cases. In 22 of them, the etiological agent was represented by percentages >99% of the reads and in two by [~]70%. Staphylococcus aureus was detected in a previously undiagnosed patient, making the microbiological diagnosis possible in one more sample than with previously used techniques. The remaining two patients showed no coincidence between traditional and NGS microbiological diagnoses. Minority records verified mixed infections in four cases and suggested confections in two cases, supported by clinical data. In conclusion: 16S rRNA gene-targeted NGS allowed to diagnose one case of IE without microbiological entity based on traditional techniques. However, the application of metagenomics to the study of IE in resected heart valves provides no benefits in comparison with BC and/or PCR. More studies are needed before implementation of NGS for the diagnosis of IE. | infectious diseases |
10.1101/2021.01.25.21250189 | Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity | Severe COVID-19 disproportionately impacts older individuals and those with comorbidities. It is estimated that approximately 80% of COVID-19 deaths are observed among individuals >65 years of age. However, the immunological underpinnings of severe COVID-19 in the aged have yet to be defined. This study captures the longitudinal immune response to SARS-CoV-2 infection in a cohort of young and aged patients with varying disease severity. Phenotypic transcriptional and functional examination of the peripheral mononuclear cells revealed age-, time, and disease severity-specific adaptations. Gene expression signatures within memory B cells suggest qualitative differences in the antibody responses in aged patients with severe disease. Examination of T cells showed profound lymphopenia, that worsened over time and correlated with lower levels of plasma cytokines important for T cell survival in aged patients with severe disease. Single cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity, and type-I interferon signaling in memory T cells and NK cells. Although hallmarks of a cytokine storm were evident in both groups, older individuals exhibited elevated levels of chemokines that mobilize inflammatory myeloid cells, notably in those who succumbed to disease. Correspondingly, we observed a re-distribution of DC and monocytes with severe disease that was accompanied by a rewiring towards a more regulatory phenotype. Several of these critical changes, such as the reduction of surface HLA-DR on myeloid cells, were reversed in young but not aged patients over time. In summary, the data presented here provide novel insights into the impact of aging on the host response to SARS-CoV2 infection. | infectious diseases |
10.1101/2021.01.26.21249582 | Risk-stratified lifestyle intervention to prevent type 2 diabetes | BackgroundLifestyle intervention (LI) can successfully prevent type 2 diabetes, but response to LI strongly varies depending on risk subphenotypes. We tested if individuals with prediabetes and a high-risk phenotype benefit from an intensification of LI.
Methods and findingsWe conducted a risk stratified multicenter randomized controlled intervention study over 12 months with additional 2 year follow up. In eight University Hospitals in Germany, 1105 individuals (female 59%, age 58{+/-}11 years, BMI 31.1{+/-}6.0 kg/m2 (mean{+/-}SD)) with impaired fasting glucose and/or impaired glucose tolerance were included between May 2012 and May 2016 in the study. Participants were stratified into 2 groups; a high- and low-risk phenotype, based on insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI or control (1:1), high-risk individuals to conventional or intensified LI (1:1), each over one year. Intensified LI included doubling of physical exercise and time of counselling. The primary endpoint was change in post-challenge glucose levels, assessed by frequently sampled oral glucose tolerance tests. Secondary endpoints included changes in liver fat content, assessed by magnetic resonance spectroscopy. A total of 908 (82%) participants completed the study after 12 months of LI. In high-risk individuals, the mean difference estimate between conventional and intensified LI in change in post-challenge glucose levels from baseline was -0.290 mmol/l [CI: -0.544;-0.036], p=0.025. Liver fat content was more reduced by intensified LI than by conventional LI (mean difference estimate: -1.34 percentage points [CI: -2.17;-0.50], p=0.002), and cardiovascular risk decreased stronger with intensified LI than with conventional LI (mean difference estimate -1.82 [CI: -3.13-0.50], p=0.007). In low-risk individuals, conventional LI was not superior to control in reducing postprandial glucose, liver fat or cardiovascular risk. During the total observation period of 3 years, high-risk participants with intensified LI had a higher probability to normalize glucose tolerance compared to conventional LI (p=0.003). The limitations of this study include a relative short duration of LI, a non-completer rate of 18% and an underrepresentation of low risk individuals.
ConclusionsIn high-risk individuals with prediabetes it is possible to improve glycemic and cardiometabolic outcomes by intensification of the commonly recommended conventional LI. Our results show that individualized, risk-phenotype-based LI can be implemented for the prevention of diabetes.
RegistrationNCT01947595
Author summaryO_ST_ABSWhy Was This Study Done?C_ST_ABSO_LIClinical trials in individuals with prediabetes have shown that the onset of type 2 diabetes can be delayed or prevented with lifestyle intervention.
C_LIO_LIAmong individuals with prediabetes, there is a large variability in the response to lifestyle intervention.
C_LIO_LIIt is unknown whether an intensification of intervention is able to improve the beneficial response.
C_LI
What Did the Researchers Do and Find?O_LIThe present multicenter, risk stratified randomized and controlled intervention trial in 1105 German individuals with prediabetes prospectively confirms the existence of a high-risk prediabetes phenotype
C_LIO_LIThe intensification of lifestyle intervention in high-risk individuals improves the glycemic outcome after 1 year of lifestyle intervention, and additionally results in a higher frequency of regression to normal glucose tolerance after 3 years of follow up.
C_LIO_LI.Intensification of lifestyle intervention results in a larger reduction of liver fat content and stronger improves cardiometabolic outcomes in high-risk individuals.
C_LI
What Do These Findings Mean?O_LIStrategies for the prevention of type 2 diabetes should include risk stratification and individualised interventions.
C_LIO_LIOur results highlight a dose-effect relationship for lifestyle intervention and suggest that "one size fits NOT all" in the field of diabetes prevention.
C_LIO_LIIt remains to be clarified whether low risk individuals benefit from lifestyle intervention, as there was a low number of individuals in this risk group in the current study.
C_LI | endocrinology |
10.1101/2021.01.22.21249651 | Timing of elective tracheotomy and duration of mechanical ventilation amongst patients admitted to intensive care with severe COVID-19: a multicentre prospective cohort study | BackgroundThe COVID-19 pandemic has strained intensive care unit (ICU) resources. Tracheotomy is the most frequent surgery performed on ICU patients and can affect the duration of ICU care. We studied the association between when tracheotomy occurs and weaning from mechanical ventilation, mortality, and intraoperative and postoperative complications.
MethodsMulticentre prospective cohort including all COVID-19 patients admitted to ICUs in 36 hospitals in Spain who received invasive mechanical ventilation and tracheotomy between 11 March and 20 July 2020. We used a target emulation trial framework to study the causal effects of early (7 to 10 days post-intubation) versus late (>10 days) tracheotomy on time from tracheotomy to weaning, postoperative mortality, and tracheotomy complications. Cause-specific Cox models were used for the first two outcomes and Poisson regression for the third, all adjusted for potential confounders.
FindingsWe included 696 patients, of whom 142 (20{middle dot}4%) received early tracheotomy. Using late tracheotomy as the reference group, multivariable cause-specific analysis showed that early tracheotomy was associated with faster post-tracheotomy weaning (fully adjusted hazard ratio (HR) [95% confidence interval (CI)]: 1{middle dot}31 [1{middle dot}02 to 1{middle dot}81]) without differences in mortality (fully adjusted HR [95% CI]: 0{middle dot}91 [0{middle dot}56 to 1{middle dot}47]) or intraoperative or postoperative complications (adjusted rate ratio [95% CI]: 0{middle dot}21 [0{middle dot}03 to 1{middle dot}57] and 1{middle dot}49 [0{middle dot}99 to 2{middle dot}24], respectively).
InterpretationEarly tracheotomy reduced post-tracheotomy weaning time, resulting in fewer mechanical ventilation days and shorter ICU stays, without changing complication or mortality rates. These results support early tracheotomy for COVID-19 patients when clinically indicated.
FundingSupported by the NIHR, FAME, and MRC.
Research in contextO_TEXTBOXEvidence before this studyThe optimal timing of tracheotomy for critically ill COVID-19 patients remains controversial. Existing guidelines and recommendations are based on limited experiences with SARS-CoV-1 and expert opinions derived from situations that differ from a pandemic outbreak. Most of the available guidance recommends late tracheotomy (>14 days), mainly due to the potential risk of infection for the surgical team and the high patient mortality rate observed early in the first wave of the COVID-19 pandemic.
Recent publications have shown that surgical teams can safely perform tracheotomies for COVID-19 patients if they use adequate personal protective equipment. Early tracheotomy seems to reduce the length of invasive mechanical ventilation without increasing complications, which may release crucial intensive care unit (ICU) beds sooner.
The current recommendations do not suggest an optimal time for tracheotomy for COVID-19 patients, and no study has provided conclusions based on objective clinical parameters.
Added value of this studyThis is the first study aiming to establish the optimal timing for tracheotomy for critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV). The study prospectively recruited a large multicentre cohort of 696 patients under IMV due to COVID-19 and collected data about the severity of respiratory failure, clinical and ventilatory parameters, and whether patients need to be laid flat during their ICU stay (proned). The analysis focused on the duration of IMV, mortality, and complication rates. We used a prospective cohort study design to compare the exposures of early (performed at day 7 to 10 after starting IMV) versus late (performed after day 10) tracheotomy and set the treatment decision time on the 7th day after orotracheal intubation.
Implications of all the available evidenceThe evidence suggests that tracheotomy within 10 days of starting COVID-19 patients on mechanical ventilation allows these patients to be removed from ventilation and discharged from ICU quicker than later tracheotomy, without added complications or increased mortality. This evidence may help to release ventilators and ICU beds more quickly during the pandemic.
C_TEXTBOX | respiratory medicine |
10.1101/2021.01.27.21250652 | Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss | PurposeThe ClinGen Variant Curation Expert Panels (VCEPS) provide disease-specific rules for accurate variant interpretation. Using hearing loss-specific American College of Medical Genetics/Association for Molecular Pathology (HL-specific ACMG/AMP) guidelines, the ClinGen Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in resolving conflicting variant interpretations.
MethodsA total of 157 variants across nine hearing loss genes were curated and submitted to ClinVar by the HL VCEP. The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.
ResultsBefore expert curation, 75% (117/157) of variants had single or multiple VUS submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS variants and 69% (69/100) of discordant variants were resolved into Benign (B), Likely Benign (LB), Likely Pathogenic (LP), or Pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant interpretation.
ConclusionExpert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study supports the utility of ClinGen VCEPs in helping the community move towards more consistent variant interpretations, which will improve the care of patients with genetic disorders. | genetic and genomic medicine |
10.1101/2021.01.28.21250666 | Structural basis of fitness of emerging SARS-COV-2 variants and considerations for screening, testing and surveillance strategy to contain their threat. | While emergence of new SAS-COV-2 variants is posing grave challenge to efforts to deal with the COVID-19 pandemic, the structural and molecular basis of their fitness remain poorly understood. We performed in silico analysis of structures of two most frequent SARS-COV-2 mutations, namely, N501Y and E484K, to identify plausible basis of their fitness over the original strain. The analysis suggested that the N501Y mutation is associated with strengthening of intra- as well as intermolecular H-bond in the hACE2 receptor-spike protein complex, which could result in increased affinity and, therefore, higher infectivity. While E484K mutation did not seem to directly affect the binding with hACE2 receptor, it disrupted H-bonding and salt-bridge interaction associated with binding with neutralizing antibody, which could affect chance of re-infection, disease outcome. Survey of several other mutations showing reduction in antibody-mediated neutralization also revealed that similar disruption of H-bonding or salt-bridge or Van der Waals interaction might explain their phenotype. Analysis of GESS database indicated that N501Y, EK484 as well as these other mutations existed since March-April, 2020, might have evolved independently across the world and may keep accumulating, which could affect efficacy of vaccination and antibody-based therapies. Our analysis also indicated that these may spread in spite of current travel restrictions focused on few countries and evolve indigenously warranting intensification of surveillance for emerging mutations among all travellers as well as people in their dwelling zones. Meta-analysis of existing literature showed that repeat testing of travellers, contacts and others under scrutiny 7-11 days after the initial RT-PCR test may significantly help to contain the spread of emerging variants by catching false negative results. In addition, existing evidence calls for development of strain-specific tests, escalated sequencing and broadening the scope of surveillance including in hospitals and animal farms to contain the threat of emerging variants. | public and global health |
10.1101/2021.01.27.21250628 | Assessing antimicrobial resistance, utilization and stewardship in Yemen: An exploratory mixed-methods study | Antimicrobial resistance (AMR), largely driven by irrational use of antimicrobials, is a global, multi-faceted problem calling for a complete understanding of all contributory factors for effective containment. In conflict settings, war-wounds and malnutrition can combine with existing social determinants to increase demand for antibiotics, compounding irrational use. In this study, we focus on Yemen, a low-income country with active conflict for the last five years, and analyze the current status of awareness and stewardship efforts regarding AMR. We performed a survey of prescribers/physicians and pharmacists to describe perceptions of AMR prevalence, antibiotic use practices and stewardship in Yemen, supported by a non-systematic scoping literature review and a key informant interview. Participants (96%, n=57) reported a perceived high AMR prevalence rate. Prescribers (74%, 20/27) reported pressure to prescribe broad-spectrum antibiotics. In the majority of cases (81%, 22/27), Antimicrobial Sensitivity Tests (AST) were not performed to inform antibiotic choice. The main barrier to AST was cost. Most pharmacists (67%, 18/27) sold antibiotics without prescriptions. Amoxicillin (including amoxicillin-clavulanate) was the most-commonly prescribed (63%, 17/27) or dispensed (82%, 22/27) antibiotic. AST was rated the least important solution to AMR in Yemen. While there was awareness of a high AMR rate, stewardship is poor in Yemen. We note that barriers to the use of AST could be addressed through the deployment of low-cost AST kits. Compulsory continuing education emphasizing the use of AST to guide prescribing and patients awareness programs could help avoid irrational use. | public and global health |
10.1101/2021.01.27.21250628 | Assessing antimicrobial resistance, utilization and stewardship in Yemen: An exploratory mixed-methods study | Antimicrobial resistance (AMR), largely driven by irrational use of antimicrobials, is a global, multi-faceted problem calling for a complete understanding of all contributory factors for effective containment. In conflict settings, war-wounds and malnutrition can combine with existing social determinants to increase demand for antibiotics, compounding irrational use. In this study, we focus on Yemen, a low-income country with active conflict for the last five years, and analyze the current status of awareness and stewardship efforts regarding AMR. We performed a survey of prescribers/physicians and pharmacists to describe perceptions of AMR prevalence, antibiotic use practices and stewardship in Yemen, supported by a non-systematic scoping literature review and a key informant interview. Participants (96%, n=57) reported a perceived high AMR prevalence rate. Prescribers (74%, 20/27) reported pressure to prescribe broad-spectrum antibiotics. In the majority of cases (81%, 22/27), Antimicrobial Sensitivity Tests (AST) were not performed to inform antibiotic choice. The main barrier to AST was cost. Most pharmacists (67%, 18/27) sold antibiotics without prescriptions. Amoxicillin (including amoxicillin-clavulanate) was the most-commonly prescribed (63%, 17/27) or dispensed (82%, 22/27) antibiotic. AST was rated the least important solution to AMR in Yemen. While there was awareness of a high AMR rate, stewardship is poor in Yemen. We note that barriers to the use of AST could be addressed through the deployment of low-cost AST kits. Compulsory continuing education emphasizing the use of AST to guide prescribing and patients awareness programs could help avoid irrational use. | public and global health |
10.1101/2021.01.27.21250645 | How well do face masks protect the wearer compared to public perceptions? | IntroductionThere is a growing body of evidence to support the wearing of face masks to reduce spread of infectious respiratory pathogens, including SARS-CoV-2. However, the literature exploring the effectiveness of homemade fabric face masks is still in its infancy. Developing an evidence base is an important step to ensure that public policy is evidence based and truly effective.
MethodsTwo methodologies were used in this study: quantitative fit testing of various face masks to indicate their effectiveness and a survey of 710 US residents about their perceptions of face mask effectiveness. N95, surgical and two fabric face masks were tested on an individual twenty five times each using a TSI 8038+ machine. Our survey was distributed by Qualtrics XM, asking participants to estimate the effectiveness of N95, surgical and fabric face masks.
Results and DiscussionOur results indicate that fabric face masks blocked between 62.6% and 87.1% of fine particles, whereas surgical masks protected against an average of 78.2% of fine particles. N95 masks blocked 99.6% of fine particles. Survey respondents tended to underestimate the effectiveness of masks, especially fabric masks. Together these results suggest that fabric masks may be a useful tool in the battle against the COVID-19 pandemic and that increasing public awareness of the effectiveness of fabric masks may help in this endeavour. | public and global health |
10.1101/2021.01.28.21250556 | The Impact of Distractions on Intracortical Brain-Computer Interface Control of a Robotic Arm | This was an investigational device observational trial with the objective to evaluate the impact of distractions on intracortical brain-computer interface (BCI) performance. Two individuals with tetraplegia had microelectrode arrays implanted into their motor cortex for trials of intracortical BCI safety and performance. The primary task was moving a robotic arm between two targets as quickly as possible, performed alone and with various secondary distraction conditions. Primary outcomes included targets acquired, path efficiency, and subjective difficulty. There was no difference in the number of targets acquired for either subject with or without distractions. Median path efficiency was similar across all conditions (range: 0.766-0.846) except the motor distraction for Subject P2, where the median path efficiency dropped to 0.675 (p = 0.033, Mann-Whitney U test). Both subjects rated the overall difficulty of the task with and without distractions as low. Overall, intracortical BCI performance was robust to various distractions. | rehabilitation medicine and physical therapy |
10.1101/2021.01.27.21250591 | High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19 | Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in SARS-CoV-2-infected patients is lacking. In this study, we used high-dimensional flow cytometry for granulocyte immunophenotyping in peripheral blood collected from COVID-19 patients during acute and convalescent phases. Severe COVID-19 was associated with increased levels of both mature and immature neutrophils, and decreased counts of eosinophils and basophils. Distinct immunotypes were evident in COVID-19 patients, with altered expression of several receptors involved in activation, adhesion and migration of granulocytes (e.g. CD62L, CD11a/b, CD69, CD63, CXCR4). Paired sampling revealed recovery and phenotypic restoration of the granulocytic signature in the convalescent phase. The identified granulocyte immunotypes correlated with distinct sets of soluble inflammatory markers supporting pathophysiologic relevance. Furthermore, clinical features, including multi-organ dysfunction and respiratory function, could be predicted using combined laboratory measurements and immunophenotyping. This study provides a comprehensive granulocyte characterization in COVID-19 and reveals specific immunotypes with potential predictive value for key clinical features associated with COVID-19.
SignificanceAccumulating evidence shows that granulocytes are key modulators of the immune response to SARS-CoV-2 infection and their dysregulation could significantly impact COVID-19 severity and patient recovery after virus clearance. In the present study, we identify selected immune traits in neutrophil, eosinophil and basophil subsets associated to severity of COVID-19 and to peripheral protein profiles. Moreover, computational modeling indicates that the combined use of phenotypic data and laboratory measurements can effectively predict key clinical outcomes in COVID-19 patients. Finally, patient-matched longitudinal analysis shows phenotypic normalization of granulocyte subsets 4 months after hospitalization. Overall, in this work we extend the current understanding of the distinct contribution of granulocyte subsets to COVID-19 pathogenesis. | allergy and immunology |
10.1101/2021.01.27.21250121 | Preoperative mu-opioid receptor availability predicts weight loss following bariatric surgery | BackgroundBariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the {micro}-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity, appetite control, and reward processing. The magnitude of initial brain receptor system perturbation is a plausible predictor of long-term surgical weight loss outcomes. The aim was to test this hypothesis by measuring obese subjects MOR and D2R availability with positron emission tomography (PET) preoperatively before bariatric surgery and then assessing their weight development association with regional MOR and D2R availabilities at 2-year follow-up.
MethodsWe studied 19 morbidly obese women (mean BMI 40, mean age 43) scheduled to undergo bariatric surgery, i.e. Roux-en-Y gastric bypass or sleeve gastrectomy, according to their standard clinical treatment. Preoperative MOR and D2R availabilities were measured using PET with [11C]carfentanil and [11C]raclopride, respectively. Subject weight was recorded at 3, 6, 12, and 24 months after surgery. Radiotracer binding potentials (BPND) were extracted and correlated with patient weight at different time points. ROIs were delineated in the striatum and in limbic and paralimbic components of the emotion and reward networks.
ResultsMOR availabilities were not correlated with preoperative weight. MOR availabilities in the amygdala (r = -0.54), insula (r = -0.46), ventral striatum (r = -0.48) and putamen (r = -0.49) were associated with subject weight at 3 months. Significant association was found in the amygdala at 6 months (r = -0.53), 12 (r = -0.49), and 24 months (r = -0.50). D2R availabilities were associated with neither preoperative weight nor weight loss at any follow-up time point.
ConclusionsTo our knowledge, this is the first study to demonstrate that neuroreceptor markers prior to bariatric surgery in patients with morbid obesity are associated with the postoperative weight loss. Preoperative MOR availability in the amygdala was associated with long-term postoperative weight development after surgery suggesting that postoperative weight regain may derive from dysfunction in the opioid system. Postoperative weight loss outcomes after bariatric surgery may be partially predicted based on preoperative receptor availability opening up new potential for treatment possibilities.
Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov | endocrinology |
10.1101/2021.01.27.21250597 | Modeling the asymptomatic prevalence of SARS-CoV-2 epidemic in Italy and the ISTAT survey | objectivesAugust 3rd, 2020, the Italian National Institute of Statistics (ISTAT) presented preliminary results of seroprevalence survey on the percentage of individuals affected by Covid-19. The survey aims to define (within the entire population of Italy) the portion of individuals that developed an antibody response against SARS-CoV-2. For the first time one has an estimate of the asymptomatic infected population and the possibility to acknowledge its potential role in the infection spread in Italy, one of the most affected areas in Europe. The information obtained allow a particularly sensitive validation of epidemiological models which include the asymptomatic class.
methodsThe present study is devoted to the construction of a model able to simulate, in a systematic way, the asymptomatic group whose relevance in the, SARS-CoV-2 epidemic, has been recently investigated and discussed. The investigation involves the description of the first epidemic outbreak in Italy as well as the predictive analysis of the ongoing second wave. In particular the possible correction to the data of the serological tests because of their sensitivity and specificity.
resultsThe model: taken as an example of the models presently used, satisfactory reproduces the data of the ISTAT survey showing a relevant predictive power and relegating in a secondary position models which do not include, in the simulation, the presence of asymptomatic groups. The corrections due to the serological test sensitivity (in particular those ones depending on the symptoms onset) make the comparison between data and models less accurate.
conclusionsThe predictions of the model confirm a relevant presence of asymptomatic individuals also during the second pandemic wave in Italy. The ratio of reported to unreported cases is predicted to be roughly 1:4. A more detailed knowledge of the results of the survey could allow to correct, in a relevant way, the data by means of the experimental evidences on the antibodies sensibility. The model analyses of the vaccination strategies, confirms the relevance of a massive administration with the beginning of the year to arrive at the end of the infection within August 2021. | epidemiology |
10.1101/2021.01.27.21250618 | Neighbourhood-level risk factors of COVID-19 incidence and mortality | BackgroundRacialized and low income communities face disproportionally high rates of coronavirus 2019 (COVID-19) infection and death. However, data on inequities in COVID-19 across granular categories of socio-demographic characteristics is more sparse.
MethodsNeighbourhood-level counts of COVID-19 cases and deaths in Ontario, Canada recorded as of July 28th, 2020 were extracted from provincial and local reportable infectious disease surveillance systems. Associations between COVID-19 incidence and mortality and 18 neighbourhood-level measures of immigration, race, housing and socio-economic characteristics were estimated with Poisson generalized linear mixed models. Housing characteristic variables were subsequently added to models to explore if housing may have a confounding influence on the relationships between immigration, race, and socio-economic status and COVID-19 incidence.
ResultsThere were large inequities in COVID-19 incidence and mortality across the socio-demographic variables examined. Neighbourhoods having a higher proportion immigrants, racialized populations, large households and low socio-economic status were associated with COVID-19 risk. Adjusting for housing characteristics, especially unsuitably crowded housing, attenuated COVID-19 risks. However persistent risk remained for neighbourhoods having high proportions of immigrants, racialized populations, and proportion of Black, Latin American, and South Asian residents.
ConclusionsSocio-demographic factors account for some of the neighbourhood-level differences in COVID-19 across Ontario. Housing characteristics account for a portion, but not all, of the excess burden of COVID-19 experienced by immigrant, racialized, low income and low education populations. | epidemiology |
10.1101/2021.01.27.21250642 | Forecasting virus outbreaks with social media data via neural ordinary differential equations | In the midst of the covid-19 pandemic, social media data collected in real time has the potential of being an early indicator of a new epidemic wave. This possibility is explored here by using a neural ordinary differential equation (neural ODE) that is trained to predict virus outbreaks for a geographic region. It learns from multivariate time series of signals obtained from a novel set of massive online surveys about COVID-19 symptoms. Once trained, the neural ODE is able to capture the dynamics of the interlinked local signals and accurately predict the number of new infections up to two months in advance. Moreover, it can estimate the future effects of changes in the number of infected at a given time, which can be associated with the flow of people entering or leaving a given region or, for instance, with a local vaccination campaign. This work gives compelling preliminary evidence for the predictive power of widely distributed social media surveys for public health application | epidemiology |
10.1101/2021.01.27.21250651 | Mitigation policies and vaccination in the COVID-19 pandemic: a modelling study | The perspective of vaccination to protect human population from infection of SARS-CoV-2 virus has great potential to control the pandemic. Nevertheless, vaccine planning requires phased introduction with age groups, health workers, and vulnerable people. We developed a mathematical model capable of capturing the dynamics of the SARS-CoV-2 dissemination aligned with social distancing, isolation measures, and vaccination. The city of Rio de Janeiro provides a case study to analyze possible scenarios including non-pharmaceutical interventions and vaccination in the epidemic scenario. Our results shows that a combination of different policies such as case isolation and social distancing are more effective for mitigating the epidemics. Furthermore, these policies will still be necessary in a phased vaccination program. Therefore, health surveillance activities should be maintained along with vaccination planning in scheduled groups until a large vaccinated coverage is reached. | epidemiology |
10.1101/2021.01.27.21250567 | Impact of age, gender, ethnicity and prior disease status on immunogenicity following administration of a single dose of the BNT162b2 mRNA Covid-19 Vaccine: real-world evidence from Israeli healthcare workers, December-January 2020 | The Pfizer Covid-19 vaccine showed high efficacy in clinical trials but observational data from populations not included in trials are needed. We described immunogenicity 21 days post-dose 1 among 514 Israeli healthcare workers by age, gender, ethnicity and prior COVID19 infection. Immunogenicity was similar by gender and ethnicity but decreased with age. Those with prior infection had antibody titres one magnitude order higher than naive individuals regardless of the presence of detectable IgG antibodies pre-vaccination. | epidemiology |
10.1101/2021.01.28.21250606 | REACT-1 round 8 final report: high average prevalence with regional heterogeneity of trends in SARS-CoV-2 infection in the community in England during January 2021 | In early January 2021, England entered its third national lockdown of the COVID-19 pandemic to reduce numbers of deaths and pressure on healthcare services, while rapidly rolling out vaccination to healthcare workers and those most at risk of severe disease and death. REACT-1 is a survey of SARS-CoV-2 prevalence in the community in England, based on repeated cross-sectional samples of the population. Between 6th and 22nd January 2021, out of 167,642 results, 2,282 were positive giving a weighted national prevalence of infection of 1.57% (95% CI, 1.49%, 1.66%). The R number nationally over this period was estimated at 0.98 (0.92, 1.04). Prevalence remained high throughout, but with suggestion of a decline at the end of the study period. The average national trend masked regional heterogeneity, with robustly decreasing prevalence in one region (South West) and increasing prevalence in another (East Midlands). Overall prevalence at regional level was highest in London at 2.83% (2.53%, 3.16%). Although prevalence nationally was highest in the low-risk 18 to 24 year old group at 2.44% (1.96%, 3.03%), it was also high in those over 65 years who are most at risk, at 0.93% (0.82%, 1.05%). Large household size, living in a deprived neighbourhood, and Black and Asian ethnicity were all associated with higher levels of infections compared to smaller households, less deprived neighbourhoods and other ethnicities. Healthcare and care home workers, and other key workers, were more likely to test positive compared to other workers. If sustained lower prevalence is not achieved rapidly in England, pressure on healthcare services and numbers of COVID-19 deaths will remain unacceptably high. | infectious diseases |
10.1101/2021.01.27.21250570 | Mapping a Pandemic: SARS-CoV-2 Seropositivity in the United States | Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates. To address this, we analyzed seropositivity in US adults who have not previously been diagnosed with COVID-19. Individuals with characteristics that reflect the US population (n = 11,382) and who had not previously been diagnosed with COVID-19 were selected by quota sampling from 241,424 volunteers (ClinicalTrials.gov NCT04334954). Enrolled participants provided medical, geographic, demographic, and socioeconomic information and 9,028 blood samples. The majority (88.7%) of samples were collected between May 10th and July 31st, 2020. Samples were analyzed via ELISA for anti-Spike and anti-RBD antibodies. Estimation of seroprevalence was performed by using a weighted analysis to reflect the US population. We detected an undiagnosed seropositivity rate of 4.6% (95% CI: 2.6 - 6.5%). There was distinct regional variability, with heightened seropositivity in locations of early outbreaks. Subgroup analysis demonstrated that the highest estimated undiagnosed seropositivity within groups was detected in younger participants (ages 18-45, 5.9%), females (5.5%), Black/African American (14.2%), Hispanic (6.1%), and Urban residents (5.3%), and lower undiagnosed seropositivity in those with chronic diseases. During the first wave of infection over the spring/summer of 2020 an estimate of 4.6% of adults had a prior undiagnosed SARS-CoV-2 infection. These data indicate that there were 4.8 (95% CI: 2.8-6.8) undiagnosed cases for every diagnosed case of COVID-19 during this same time period in the United States, and an estimated 16.8 million undiagnosed cases by mid-July 2020. | infectious diseases |
10.1101/2021.01.28.21250676 | Trends and opportunities in tick-borne disease geography | Tick-borne diseases are a growing problem in many parts of the world, and their surveillance and control touches on challenging issues in medical entomology, agricultural health, veterinary medicine, and biosecurity. Spatial approaches can be used to synthesize the data generated by integrative One Health surveillance systems, and help stakeholders, managers, and medical geographers understand the current and future distribution of risk. Here, we performed a systematic review of over 8,000 studies, and identified a total of 303 scientific publications that map tick-borne diseases using data on vectors, pathogens, and hosts (including wildlife, livestock, and human cases). We find that the field is growing rapidly, with the major Ixodes-borne diseases (Lyme disease and tick-borne encephalitis in particular) giving way to monitoring efforts that encompass a broader range of threats. We find a tremendous diversity of methods used to map tick-borne disease, but also find major gaps: data on the enzootic cycle of tick-borne pathogens is severely underutilized, and mapping efforts are mostly limited to Europe and North America. We suggest that future work can readily apply available methods to track the distributions of tick-borne diseases in Africa and Asia, following a One Health approach that combines medical and veterinary surveillance for maximum impact. | infectious diseases |
10.1101/2021.01.27.21250564 | Point-of-Care CRISPR-Cas-Assisted SARS-CoV-2 Detection in an Automated and Mobile Droplet Magnetofluidic Device | In the fight against COVID-19, there remains unmet needs in developing point-of-care (POC) diagnostic testing tools that can rapidly and sensitively detect the causative SARS-CoV-2 virus to control disease transmission and improve patient management. Although recent CRISPR-Cas-assisted SARS-CoV-2 detection assays (such as DETECTR and SHERLOCK) are viewed as transformative solutions for POC diagnostic testing, their lack of simple sample processing and full integration within an automated and portable device hamper their potential for POC use. We report herein POC-CRISPR - a new single-step CRISPR-Cas-assisted assay that is coupled to droplet magnetofluidics (DM) - that leverages simple magnetic concentration and transport of nucleic acid-binding magnetic beads to accomplish sample preparation and assay automation. By further adapting the assay into a fully integrated thermoplastic cartridge within a palm-sized mobile device, POC-CRISPR was able to detect 1 genome equivalent (GE)/{micro}L SARS-CoV-2 RNA from a sample volume of 100 {micro}L in 30 min. Moreover, when evaluated with unprocessed clinical nasopharyngeal (NP) swab eluates, POC-CRISPR identified SARS-CoV-2 positive samples in as short as 20 min and achieved full concordance with standard RT-qPCR. | infectious diseases |