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10.1101/2021.01.28.21250598 | Nationwide Seroprevalence of SARS-CoV-2 in Saudi Arabia | BackgroundEstimated seroprevalence of Coronavirus Infectious Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is a critical evidence for a better evaluation of the virus spread and monitoring the progress of the COVID-19 pandemic in a population. In the Kingdom of Saudi Arabia (KSA), SARS-CoV-2 seroprevalence has been reported in specific regions, but an extensive nationwide study has not been reported. Here, we report a nationwide study to determine the prevalence of SARS-CoV-2 in the population of KSA during the pandemic, using serum samples from healthy blood donors, non-COVID patients and healthcare workers (HCWs) in six different regions of the kingdom, with addition samples from COVID-19 patients.
MethodsA total of 11703 serum samples were collected from different regions of the KSA including; 5395 samples from residual healthy blood donors (D); 5877 samples from non-COVID patients collected through residual sera at clinical biochemistry labs from non-COVID patients (P); and 400 samples from consented HCWs. To determine the seroprevalence of SARS-CoV-2, all serum samples, in addition to positive control sera from RT-PCR confirmed COVID-19 patients, were subjected to in-house ELISA with a sample pooling strategy, which was further validated by testing individual samples that make up some of the pools, with a statistical estimation method to report seroprevalence estimates
ResultsOverall (combining D and P groups) seroprevalence estimate was around 11% in Saudi Arabia; and was 5.1% (Riyadh), 1.5% (Jazan), 18.4% (Qassim), 20.8% (Hail), 14.7% (ER; Alahsa), and 18.8% in Makkah. Makkah samples were only D group and had a rate of 24.4% and 12.8% in the cities of Makkah and Jeddah, respectively. The seroprevalence in Saudi Arabia across the sampled areas would be 12 times the COVID-19 infection rate. Among HCWs, 7.5% (4.95-10.16 CI 95%) had reactive antibodies to SARS-CoV-2 without reporting any previously confirmed infection. This was higher in HCWs with hypertension. The study also presents the demographics and prevalence of co-morbidities in HCWs and subset of non-COVID-19 population.
ConclusionOur study estimates the overall national serological prevalence of COVID-19 in Saudi Arabia to be 11%, with an apparent disparity between regions. | infectious diseases |
10.1101/2021.01.27.21250637 | Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 patients | SARS-CoV-2 infection has so far affected over 42 million people worldwide, causing over 1.1 million deaths. With the large majority of SARS-CoV-2 infected individuals being asymptomatic, major concerns have been raised about possible long-term consequences of the infection. We developed an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from COVID-19 patients whose diagnosis was confirmed by PCR from nasopharyngeal swabs (NP-PCR+). The study used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Childrens Hospital of Philadelphia obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-) as well as a collection of 20 urine samples from 20 individuals collected before the pandemic. Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, 1 NP-PCR-child was found to be positive for spike protein in urine. Of the 23 Ur-S+ adults, only 1 individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of NP-PCR+ adults have high levels of albumin and cystatin C in urine, respectively. Among individuals with albuminuria (>0.3 mg/mg of creatinine) statistical correlation could be found between albumin and spike protein in urine. Together, our data showe that 1 of 4 of SARS-CoV-2 infected individuals develop renal abnormalities such as albuminuria. Awareness about the long-term impact of these findings is warranted. | infectious diseases |
10.1101/2021.01.27.21250502 | Serosurveillance of SARS CoV 2 among the healthcare workers of a tertiary care teaching institution in Central Kerala during the post lockdown phase | BackgroundKerala was the first state to have the confirmed case of COVID-19 in the country and it was first confirmed in Thrissur district on 30 January2020.Our institute being in the heart of the city had to take adequate measures to mitigate the spread and treat the required patients by keeping its staff safe & Healthy. The hallmark of COVID 19 infection is high infectivity, pre-symptomatic transmission and asymptomatic prevalence which could result in high cumulative numbers of infections, hospitalizations, and deaths. Kerala was the first state to confirm community transmission in July 2020.Health care workers being in the forefront in the war against COVID19 are very prone in acquiring the infection and are possible to be asymptomatic sources for cluster formation. Knowing the development of immunity as shown by the presence of anti COV2 antibodies in the population contributes to the epidemiological understanding of the disease. The intent of the study is to do an antibody testing in our hospital to find the serosurveillance of SARS CoV 2 among the healthcare workers in our hospital.
AimTo estimate the seropositivity of SARS CoV 2 among the healthcare workers at Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, six months after revoking the lockdown
MethodologyA cross sectional study among the health care workers of the medical college. Multistage Sampling was done with the hospital block as the first stage and departments as the second stage. In the final stage of sampling the test individuals were selected on a first come first served basis after the antibody test availability was declared open and free for all staff. A consent form and a Google form were given to all staff who volunteered for participating in the study. Each consented participant recruited into the investigation completed a questionnaire which covers details regarding demographics, exposure history, Residence & travel. Blood sample was collected and Anti-SARS COV2 IgG antibody testing which targets the Spike Protein 1(SP1) was done using the VITROS chemiluminescence platform (Orthoclinical diagnostics, USA). Sampling & testing ranged over a time frame from September 5th to December 15th, 2020
ResultsJubilee Mission Medical College has 2785 working staff at the time of study. A total of 420 staff consented and their samples were tested. 37 staff members tested positive for COVID-19 antibody, yielding an overall prevalence of 8.75% (95% CI, 6.23-11.86). 86.5 % (32/37) of them were having a history of COVID-19 Antigen / RT PCR Positivity. We identified a statistically significant linear trend (p value =0.00001), between seropositivity and the degree of severity of COVID 19. Among the various factors which increase the risk of seroconversion, history of undergoing quarantine (p value < 0.001), contact with a confirmed case (p value = 0.002), contact with a caregiver for COVID 19 (p value =0.001) and history of Upper respiratory symptoms (p value =0.001), were found to be significantly associated with positive serology.
ConclusionsThe overall seropositivity in the current study was found to be 8.75% which is comparable to seroprevalence studies conducted in the United States and Wuhan in China. The pattern of seropositivity across the different category of health workers observed in the present study showed a higher prevalence among nurses. This result is also in agreement with a recent published report from united states. Various measures advised by the national and state health authorities were adequately adhered to. Keeping track of the pattern of development of immunity in the community is part of understanding the illness and forecasting the spread. For the tested HCW, it will boost up morale by ending uncertainty. For the hospital administration it will help in decision making about relative focusing of interventions on patients in general and HCWs. By knowing the immunity status of HCWs, the Institution will be able to contribute authentically to the development of intervention strategies and guidelines from time to time, besides following the available guidelines. Being an educational institution, it is obligatory to train all the elements of care delivery to the future generation of health care workers. Getting experienced from a small but relevant sample was expected to facilitate larger community study envisaged in peripheral areas Jubilee served | infectious diseases |
10.1101/2021.01.27.21250659 | SARS-CoV-2 antigen rapid diagnostic test enhanced with silver amplification technology | Rapid diagnosis of COVID-19 is essential for instituting measures to prevent viral spread. SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) based on lateral flow immunochromatography assay (LFIA) principle can visually indicate the presence of SARS-CoV-2 antigens as a band. Ag-RDT is clinically promising as a point-of-care testing because it can give results in a short time without the need for special equipment. Although various antigen capture LFIAs are now available for rapid diagnosis for SARS-CoV-2 infection, they face the problems of low sensitivity. We have previously developed highly specific monoclonal antibodies (mAb) against SARS-CoV-2 nucleocapsid protein (NP) and in this study, we have employed these mAbs to develop a new LFIA that can detect SARS-CoV-2 NP in nasopharyngeal swab samples with higher sensitivity by combining them with silver amplification technology. We also compared the performance of our Ag-RDT against the commercially available Ag-RDTs using clinical samples to find that our newly developed LFIA performed best among tested, highlighting the superiority of silver amplification technology. | infectious diseases |
10.1101/2021.01.26.21250284 | Automated detection and staging of malaria parasites from cytological smears using convolutional neural networks | Microscopic examination of blood smears remains the gold standard for diagnosis and laboratory studies with malaria. Inspection of smears is, however, a tedious manual process dependent on trained microscopists with results varying in accuracy between individuals, given the heterogeneity of parasite cell form and disagreement on nomenclature. To address this, we sought to develop an automated image analysis method that improves accuracy and standardisation of cytological smear inspection but retains the capacity for expert confirmation and archiving of images. Here we present a machine-learning method that achieves red blood cell (RBC) detection, differentiation between infected and uninfected RBCs and parasite life stage categorisation from raw, unprocessed heterogeneous images of thin blood films. The method uses a pre-trained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection that performs accurately, with an average precision of 0.99 at an intersection-over-union threshold of 0.5. A residual neural network (ResNet)-50 model applied to detect infection in segmented RBCs also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Lastly, using a regression model our method successfully recapitulates intra-erythrocytic developmental cycle (IDC) stages with accurate categorisation (ring, trophozoite, schizont), as well as differentiating asexual stages from gametocytes. To accelerate our methods utility, we have developed a mobile-friendly web-based interface, PlasmoCount, which is capable of automated detection and staging of malaria parasites from uploaded heterogeneous input images of Giemsa-stained thin blood smears. Results gained using either laboratory or phone-based images permit rapid navigation through and review of results for quality assurance. By standardising the assessment of parasite development from microscopic blood smears, PlasmoCount markedly improves user consistency and reproducibility and thereby presents a realistic route to automating the gold standard of field-based malaria diagnosis.
Significance StatementMicroscopy inspection of Giemsa-stained thin blood smears on glass slides has been used in the diagnosis of malaria and monitoring of malaria cultures in laboratory settings for >100 years. Manual evaluation is, however, time-consuming, error-prone and subjective with no currently available tool that permits reliable automated counting and archiving of Giemsa-stained images. Here, we present a machine learning method for automated detection and staging of parasite infected red cells from heterogeneous smears. Our method calculates parasitaemia and frequency data on the malaria parasite intraerythrocytic development cycle directly from raw images, standardizing smear assessment and providing reproducible and archivable results. Developed into a web tool, PlasmoCount, this method provides improved standardisation of smear inspection for malaria research and potentially field diagnosis. | infectious diseases |
10.1101/2021.01.28.21250212 | Predicting and simulating effects of PEEP changes with machine learning | Background/ObjectivesChoosing ventilator settings, especially positive end-expiratory pressure (PEEP), is a very common and non-trivial task in intensive care units (ICUs). Established solutions to this problem are either poorly individualised or come with high costs in terms of used material or time. We propose a novel method relying on machine learning utilising only already routinely measured data.
MethodsUsing the MIMIC-III (with over 60000 ICU stays) and eICU databases (with over 200000 ICU stays) we built a deep learning model that predicts relevant success parameters of ventilation (oxygenation, carbon dioxide elimination and respiratory mechanics). We compare a random forest, individual neural networks and a multi-tasking neural network. Our final model also allows to simulate the expected effects of PEEP changes.
ResultsThe model predicts arterial partial pressures of oxygen and carbon dioxide and respiratory system compliance 30 minutes into the future with mean absolute percentage errors of about 22 %, 10 % and 11 %, respectively.
ConclusionsThe deep learning approach to ventilation optimisation is promising and comes with low cost compared to other approaches. | intensive care and critical care medicine |
10.1101/2021.01.27.21250631 | Awake prone positioning and oxygen therapy in patients with COVID-19: The APRONOX study | PurposeThe awake prone position (PP) strategy for patients with acute respiratory distress syndrome (ARDS) is a safe, simple, and cost-effective technique used to improve hypoxemia. We aimed to evaluate the relationship between awake PP (AP) and endotracheal intubation in patients with coronavirus disease (COVID-19).
MethodsIn this retrospective, multicentre observational study conducted between 1 May and 12 June 2020 in 27 hospitals in Mexico and Ecuador, non-intubated patients with COVID-19 managed with AP or awake supine positioning (AS) were included to evaluate intubation and mortality risk in AP patients through logistic regression models; multivariable adjustment, propensity score analyses, and E-values were calculated to limit confounding. A CART model with cross-validation was also built. This study was registered at https://clinicaltrials.gov/ct2/show/NCT04407468
Results827 non-intubated patients with COVID-19 in the AP (n=505) and AS (n=322) groups were included for analysis. Less patients in the AP group required endotracheal intubation (23.6% vs 40.4%) or died (20% vs 37.9%). AP was a protective factor for intubation even after multivariable adjustment (OR=0.39, 95%CI:0.28-0.56, p<0.0001, E-value=2.01), which prevailed after propensity score analysis (OR=0.32, 95%CI:0.21-0.49, p<0.0001, E-value=2.21), and mortality (adjusted OR=0.38, 95%CI:0.25-0.57, p<0.0001, E-value=1.98). The main variables associated with PP failure in AP patients were age, lower SpO2/FiO2, and management with a non-rebreather mask. In the CART model, only two variables were used: SpO2/FiO2 (F 97.7, p<0.001) and PP (X2 50.5, p<0.001), with an overall percentage of 75.2%.
ConclusionPP in awake hospitalised patients with COVID-19 is associated with a lower risk of intubation and mortality. | intensive care and critical care medicine |
10.1101/2021.01.28.21250466 | SARS-CoV-2 Seroepidemiology in Children and Adolescents | ObjectivesPediatric SARS-CoV-2 data remain limited and seropositivity rates in children were reported as <1% early in the pandemic. Seroepidemiologic evaluation of SARS-CoV-2 in children in a major metropolitan region of the United States was performed.
MethodsChildren and adolescents [≤]19 years were enrolled in a cross-sectional, observational study of SARS-CoV-2 seroprevalence from July-October 2020 in Northern Virginia, United States. Demographic, health, and COVID-19 exposure information was collected, and blood was analyzed for SARS-CoV-2 spike protein total antibody. Risk factors associated with SARS-CoV-2 seropositivity were analyzed. Orthogonal antibody testing was performed, and samples were evaluated for responses to different antigens.
ResultsIn 1038 children, the anti-SARS-CoV-2 total antibody positivity rate was 8.5%. After multivariate logistic regression, significant risk factors included Hispanic ethnicity, public or absent insurance, a history of COVID-19 symptoms, exposure to person with COVID-19, a household member positive for SARS-CoV-2 and multi-family or apartment dwelling without a private entrance. 66% of seropositive children had no symptoms of COVID-19. Orthogonal antibody testing with a receptor binding domain specific antigen revealed a high concordance of 80.5%. Children also demonstrated a robust immune response to the nucleocapsid antigen.
ConclusionsA much higher burden of SARS-CoV-2 infection, as determined by seropositivity, was found in children than previously reported; this was also higher compared to adults in the same region at a similar time. Contrary to prior reports, we determined children shoulder a significant burden of COVID-19 infection. The role of childrens disease transmission must be considered in COVID-19 mitigation strategies including vaccination.
Article Summary8.5% of children had SARS-CoV-2 antibodies in Fall 2020, double the adult rate. The role of pediatric infection is important to consider in mitigation strategies.
Whats Known on This SubjectSARS-CoV-2 pediatric seroepidemiologic data is limited. Reported viral rates underestimate the burden of infection in children due to mild or asymptomatic disease. Limited cohorts of children suggest low seropositivity rates compared to adults.
What This Study AddsUS children in the largest SARS-CoV-2 seroepidemiology study to date had double the rate of antibodies compared to adults. Most children were asymptomatic. Risk factors include age, ethnicity and living conditions. Most children made antibodies to different antigens of SARS-CoV-2. | pediatrics |
10.1101/2021.01.28.21250669 | Title: Health and Healthcare Variables Associated with Italy's Excess Mortality during the First Wave of the COVID-19 pandemic: An Ecological Study. | BackgroundHealthcare factors have strongly influenced the propagation of COVID-19. The present study aims to examine whether excess mortality during the first phase of the COVID-19 outbreak in Italy was associated with health, healthcare, demographic, and socioeconomic indicators measured at a provincial level.
MethodsThe present ecological study concerns the raw number of deaths from Jan. 1 to Apr. 30, 2020 and the mean number of deaths in the same months of 2015 to 2019, per province. Information on socioeconomic factors and healthcare settings were extracted from the most recently updated databases on the ISTAT website. Two multilevel, multivariate models were constructed to test whether excess mortality was associated with the indicators across 107 provinces in Italy.
ResultsOn linear multilevel, multivariate analysis, AIDS mortality rate (p-value <0.05) correlates positively with excess mortality, while a higher density of General Practitioners (number of GPs per 1,000 population) is associated with lower excess mortality (p-value <0.05). After controlling for the diffusion of COVID-19 in each province, the significance of GP density increases (p-value <0.001) and the rate of hospitalization in long-term care wards is positively associated (p-value <0.05) with excess mortality.
ConclusionSome health and healthcare variables are strongly associated with excess mortality caused by COVID-19 in Italy and should be considered to implement mitigation policies and increase healthcare resilience. | public and global health |
10.1101/2021.01.28.21250671 | Frequency of hospitalization of infants with bronchiolitis during 2017 in Puerto Madryn, Argentina | IntroductionBronchiolitis is considered the most frequent disease in infants and still represents an important cause of morbidity and mortality worldwide. Despite its viral etiology, socioeconomic variables could influence the disease outcome. We aimed to determine the frequency of hospital discharge for bronchiolitis in a local Hospital in the city of Puerto Madryn, in the province of Chubut, Patagonia Argentina.
Population and methodsWe performed a cross-sectional study that analyzed all hospitalized patients discharged for bronchiolitis in Hospital "Dr. Andres R. Isola" during the year 2017 and based on data provided by the hospital administrative staff. The study variables were the length of stay, readmission rate and place of origin of hospitalized patients.
ResultsA total of 120 patients were included. The median age was 4.45 months (3.9-5). The mean length-of-stay (LOS) was 7.30 days (5.52-9.08). Of the total number of patients, 24 (20%) had a LOS [≤]3 days and 96 (80%) a >3 days. One hundred patients (88.33%) had no hospital readmissions and 10 patients (8.33%) had hospital readmissions. The median age of patients with readmissions was 4.2 months (2.69-5.71). The mean LOS during readmission was 17.3 days (5.25-29.35). Of the 120 hospitalized children, 100 infants (83.33%) live in areas identified as having "unsatisfied basic needs" in Puerto Madryn.
ConclusionsThe overcrowding as a result of the demographic transformation on the frequency of hospitalization of infants with bronchiolitis was homogeneous within the Puerto Madryn population with "unsatisfied basic needs". | respiratory medicine |
10.1101/2021.01.28.21250689 | Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites | Plasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Our analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse. We predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding likely reinfections that occur during follow-up using parasite genotyping methods.
AUTHOR SUMMARYRadical cure holds promise as a strategy for Plasmodium vivax malaria control by clearing the parasites known as hypnozoites that latently infect the liver and cause relapsing infections. The efficacy of radical cure treatment regimens is evaluated in phase-III clinical trials. Recent trial results have noted substantial variation in efficacy estimates across trial sites, complicating the interpretation of the benefit of radical cure. However, P. vivax infections identified during the course of the clinical trial could include reinfections from mosquito biting that do not directly reflect the effect of the therapeutic being trialed, potentially biasing efficacy estimates. In this study, we simulated clinical trials to identify the causes and solutions of these site-specific biases. We found that features of both the trial location, such as the transmission intensity, and the trial design, such as the duration of follow-up, lead to an underestimate of the effect of radical cure against hypnozoites. We then demonstrated that vector control and parasite genotyping are two possible strategies to reduce these biases. These insights can be leveraged to aid in the interpretation of past trial results and to help design future clinical trials that minimize site-specific biases. | epidemiology |
10.1101/2021.01.28.21250689 | How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites | Plasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Our analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse. We predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding likely reinfections that occur during follow-up using parasite genotyping methods.
AUTHOR SUMMARYRadical cure holds promise as a strategy for Plasmodium vivax malaria control by clearing the parasites known as hypnozoites that latently infect the liver and cause relapsing infections. The efficacy of radical cure treatment regimens is evaluated in phase-III clinical trials. Recent trial results have noted substantial variation in efficacy estimates across trial sites, complicating the interpretation of the benefit of radical cure. However, P. vivax infections identified during the course of the clinical trial could include reinfections from mosquito biting that do not directly reflect the effect of the therapeutic being trialed, potentially biasing efficacy estimates. In this study, we simulated clinical trials to identify the causes and solutions of these site-specific biases. We found that features of both the trial location, such as the transmission intensity, and the trial design, such as the duration of follow-up, lead to an underestimate of the effect of radical cure against hypnozoites. We then demonstrated that vector control and parasite genotyping are two possible strategies to reduce these biases. These insights can be leveraged to aid in the interpretation of past trial results and to help design future clinical trials that minimize site-specific biases. | epidemiology |
10.1101/2021.01.28.21250689 | How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites | Plasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Our analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse. We predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding likely reinfections that occur during follow-up using parasite genotyping methods.
AUTHOR SUMMARYRadical cure holds promise as a strategy for Plasmodium vivax malaria control by clearing the parasites known as hypnozoites that latently infect the liver and cause relapsing infections. The efficacy of radical cure treatment regimens is evaluated in phase-III clinical trials. Recent trial results have noted substantial variation in efficacy estimates across trial sites, complicating the interpretation of the benefit of radical cure. However, P. vivax infections identified during the course of the clinical trial could include reinfections from mosquito biting that do not directly reflect the effect of the therapeutic being trialed, potentially biasing efficacy estimates. In this study, we simulated clinical trials to identify the causes and solutions of these site-specific biases. We found that features of both the trial location, such as the transmission intensity, and the trial design, such as the duration of follow-up, lead to an underestimate of the effect of radical cure against hypnozoites. We then demonstrated that vector control and parasite genotyping are two possible strategies to reduce these biases. These insights can be leveraged to aid in the interpretation of past trial results and to help design future clinical trials that minimize site-specific biases. | epidemiology |
10.1101/2021.01.28.21250699 | Investigating the DNA methylation profile of e-cigarette use | Rationale and objectivesLittle evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.
MethodsAmong 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. We tested associations between e-cigarette use and methylation scores known to predict smoking and smoking-related disease. We assessed the ability of a methylation score for predicting e-cigarette use and for discriminating lung cancer.
Measurements and Main Results7 CpGs were identified in relation to e-cigarette use at p<1x10-5 and none at p<5.91x10-8. 13 CpGs were associated with smoking at p<1x10-5 and one at p<5.91x10-8. CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41-0.69) and externally (AUC 0.57, 0.36-0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52-0.76 versus AUC 0.73, 0.61-0.85).
ConclusionsThe DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation.
Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSIs there a DNA methylation signature of e-cigarette use and is it distinct from that of smoking?
What is the bottom line?Smoke exposure is known to lead to widespread changes in DNA methylation which have been identified in different populations and samples, persist for many years after smoking cessation, and may act as a biomarker for smoking-related disease risk and mortality. Whether a similar methylation profile exists in relation to e-cigarette use has not been widely investigated.
Why read on?We obtained saliva samples from 116 e-cigarette users and compared their DNA methylation profile with 117 smokers and 117 non-smokers. The e-cigarette users in this study had a minimal smoking history, and so we were able to distinguish the effects of e-cigarette use from those of smoke exposure. Overall, we found that the methylation profile associated with e-cigarette use is less pronounced and distinct from that associated with cigarette smoking. | epidemiology |
10.1101/2021.01.28.21250692 | A control framework to optimize public health policies in the course of the COVID-19 pandemic | The SARS-CoV-2 pandemic triggered substantial economic and social disruptions. Mitigation policies varied across countries based on resources, political conditions, and human behavior. In the absence of widespread vaccination able to induce herd immunity, strategies to coexist with the virus while minimizing risks of surges are paramount, which should work in parallel with reopening societies. To support these strategies, we present a predictive control system coupled with a nonlinear model able to optimize the level of policies to stop epidemic growth. We applied this system to study the unfolding of COVID-19 in Bahia, Brazil, also assessing the effects of varying population compliance. We show the importance of finely tuning the levels of enforced measures to achieve SARS-CoV-2 containment, with periodic interventions emerging as an optimal control strategy in the long-term.
One-sentence summaryWe present an adaptive predictive control algorithm to provide optimal public health measures to slow the COVID-19 transmission rate. | public and global health |
10.1101/2021.01.28.21249411 | Racial and Ethnic Disparities in Years of Potential Life Lost Attributable to COVID-19 in the United States: An Analysis of 45 States and the District of Columbia | The coronavirus disease 2019 (COVID-19) epidemic in the United States has disproportionately impacted communities of color across the country. Focusing on COVID-19-attributable mortality, we expand upon a national comparative analysis of years of potential life lost (YPLL) attributable to COVID-19 by race/ethnicity (Bassett et al., 2020), estimating percentages of total YPLL for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, non-Hispanic Asians, and non-Hispanic American Indian or Alaska Natives, contrasting them with their respective percent population shares, as well as age-adjusted YPLL rate ratios - anchoring comparisons to non-Hispanic Whites - in each of 45 states and the District of Columbia using data from the National Center for Health Statistics as of December 30, 2020. Using a novel Monte Carlo simulation procedure to quantify estimation uncertainty, our results reveal substantial racial/ethnic disparities in COVID-19-attributable YPLL across states, with a prevailing pattern of non-Hispanic Blacks and Hispanics experiencing disproportionately high and non-Hispanic Whites experiencing disproportionately low COVID-19-attributable YPLL. Furthermore, observed disparities are generally more pronounced when measuring mortality in terms of YPLL compared to death counts, reflecting the greater intensity of the disparities at younger ages. We also find substantial state-to-state variability in the magnitudes of the estimated racial/ethnic disparities, suggesting that they are driven in large part by social determinants of health whose degree of association with race/ethnicity varies by state. | public and global health |
10.1101/2021.01.28.21249614 | R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils | Gain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinsons disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73.
In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls.
We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state.
We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell. | neurology |
10.1101/2021.01.28.21250687 | Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock | BackgroundSepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent study demonstrated a non-significant reduction in mortality.
MethodsA pharmacometabolomics study of patients (n=250) in a Phase II trial of L-carnitine to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine. The independent predictive value of each pre-treatment metabolite concentration, adjusted for L-carnitine dose, on 90-day mortality was determined by logistic regression. A grid-search analysis maximizing the Z-statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L-carnitine responsive patients. Threshold concentrations were further assessed by hazard-ratio and Kaplan-Meier estimate.
FindingsAccounting for L-carnitine treatment and dose, 11 1H-NMR metabolites and 12 acylcarnitines were independent predictors of 90-day mortality. Based on the grid-search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L-carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with acetylcarnitine [≥]35{micro}M were less likely to die at 90 days if treated with L-carnitine (18 g) versus placebo (p=0.01 by log rank test).
InterpretationMetabolomics identified independent predictors of 90-day sepsis mortality. Our proof-of-concept approach shows how pharmacometabolomics may be useful for tackling the heterogeneity of sepsis and informing clinical trial design. Also, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, since sepsis induces alterations in numerous metabolite concentrations. | pharmacology and therapeutics |
10.1101/2021.01.28.21250700 | Surveillance-to-Diagnostic Testing Program for Asymptomatic SARS-CoV-2 Infections on a Large, Urban Campus - Georgia Institute of Technology, Fall 2020 | A SARS-CoV-2 testing program combining pooled saliva sample surveillance leading to diagnosis and intervention surveyed over 112,000 samples from 18,029 students, staff and faculty, as part of integrative efforts to mitigate transmission at the Georgia Institute of Technology in Fall 2020. Cumulatively, 1,508 individuals were confirmed diagnostically. The surveillance strategy, including focused intensification of testing given case clusters, was effective in disrupting transmission following rapid case increases upon entry in August 2020, and again in November 2020. Owing to broad adoption by the campus community, the program protected higher risk staff while allowing some normalization of research activities. | infectious diseases |
10.1101/2021.01.24.21250414 | Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis | BackgroundAntigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFN{beta}1a) develop neutralizing antibodies to IFN{beta}1a that do not disappear in repeated tests over years.
MethodsOne PwMS was recruited, as part of a planned phase IIa trial (n=15), who had developed neutralizing antibodies to subcutaneous IFN{beta}1a. Mitoxantrone (12mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88g/day + three 132g/day) intravenous IFN{beta}1a. Subcutaneous IFN{beta}1a three times a week was maintained during follow-up. IFN{beta}1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months.
FindingsOne participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased.
InterpretationThe data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted.
FundingThe study was supported by an unrestricted research grant from Merck-Serono. | allergy and immunology |
10.1101/2021.01.28.21250718 | Prediction Models for Severe Manifestations and Mortality due to COVID-19: A Rapid Systematic Review | BackgroundThroughout 2020, the coronavirus disease 2019 (COVID-19) has become a threat to public health on national and global level. There has been an immediate need for research to understand the clinical signs and symptoms of COVID-19 that can help predict deterioration including mechanical ventilation, organ support, and death. Studies thus far have addressed the epidemiology of the disease, common presentations, and susceptibility to acquisition and transmission of the virus; however, an accurate prognostic model for severe manifestations of COVID-19 is still needed because of the limited healthcare resources available.
ObjectiveThis systematic review aims to evaluate published reports of prediction models for severe illnesses caused COVID-19.
MethodsSearches were developed by the primary author and a medical librarian using an iterative process of gathering and evaluating terms. Comprehensive strategies, including both index and keyword methods, were devised for PubMed and EMBASE. The data of confirmed COVID-19 patients from randomized control studies, cohort studies, and case-control studies published between January 2020 and July 2020 were retrieved. Studies were independently assessed for risk of bias and applicability using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). We collected study type, setting, sample size, type of validation, and outcome including intubation, ventilation, any other type of organ support, or death. The combination of the prediction model, scoring system, performance of predictive models, and geographic locations were summarized.
ResultsA primary review found 292 articles relevant based on title and abstract. After further review, 246 were excluded based on the defined inclusion and exclusion criteria. Forty-six articles were included in the qualitative analysis. Inter observer agreement on inclusion was 0.86 (95% confidence interval: 0.79 - 0.93). When the PROBAST tool was applied, 44 of the 46 articles were identified to have high or unclear risk of bias, or high or unclear concern for applicability. Two studied reported prediction models, 4C Mortality Score from hospital data and QCOVID from general public data from UK, and were rated as low risk of bias and low concerns for applicability.
ConclusionSeveral prognostic models are reported in the literature, but many of them had concerning risks of biases and applicability. For most of the studies, caution is needed before use, as many of them will require external validation before dissemination. However, two articles were found to have low risk of bias and low applicability can be useful tools. | emergency medicine |
10.1101/2021.01.28.21250622 | The mobility gap: estimating mobility levels required to control Canada's winter COVID-19 surge | BackgroundNon-pharmaceutical interventions remain a primary means of suppressing COVID-19 until vaccination coverage is sufficient to achieve herd immunity. We used anonymized smartphone mobility measures in seven Canadian provinces to quantify the mobility level needed to suppress COVID-19 (mobility threshold), and the difference relative to current mobility levels (mobility gap).
MethodsWe conducted a longitudinal study of weekly COVID-19 incidence from March 15, 2020 to January 16, 2021, among provinces with 20 COVID-19 cases in at least 10 weeks. The outcome was weekly growth rate defined as the ratio of current cases compared to the previous week. We examined the effects of average time spent outside the home (non-residential mobility) in the prior three weeks using a lognormal regression model accounting for province, season, and mean temperature. We calculated the COVID-19 mobility threshold and gap.
ResultsAcross the 44-week study period, a total of 704,294 persons were infected with COVID-19. Non-residential mobility dropped rapidly in the spring and reached a median of 36% (IQR: 31,40) in April 2020. After adjustment, each 5% increase in non-residential mobility was associated with a 9% increase in the COVID-19 weekly growth rate (ratio=1.09, 95%CI: 1.07,1.12). The mobility gap increased through the fall months, which was associated with increasing case growth.
InterpretationMobility strongly and consistently predicts weekly case growth, and low levels of mobility are needed to control COVID-19 through winter 2021. Mobility measures from anonymized smartphone data can be used to guide the provincial and regional implementation and loosening of physical distancing measures. | epidemiology |
10.1101/2021.01.28.21250701 | How dynamic social activity shapes an epidemic: waves, plateaus, and endemic state | It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state. | epidemiology |
10.1101/2021.01.28.21250701 | How dynamic social activity shapes COVID-19 epidemic: waves, plateaus, and endemic state | It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state. | epidemiology |
10.1101/2021.01.28.21250701 | Stochastic social behavior coupled to COVID-19 dynamics leads to waves, plateaus and an endemic state | It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state. | epidemiology |
10.1101/2021.01.28.21250701 | Stochastic social behavior coupled to COVID-19 dynamics leads to waves, plateaus and an endemic state | It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state. | epidemiology |
10.1101/2021.01.28.21250723 | TIME TO LUNG VOLUME STABILITY AFTER PRESSURE CHANGE DURING HIGH-FREQUENCY OSCILLATORY VENTILATION | ObjectivesClinicians have little guidance on the time needed before assessing the effect of a mean airway pressure (PAW) change during high-frequency oscillatory ventilation (HFOV). We aimed to determine 1) time to stable lung volume after a PAW change during HFOV and, 2) the relationship between time to volume stability and the volume state of the lung.
MethodsContinuous lung volume measurements (respiratory inductive plethysmography) after 1-2 cmH2O PAW changes made every 10 minutes during an open lung strategy (n=13 infants) were analysed with a bi-exponential model. Time to stable lung volume (extrapolated to maximum 3600s) was calculated if the model R2 was >0.6.
Results196 PAW changes were made, with no volume change in 33 (17%) occurrences. 125 volume signals met modelling criteria for inclusion; median (IQR) R2 0.96 (0.91, 0.98). The time to stable lung volume was 1131 (718, 1959)s (PAW increases) and 647 (439, 1309)s (PAW decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic.
ConclusionsDuring HFOV, the time to stable lung volume after a PAW change is variable, often requires more than 10 minutes and is dependent on the preceding volume state.
Impact StatementO_LIIn infants without preterm respiratory distress syndrome the time to achieve lung volume stability after a PAW change during HFOV is usually greater than 10 minutes.
C_LIO_LIThe volume state of the lung at the time of PAW change influences the time required to achieve a stable new lung volume; being shorter when the lung is well recruited and longer when the lung is already atelectatic.
C_LIO_LIClinicians should be aware that it may require least 10 minutes before assessing the clinical response to a change in PAW during HFOV
C_LI | pediatrics |
10.1101/2021.01.28.21250369 | Identification of Nonverbal Communication Tools for Use in Dementia | IntroductionNon-verbal communication remains a relatively unexplored area in dementia care with a lack of validated assessment tools available to measure non-verbal communication function in dementia.
MethodsThis scoping review identifies assessment scales of nonverbal communication in dementia and evaluates the psychometric properties and clinical utility of these instruments. Relevant publications in English, from 1947 to 2017, were identified through an extensive search strategy in Medline, Psychinfo and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane and generic search engines (Google) and available off-line resources. Quality judgement criteria was formulated and used to evaluate the psychometric aspects of the scales.
ResultsForty-one tools were identified measuring various communication channels including verbal, nonverbal (e.g., facial expressions, gestures, eye contact) and functional, communication means; within various settings and populations, for instance, those assessing cognition and verbal language difficulties secondary to stroke, aphasia and nonverbal cues associated with pain. A number of tools presented psychometrics qualities; only nine of the forty-one tools specifically focussed on nonverbal communication, however, comprehensive assessment of nonverbal communication function was not presented in majority of the identified tools. Two tools provided a detailed assessment of nonverbal communication, the Emory dyssemia Index (EDI) and the Threadgold Communication Tool (TCT).
ConclusionBased on the psychometric qualities and criteria regarding sensitivity and clinical utility, we concluded that although it is difficult to recommend one particular tool, the EDI and TCT are the most appropriate scales currently available. Further research should focus on improving these scales by further testing their validity, reliability and clinical utility in dementia. | psychiatry and clinical psychology |
10.1101/2021.01.28.21250694 | Uncovering Survivorship Bias in Longitudinal Mental Health Surveys | AimsMarkedly elevated adverse mental health symptoms were widely observed early in the coronavirus disease 2019 (COVID-19) pandemic. Unlike the U.S., where cross-sectional data indicate anxiety and depression symptoms have remained elevated, such symptoms reportedly declined in the U.K., according to analysis of repeated measures from a largescale longitudinal study. However, nearly 40% of U.K. respondents (those who did not complete multiple follow-up surveys) were excluded from analysis, suggesting that survivorship bias might partially explain this discrepancy. We therefore sought to assess survivorship bias among participants in our longitudinal survey study as part of The COVID-19 Outbreak Public Evaluation (COPE) Initiative.
MethodsSurvivorship bias was assessed 4,039 U.S. respondents who completed surveys including the assessment of mental health as part of The COPE Initiative in April 2020 and were invited to complete follow-up surveys. Participants completed validated screening instruments for symptoms of anxiety, depression, and insomnia. Survivorship bias was assessed for (1) demographic differences in follow-up survey participation, (2) differences in initial adverse mental health symptom prevalences adjusted for demographic factors, and (3) differences in follow-up survey participation based on mental health experiences adjusted for demographic factors.
ResultsAdjusting for demographics, individuals who completed only one or two out of four surveys had higher prevalences of anxiety and depression symptoms in April 2020 (e.g., one-survey versus four-survey, anxiety symptoms, adjusted prevalence ratio [aPR]: 1.30, 95% confidence interval [CI]: 1.08-1.55, P=0.0045; depression symptoms, aPR: 1.43, 95% CI: 1.17-1.75, P=0.00052). Moreover, individuals who experienced incident anxiety or depression symptoms had higher odds of not completing follow-up surveys (adjusted odds ratio [aOR]: 1.68, 95% CI: 1.22-2.31, P=0.0015, aOR: 1.56, 95% CI: 1.15-2.12, P=0.0046, respectively).
ConclusionsOur findings revealed significant survivorship bias among longitudinal survey respondents, indicating that restricting analytic samples to only respondents who provide repeated assessments in longitudinal survey studies could lead to overly optimistic interpretations of mental health trends over time. Cross-sectional or planned missing data designs may provide more accurate estimates of population-level adverse mental health symptom prevalences than longitudinal surveys. | psychiatry and clinical psychology |
10.1101/2021.01.28.21250694 | Uncovering Survivorship Bias in Longitudinal Mental Health Surveys During the COVID-19 Pandemic | AimsMarkedly elevated adverse mental health symptoms were widely observed early in the coronavirus disease 2019 (COVID-19) pandemic. Unlike the U.S., where cross-sectional data indicate anxiety and depression symptoms have remained elevated, such symptoms reportedly declined in the U.K., according to analysis of repeated measures from a largescale longitudinal study. However, nearly 40% of U.K. respondents (those who did not complete multiple follow-up surveys) were excluded from analysis, suggesting that survivorship bias might partially explain this discrepancy. We therefore sought to assess survivorship bias among participants in our longitudinal survey study as part of The COVID-19 Outbreak Public Evaluation (COPE) Initiative.
MethodsSurvivorship bias was assessed 4,039 U.S. respondents who completed surveys including the assessment of mental health as part of The COPE Initiative in April 2020 and were invited to complete follow-up surveys. Participants completed validated screening instruments for symptoms of anxiety, depression, and insomnia. Survivorship bias was assessed for (1) demographic differences in follow-up survey participation, (2) differences in initial adverse mental health symptom prevalences adjusted for demographic factors, and (3) differences in follow-up survey participation based on mental health experiences adjusted for demographic factors.
ResultsAdjusting for demographics, individuals who completed only one or two out of four surveys had higher prevalences of anxiety and depression symptoms in April 2020 (e.g., one-survey versus four-survey, anxiety symptoms, adjusted prevalence ratio [aPR]: 1.30, 95% confidence interval [CI]: 1.08-1.55, P=0.0045; depression symptoms, aPR: 1.43, 95% CI: 1.17-1.75, P=0.00052). Moreover, individuals who experienced incident anxiety or depression symptoms had higher odds of not completing follow-up surveys (adjusted odds ratio [aOR]: 1.68, 95% CI: 1.22-2.31, P=0.0015, aOR: 1.56, 95% CI: 1.15-2.12, P=0.0046, respectively).
ConclusionsOur findings revealed significant survivorship bias among longitudinal survey respondents, indicating that restricting analytic samples to only respondents who provide repeated assessments in longitudinal survey studies could lead to overly optimistic interpretations of mental health trends over time. Cross-sectional or planned missing data designs may provide more accurate estimates of population-level adverse mental health symptom prevalences than longitudinal surveys. | psychiatry and clinical psychology |
10.1101/2021.01.28.21250694 | Uncovering Survivorship Bias in Longitudinal Mental Health Surveys During the COVID-19 Pandemic | AimsMarkedly elevated adverse mental health symptoms were widely observed early in the coronavirus disease 2019 (COVID-19) pandemic. Unlike the U.S., where cross-sectional data indicate anxiety and depression symptoms have remained elevated, such symptoms reportedly declined in the U.K., according to analysis of repeated measures from a largescale longitudinal study. However, nearly 40% of U.K. respondents (those who did not complete multiple follow-up surveys) were excluded from analysis, suggesting that survivorship bias might partially explain this discrepancy. We therefore sought to assess survivorship bias among participants in our longitudinal survey study as part of The COVID-19 Outbreak Public Evaluation (COPE) Initiative.
MethodsSurvivorship bias was assessed 4,039 U.S. respondents who completed surveys including the assessment of mental health as part of The COPE Initiative in April 2020 and were invited to complete follow-up surveys. Participants completed validated screening instruments for symptoms of anxiety, depression, and insomnia. Survivorship bias was assessed for (1) demographic differences in follow-up survey participation, (2) differences in initial adverse mental health symptom prevalences adjusted for demographic factors, and (3) differences in follow-up survey participation based on mental health experiences adjusted for demographic factors.
ResultsAdjusting for demographics, individuals who completed only one or two out of four surveys had higher prevalences of anxiety and depression symptoms in April 2020 (e.g., one-survey versus four-survey, anxiety symptoms, adjusted prevalence ratio [aPR]: 1.30, 95% confidence interval [CI]: 1.08-1.55, P=0.0045; depression symptoms, aPR: 1.43, 95% CI: 1.17-1.75, P=0.00052). Moreover, individuals who experienced incident anxiety or depression symptoms had higher odds of not completing follow-up surveys (adjusted odds ratio [aOR]: 1.68, 95% CI: 1.22-2.31, P=0.0015, aOR: 1.56, 95% CI: 1.15-2.12, P=0.0046, respectively).
ConclusionsOur findings revealed significant survivorship bias among longitudinal survey respondents, indicating that restricting analytic samples to only respondents who provide repeated assessments in longitudinal survey studies could lead to overly optimistic interpretations of mental health trends over time. Cross-sectional or planned missing data designs may provide more accurate estimates of population-level adverse mental health symptom prevalences than longitudinal surveys. | psychiatry and clinical psychology |
10.1101/2021.01.28.21250694 | Uncovering Survivorship Bias in Longitudinal Mental Health Surveys During the COVID-19 Pandemic | AimsMarkedly elevated adverse mental health symptoms were widely observed early in the coronavirus disease 2019 (COVID-19) pandemic. Unlike the U.S., where cross-sectional data indicate anxiety and depression symptoms have remained elevated, such symptoms reportedly declined in the U.K., according to analysis of repeated measures from a largescale longitudinal study. However, nearly 40% of U.K. respondents (those who did not complete multiple follow-up surveys) were excluded from analysis, suggesting that survivorship bias might partially explain this discrepancy. We therefore sought to assess survivorship bias among participants in our longitudinal survey study as part of The COVID-19 Outbreak Public Evaluation (COPE) Initiative.
MethodsSurvivorship bias was assessed 4,039 U.S. respondents who completed surveys including the assessment of mental health as part of The COPE Initiative in April 2020 and were invited to complete follow-up surveys. Participants completed validated screening instruments for symptoms of anxiety, depression, and insomnia. Survivorship bias was assessed for (1) demographic differences in follow-up survey participation, (2) differences in initial adverse mental health symptom prevalences adjusted for demographic factors, and (3) differences in follow-up survey participation based on mental health experiences adjusted for demographic factors.
ResultsAdjusting for demographics, individuals who completed only one or two out of four surveys had higher prevalences of anxiety and depression symptoms in April 2020 (e.g., one-survey versus four-survey, anxiety symptoms, adjusted prevalence ratio [aPR]: 1.30, 95% confidence interval [CI]: 1.08-1.55, P=0.0045; depression symptoms, aPR: 1.43, 95% CI: 1.17-1.75, P=0.00052). Moreover, individuals who experienced incident anxiety or depression symptoms had higher odds of not completing follow-up surveys (adjusted odds ratio [aOR]: 1.68, 95% CI: 1.22-2.31, P=0.0015, aOR: 1.56, 95% CI: 1.15-2.12, P=0.0046, respectively).
ConclusionsOur findings revealed significant survivorship bias among longitudinal survey respondents, indicating that restricting analytic samples to only respondents who provide repeated assessments in longitudinal survey studies could lead to overly optimistic interpretations of mental health trends over time. Cross-sectional or planned missing data designs may provide more accurate estimates of population-level adverse mental health symptom prevalences than longitudinal surveys. | psychiatry and clinical psychology |
10.1101/2021.01.29.21250592 | Hot days and Covid19 - unusual heat stress for nursing professions in Germany | ObjectivesOur aim was to identify whether working during hot days alongside with Covid-19 related personal protective equipment causes heat stress for nursing professionals in Germany.
MethodsUsing an online survey, we assessed the impact of hot weather on nursing staff performing in personal protective equipment. A random selection of nursing staff from hospitals, nursing homes and outpatient care participated in the survey.
ResultsOut of 428 participants, 6.3% were between 16 and 25 years old, 22.8% between 26 and 35 years, 21.9% between 36 and 45 years, 30.5% between 45 and 55 years, 18.2% between 56 and 65 years, and 0.3% were older than 65 years. Out of all participants, 18.2% were male and 82.5% female. The results of the survey showed that 48.3% had more than 20 years of experience in nursing and 46.2% cardiac, pulmonary, or other pre-existing conditions. Work was found exhaustive while working in PPE by 96.5% of the participants, and 93% complained of worse breathing. We found out that 85.8% reported difficulties to focus. Many workplaces turned out to lack adequate heat protection, with distinct differences concerning the amount of prophylactic and heat mitigating measures across institutions.
ConclusionsOur results clearly show that employers must make more of an effort to provide adequate heat protection for their nursing staff. In order to secure the public health care, there is a need for action, especially in the case of previous conditions of caregivers.
What is already known about this subject?{blacktriangleright} Working in personal protective equipment is often needed during pandemics, to protect nurses, doctors and staff from an infection.
{blacktriangleright}However, the equipment can also hamper efficiency and productivity of healthcare workers and lead to personal discomfort, for example, during heat waves.
What are the new findings?{blacktriangleright} According to our study, nurses and nursing assistants in Germany are often older than 45 years and, in many cases, suffer from pre-existing conditions, which exacerbate the problems with personal protective equipment during periods of hot temperatures.
{blacktriangleright}Many healthcare institutions do not offer adequate ways to mitigate heat stress for their staff.
How might this impact on policy or clinical practice in the foreseeable future?{blacktriangleright} The results from this study can inform policy makers and clinical practitioners to modify their protocols to include better protective measures during extreme heat or other adverse environmental conditions. | occupational and environmental health |
10.1101/2021.01.29.21250218 | Metastatic risk stratification of leiomyosarcoma patients using transcription- and replication-associated chromosomal instability mechanisms | Leiomyosarcoma (LMS) is an aggressive smooth muscle cancer with few therapeutic options. LMSs show a high level of genomic instability (GI) and the mechanisms underlying their oncogenic processes are poorly understood. While the level of GI influences treatment efficacy and resistance, an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP "hotspotness" magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (Transcription-Associated Chromosomal instability index (iTRAC) and iRACIN (Replication-Associated Chromosomal INstability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in LMS and that they may be combined to form a new classifier called MAGIC (Mixed transcription-and replication-Associated Genomic Instability Classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers. | oncology |
10.1101/2021.01.28.21250575 | Hematopoietic fitness of JAK2V617F Myeloproliferative Neoplasms is linked to clinical outcome | Myeloproliferative Neoplasms (MPN) harbor highly recurrent driver mutations affecting targetable kinases yet treatment options for these phenotypically diverse diseases are limited, and patients experience significant morbidity and shortened survival. The most important disease-related complications--thrombosis, transformation and death--are not used as clinical trial endpoints due to the long follow-up required to assess such disease modifying activity. A reliable monitoring biomarker linking MPN biology with these important clinical outcomes is missing. MPN driver mutation allele frequency (MAF) from whole blood or marrow (WB) does not faithfully predict MPN phenotype, clinical progression or response. This is likely because WB MAF is a composite measure of alleles from a heterogenous and variable mixture of mature leukocytes and, as such, does not report any information about the critical MPN stem and progenitor cells (MPN-SPCs). Driver mutations allow MPN cells to outcompete their normal hematopoietic counterparts and this competitive advantage--increased "fitness"--underlies core biology of MPN pathogenesis. We developed an approach to directly measure MPN fitness from samples. We measured fitness in 115 samples from 84 patients with JAK2V617F MPNs by quantifying MAF of 11 well-defined and strictly validated hematopoietic stem, progenitor and mature cell populations purified from routinely collected blood and marrow specimens. Unsupervised, hierarchical clustering of MPN fitness revealed 4 major fitness levels: F1, F2, F3, and F4 with significantly different but overlapping clinical features and diagnoses. Notably, these four fitness levels were associated with significantly different event-free survival (EFS): 95% (F1), 81% (F2), 73% (F3), 50% (F4) at 24 months (log-rank p=0.017). In contrast, WB MAF quartile failed to predict EFS. Multivariable models showed that fitness was associated with event risk independent of age, sex, duration of disease, MPN diagnosis and WB MAF. Principal component analysis allowed convenient projection of the 11-component MAF fitness measures to reduce dimensionality and develop a model for relative risk (RR) of event that could be used to assess individual or serial samples. Serial samples with more than a year of follow-up was available for 13 patients. We found that a reduction of this RR score was associated with a therapeutic response (p=0.045). In contrast, increasing RR overtime portended a disease-related event (p=0.045). Changes in WB MAF did not correlate with RR (r2=0.022) possibly explaining why WB MAF failed to predict events. These data demonstrate that fitness dynamics from serial blood samples can be used as a monitoring biomarker to assess changes in RR over time. Thus, fitness risk is a promising endpoint alongside corresponding clinical parameters such as blood counts, spleen size and marrow fibrosis grade. Our study offers a feasible approach to monitor the MPN biology central to disease progression and can be used in clinical trials to efficiently identify disease-modifying, potentially life-prolonging treatments. | oncology |
10.1101/2021.01.28.21250707 | Single-Blind and Double-Blind Peer Review: Effects on National Representation | Background/ObjectivesTo assess whether the type of peer-review (single-blinded vs double-blinded) has an impact on nationality representation in journals.
MethodsA cross-sectional study analyzing the top ten nationalities contributing to the number of articles across 16 ophthalmology journals.
ResultsThere was no significant difference in the percentage of articles published from the journals country of origin between the top single-blind journals and top double-blind journals (SB= 42.0%, DB = 26.6%, p=0.49) but there was a significant difference between the percentage of articles from the US (SB=48.0%, DB=22.8%, p=0.02). However, there was no significant difference for both country of origin (SB =38.0%, DB =26.6%, p=0.43) and articles from the US (SB=35.0%, DB=22.8%, p=0.21) when assessing the top 8 double-blind journals matched with single-blind journals of a similar impact factor. The countries that most commonly made the top ten lists for highest number of articles were the US (n=16, 100%) and England (n=16, 100%). This held true even for journals established outside the United States (US=11/12, England=11/12).
ConclusionsThere was no statistically significant difference in country-of-origin representation between single-blind journals and double-blind journals. However, higher income countries contributed most often to the journals studied even among journals based outside the US. | ophthalmology |
10.1101/2021.01.29.20248125 | Estimating the COVID-19 Prevalence in Spain with Indirect Reporting via Open Surveys | During the initial phases of the COVID-19 pandemic, accurate tracking has proven unfeasible. Initial estimation methods pointed towards case numbers that were much higher than officially reported. In the CoronaSurveys project, we have been addressing this issue using open online surveys with indirect reporting. We compare our estimates with the results of a serology study for Spain, obtaining high correlations (R squared 0.89). In our view, these results strongly support the idea of using open surveys with indirect reporting as a method to broadly sense the progress of a pandemic. | health informatics |
10.1101/2021.01.28.21250714 | Discrimination of SARS-Cov 2 and arboviruses (DENV, ZIKV and CHIKV) clinical features using machine learning techniques: a fast and inexpensive clinical screening for countries simultaneously affected by both diseases | SARS-Cov-2 (Covid-19) has spread rapidly throughout the world, and especially in tropical countries already affected by outbreaks of arboviruses, such as Dengue, Zika and Chikungunya, and may lead these locations to a collapse of health systems. Thus, the present work aims to develop a methodology using a machine learning algorithm (Support Vector Machine) for the prediction and discrimination of patients affected by Covid-19 and arboviruses (DENV, ZIKV and CHIKV). Clinical data from 204 patients with both Covid-19 and arboviruses obtained from 23 scientific articles and 1 dataset were used. The developed model was able to predict 93.1% of Covid-19 cases and 82.1% of arbovirus cases, with an accuracy of 89.1% and Area under Roc Curve of 95.6%, proving to be effective in prediction and possible screening of these patients, especially those affected by Covid-19, allowing early isolation. | health informatics |
10.1101/2021.01.28.21250716 | Socioeconomic Disparities and COVID-19 Vaccination Acceptance: Experience from Israel | COVID-19 vaccination acceptance has a key role in mitigating the pandemic. Concern has been raised that vaccination rates will be limited in demographically defined areas of lower income. Israels rapid vaccination campaign may allow to assess these assumptions in real-world and to devise tools for effectively focusing the vaccination efforts. We analyzed the correlation between COVID-19 vaccination rates, socioeconomic status (SES) and active COVID-19 disease burden. We carried out a nationwide study, based on data provided by Ministry of Health of COVID-19 vaccination rates in all municipalities in Israel up to January 12th, 2021. Municipal Vaccination rates of population older than 60 significantly correlated with the socioeconomic status (r=0.83, 95% confidence interval [0.79 to 0.87]). Finally, we established a novel metric for focusing the vaccination efforts based on % vaccinations and active disease burden. In Israel, a case-model country for COVD-19 vaccinations, vaccination rates were strongly correlated with SES. The study findings demonstrate the need to directly target vaccination acceptance to socio-economically disadvantaged populations and suggest potential tools for policymakers to focus their efforts. | health policy |
10.1101/2021.01.29.21250770 | Standardization of a flow cytometry SARS-CoV-2 serologic test | The SARS-CoV-2 virus is the causing agent of the coronavirus disease 2019 (COVID-19) pandemic which is responsible for millions of deaths worldwide. The development of the humoral response to the virus has been the subject of intensive research and development. A flow cytometry-based assay using native full-length SARS-CoV-2 Spike protein expressed in 293T cells was recently proposed as a complementary seropositivity determination assay.
The aim of our study was to further develop the flow cytometry assay for potential use as a confirmatory test and to standardize its parameters and results for reliable inter-laboratory use. We have optimized the protocol, established the Receiving Operating Characteristic (ROC) curve and tested reproducibility using pre-COVID plasma samples and convalescent, SARS-CoV-2 individual plasma samples.
The flow-based assay was simplified and standardized by cultivating the 293T cells in suspension and expressing results in Mean Equivalent Soluble Fluorochrome (MESF) using an internal antibody positive control. The ROC curve was determined with an area under the curve (AUC) of 0.996 and the assay specificity and sensitivity were established at 100% and 97.7% respectively. Reproducibility was good as determined on multiple cytometers, on different days, and with data acquisition as far as 72h post-staining. The optimized and standardized assay could be used as a high throughput confirmation confirmatory assay in flow cytometry laboratories involved in serological testing. | infectious diseases |
10.1101/2021.01.29.21250770 | Standardization of a flow cytometry SARS-CoV-2 serologic test | The SARS-CoV-2 virus is the causing agent of the coronavirus disease 2019 (COVID-19) pandemic which is responsible for millions of deaths worldwide. The development of the humoral response to the virus has been the subject of intensive research and development. A flow cytometry-based assay using native full-length SARS-CoV-2 Spike protein expressed in 293T cells was recently proposed as a complementary seropositivity determination assay.
The aim of our study was to further develop the flow cytometry assay for potential use as a confirmatory test and to standardize its parameters and results for reliable inter-laboratory use. We have optimized the protocol, established the Receiving Operating Characteristic (ROC) curve and tested reproducibility using pre-COVID plasma samples and convalescent, SARS-CoV-2 individual plasma samples.
The flow-based assay was simplified and standardized by cultivating the 293T cells in suspension and expressing results in Mean Equivalent Soluble Fluorochrome (MESF) using an internal antibody positive control. The ROC curve was determined with an area under the curve (AUC) of 0.996 and the assay specificity and sensitivity were established at 100% and 97.7% respectively. Reproducibility was good as determined on multiple cytometers, on different days, and with data acquisition as far as 72h post-staining. The optimized and standardized assay could be used as a high throughput confirmation confirmatory assay in flow cytometry laboratories involved in serological testing. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.29.21250747 | Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines | Aim and BackgroundWe aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.
MethodsBased on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established "one dose fits all" approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used.
ResultsWhen the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.
ConclusionProtecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics. | infectious diseases |
10.1101/2021.01.28.21250706 | Early Multidrug Outpatient Treatment of SARS-CoV-2 Infection (COVID-19) and Reduced Mortality Among Nursing Home Residents | The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found multidrug regimens relying on the use of hydroxychloroquine as well as other agents including doxycycline were associated with a statistically significant and >60% reductions in mortality. Going forward, we theorize and based on the evidence, that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients) has a genuine probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus that will prevent the development and/or worsening of problems associated with COVID-19, most particularly isolation, hospitalization, and death. In fact, with the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of patients with acute COVID-19 is possibly the most rational and importantly feasible strategy to reduce the risks of hospitalization and death. If the approach remains wait-and-see and elderly high-risk patients in such congregated nursing room type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. We put forth the notion that the most important factor in this regard, is making available early therapeutic intervention as described here. These drugs include and under supervision by skilled doctors, combination/sequenced ivermectin, hydroxychloroquine, colchicine, azithromycin, doxycycline, bromhexine hydrochloride, and favipiravir (outside the US), along with inhaled steroids such as budesonide and oral steroids including dexamethasone and prednisone, and anti-thrombotic anti-clotting drugs such as heparin). As the clinical trials data on treatments for COVID-19 mature, this early treatment therapeutic option deserves serious, urgent, and sober consideration by the medical establishment and respective decision-makers. | infectious diseases |
10.1101/2021.01.28.21249932 | Administration of tocilizumab to patients with high concentrations of IL-6 in the course of COVID-19 is associated with a better prognosis | BackgroundDespite the direct viral activity, the pathogenesis of coronavirus disease 2019 (COVID-19) includes an overproduction of cytokines including interleukin 6 (IL-6). Therefore tocilizumab (TCZ), a monoclonal antibody against IL-6 receptors, became considered as a possible therapeutic option.
MethodsPatients were selected from the SARSTer national database, which included 2332 individuals with COVID-19 and the current study included 825 adult patients with moderate to severe course. The retrospective analysis was performed in 170 patients treated with TCZ and 655 without this medication or any other anti-cytokine therapy. The end-points of treatment effectiveness were a rate of death, need for mechanical ventilation, and clinical improvement.
ResultsPatients treated with TCZ were balanced compared to non-TCZ regarding gender, age, BMI, and prevalence of coexisting conditions. The reduced death rate was demonstrated in patients treated with TCZ and baseline IL-6 >100 pg/ml (hazard ratio [HR]: 0.27, 95% confidence interval [CI]:0.10-0.78), or those needing oxygen supplementations who worsened within 7 days of hospitalization (HR: 0.38, 95% CI:0.16-0.88). The best effectiveness of TCZ was achieved in patients with a combination of baseline IL-6>100 pg/ml and either SpO2[≤]90% (HR for death, mechanical ventilation, and clinical improvement after 21 or 28 days: 0.07, 0.14, 5.53, 5.18 respectively) or requiring oxygen supplementation (HR for death and clinical improvement after 21 or 28 days, 0.18, 2.66, 2.85 respectively).
ConclusionsTocilizumab administered for COVID-19 in patients with a baseline concentration of IL-6>100 pg/ml is associated with reduced mortality and faster clinical improvement, particularly if there is a need for oxygen supplementation due to SpO2[≤]90%. | infectious diseases |
10.1101/2021.01.28.20181040 | Modeling the potential impact of indirect transmission on COVID-19 epidemic | The spread of SARS-CoV-2 through direct transmission (person-to-person) has been the focus of most studies on the dynamics of COVID-19. The efficacy of social distancing and mask usage at reducing the risk of direct transmission of COVID-19 has been studied by many researchers. Little or no attention is given to indirect transmission of the virus through shared items, commonly touch surfaces and door handles. The impact of the persistence of SARS-CoV-2 on hard surfaces and in the environment, on the dynamics of COVID-19 remain largely unknown. Also, the current increase in the number of cases despite the strict non-pharmaceutical interventions suggests a need to study the indirect transmission of COVID-19 while incorporating testing of infected individuals as a preventive measure. Assessing the impact of indirect transmission of the virus may improve our understanding of the overall dynamics of COVID-19. We developed a novel deterministic susceptible-exposed-infected-removed-virus-death compartmental model to study the impact of indirect transmission pathway on the spread of COVID-19, the sources of infection, and prevention/control. We fitted the model to the cumulative number of confirmed cases at episode date in Toronto, Canada using a Markov Chain Monte Carlo optimization algorithm. We studied the effect of indirect transmission on the epidemic peak, peak time, epidemic final size and the effective reproduction number, based on different initial conditions and at different stages. Our findings revealed an increase in cases with indirect transmission. Our work highlights the importance of implementing additional preventive and control measures involving cleaning of surfaces, fumigation, and disinfection to lower the spread of COVID-19, especially in public areas like the grocery stores, malls and so on. We conclude that indirect transmission of SARS-CoV-2 has a significant effect on the dynamics of COVID-19, and there is need to consider this transmission route for effective mitigation, prevention and control of COVID-19 epidemic. | infectious diseases |
10.1101/2021.01.28.21250421 | Viral sequencing reveals US healthcare personnel rarely become infected with SARS-CoV-2 through patient contact | BackgroundHealthcare personnel (HCP) are at increased risk of infection with the severe acute respiratory coronavirus 2019 virus (SARS-CoV-2). Between 12 March 2020 and 10 January 2021, >1,170 HCP tested positive for SARS-CoV-2 at a major academic medical institution in the Upper Midwest of the United States. We aimed to understand the sources of infections in HCP and to evaluate the efficacy of infection control procedures used at this institution to protect HCP from healthcare-associated transmission.
MethodsIn this retrospective case series, we used viral genomics to investigate the likely source of SARS-CoV-2 infection in 96 HCP where epidemiological data alone could not be used to rule out healthcare-associated transmission. We obtained limited epidemiological data through informal interviews and review of the electronic health record. We combined viral sequence data and available epidemiological information to infer the most likely source of HCP infection.
FindingsWe investigated 32 SARS-CoV-2 infection clusters involving 96 HCP, 140 possible patient contacts, and 1 household contact (total n = 237). Of these, 182 sequences met quality standards and were used for downstream analysis. We found the majority of HCP infections could not be linked to a patient or co-worker and therefore likely occurred in the outside community (58/96; 60.4%). We found a smaller percentage could be traced to a coworker (10/96; 10.4%) or were part of a patient-employee cluster (12/96; 12.5%). Strikingly, the smallest proportion of HCP infections could be clearly traced to a patient source (4/96; 4.2%).
InterpretationInfection control procedures, consistently followed, offer significant protection to HCP caring for COVID-19 patients in a representative American academic medical institution. Rapid SARS-CoV-2 genome sequencing in healthcare settings can be used retrospectively to reconstruct the likely source of HCP infection when epidemiological data are not available or are inconclusive. Understanding the source of SARS-CoV-2 infection can then be used prospectively to adjust and improve infection control practices and guidelines.
FundingThis project was funded in part through a COVID-19 Response grant from the Wisconsin Partnership Program at the University of Wisconsin School of Medicine and Public Health to T.C.F. and D.H.O. Author N.S. is supported by the National Institute of Allergy and Infectious Diseases Institute (NIAID) Grant 1DP2AI144244-01.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSOn 16 January 2021 we searched for "SARS-CoV-2" AND "healthcare workers" AND "viral sequencing" in Google Scholar. This search returned 57 results, and included a number of preprint articles. We found two studies that used viral sequencing to investigate healthcare-associated outbreaks in the Netherlands 1 and the United Kingdom 2. To our knowledge, no study has used viral sequencing to specifically investigate the source of SARS-CoV-2 infections in healthcare workers in the United States. Although we and others have written about the potential utility of sequencing as an infection control asset 3-6, few have demonstrated the practical application of such efforts.
Added value of this studyOur study suggests infection control measures in place at the institution evaluated in this case series are largely protecting healthcare personnel (HCP) from healthcare-associated SARS-CoV-2 infections. Even so, the majority of healthcare-associated infections we did identify appeared to be linked to HCP-to-HCP spread so additional messaging and guidelines to reduce HCP-to-HCP spread in and out of the workplace may be warranted. In addition, we demonstrated how rapid viral sequencing can be combined with, even limited, epidemiological information to reconstruct healthcare-associated SARS-CoV-2 outbreaks.
Implications of all the available evidenceHealthcare-associated SARS-CoV-2 infections negatively affect HCP, patients, and communities. Infections among HCP add further strain to the healthcare system and put patients and other HCP at risk. We found the majority of HCP infections appeared to be acquired through community exposure so measures to reduce community spread are critical. This further emphasizes the importance of mask-wearing, physical distancing, robust testing programs, and the rapid distribution of vaccines. | infectious diseases |
10.1101/2021.01.28.21250717 | Comparative performance of multiplex salivary and commercially available serologic assays to detect SARS-CoV-2 IgG and neutralization titers | Oral fluid (hereafter saliva) offers a non-invasive sampling method for the detection of SARS-CoV-2 antibodies. However, data comparing performance of salivary tests against commercially-available serologic and neutralizing antibody (nAb) assays are lacking. This study compared the performance of a multiplex salivary SARS-CoV-2 IgG assay targeting antibodies to nucleocapsid (N), receptor binding domain (RBD) and spike (S) antigens to three commercially-available SARS-CoV-2 serology enzyme immunoassays (EIAs) (Ortho Vitros, Euroimmun, and BioRad) and nAb. Paired saliva and plasma samples were collected from 101 eligible COVID-19 convalescent plasma (CCP) donors >14 days since PCR+ confirmed diagnosis. Concordance was evaluated using positive (PPA) and negative (NPA) percent agreement, overall percent agreement (PA), and Cohens kappa coefficient. The range between salivary and plasma EIAs for SARS-CoV-2-specific N was PPA: 54.4-92.1% and NPA: 69.2-91.7%, for RBD was PPA: 89.9-100% and NPA: 50.0-84.6%, and for S was PPA: 50.6-96.6% and NPA: 50.0-100%. Compared to a plasma nAb assay, the multiplex salivary assay PPA ranged from 62.3% (N) and 98.6% (RBD) and NPA ranged from 18.8% (RBD) to 96.9% (S). Combinations of N, RBD, and S and a summary algorithmic index of all three (N/RBD/S) in saliva produced ranges of PPA: 87.6-98.9% and NPA: 50-91.7% with the three EIAs and ranges of PPA: 88.4-98.6% and NPA: 21.9-34.4% with the nAb assay. A multiplex salivary SARS-CoV-2 IgG assay demonstrated comparable performance to three commercially-available plasma EIAs and a nAb assay, and may be a viable alternative to assist in screening CCP donors and monitoring population-based seroprevalence and vaccine antibody response. | infectious diseases |
10.1101/2021.01.28.21250721 | Significance of SARS-CoV-2 Specific Antibody Testing during COVID-19 Vaccine Allocation | ObjectiveTo assess the value of using SARS-CoV-2 specific antibody testing to prioritize the vaccination of susceptible individuals as part of a COVID-19 vaccine distribution plan when vaccine supply is limited.
MethodsA compartmental model was used to simulate COVID-19 spread when considering diagnosis, isolation, and vaccination of a cohort of 1 million individuals. The scenarios modeled represented 4 pandemic severity scenarios and various times when the vaccine becomes available during the pandemic. Eligible individuals have a probability p of receiving antibody testing prior to vaccination (p = 0, 0.25, 0.5, 0.75, and 1). The value of serology testing was evaluated by comparing the infection attack rate, peak infections, peak day, and deaths.
ResultsThe use of antibody testing to prioritize the allocation of limited vaccines reduces infection attack rates and deaths. The size of the reduction depends on when the vaccine becomes available relative to the infection peak day. The largest reduction in cases and deaths occurs when the vaccine is deployed before and close to the infection peak day. The reduction in the number of cases and deaths diminishes as vaccine deployment is delayed and moves closer to the peak day.
ConclusionsAntibody testing as part of the vaccination plan is an effective method to maximize the benefit of a COVID-19 vaccine. Decision-makers need to consider relative timing between the infection peak day and when the vaccine becomes available. | infectious diseases |
10.1101/2021.01.24.21250418 | Targeting TGF-b pathway with COVID-19 Drug Candidate ARTIVeda/PulmoHeal Accelerates Recovery from Mild-Moderate COVID-19 | Our COVID-19 drug candidate ARTIVeda/PulmoHeal is a novel gelatin capsule formulation of the Artemisia extract Ayurveda for oral delivery of TGF-{beta} targeting anti-malaria phytomedicine Artemisinin with documented anti-inflammatory and anti-SARS-CoV-2 activity. Here we report the safety and efficacy of ARTIVeda in adult COVID-19 patients with symptomatic mild-moderate COVID-19, who were treated in a randomized, open-label Phase IV study in Bangalore, Karnataka, India (Clinical Trials Registry India identifier: CTRI/2020/09/028044). ARTIVeda showed a very favorable safety profile, and the only ARTIVeda-related adverse events were transient mild rash and mild hypertension. Notably, ARTIVeda, when added to the SOC, accelerated the recovery of patients with mild-moderate COVID-19. While all patients were symptomatic at baseline (WHO score = 2-4), 31 of 39 (79.5%) of patients treated with ARTIVeda plus SOC became asymptomatic (WHO score = 1) by the end of the 5-day therapy, including 10 of 10 patients with severe dry cough 7 of 7 patients with severe fever. By comparison, 12 of 21 control patients (57.1%) treated with SOC alone became asymptomatic on day 5 (P=0.028, Fishers exact test). This clinical benefit was particularly evident when the treatment outcomes of hospitalized COVID-19 patients (WHO score = 4) treated with SOC alone versus SOC plus ARTIVeda were compared. The median time to becoming asymptomatic was only 5 days for the SOC plus ARTIVeda group (N=18) but 14 days for the SOC alone group (N=10) (P=0.004, Log-rank test). These data provide clinical proof of concept that targeting the TGF-{beta} pathway with ARTIVeda may contribute to a faster recovery of patients with mild-moderate COVID-19 when administered early in the course of their disease. | infectious diseases |
10.1101/2021.01.29.21250434 | The implementation and outcome of a 2-year prospective audit and feedback based antimicrobial stewardship program at a private tertiary care hospital | PurposeAntimicrobial resistance has emerged as a major public health problem with India being one of the worst affected nations. Hence effective antimicrobial stewardship programs (AMSP) are needed. We report the design, implementation and results of a prospective audit and feedback based AMSP at a private tertiary care hospital.
MethodsDuring the study period - January 2018 to December 2019 - the prescription of restricted antimicrobials required the filling of a justification form which was reviewed by the antimicrobial stewardship committee (AMSC) at 48-72 hours. Patients in whom the restricted antimicrobial was stopped earlier than 48 hours were not applicable for review. The eligible prescriptions were judged as justified/unjustified by AMSC based on the patients clinical and previous antimicrobial history, course and results of investigations/ cultures, and communicated to the treating team. Compliance to the recommendations of the AMSC was measured. Days of therapy for each restricted antimicrobial/1000 patient days was calculated. Colistin resistance rates in pathogens causing central line associated blood stream infections were compared with previous years.
ResultsA total of 2397 restricted antimicrobials in 1366 patients were prescribed in the study period of which 1801 prescriptions were applicable for review (75%). Overall, 1.4% of admitted patients were prescribed restricted antimicrobials. The total days of therapy with restricted antimicrobials was 41.5/1000 patient days. The AMSC committee adjudged 12.5% of prescriptions as unjustified and recommendations for de-escalation were accepted in 89%. There was no significant difference in any of the study outcomes between 2018 and 2019. Colistin resistance rates in CLABSI remained stable as compared to previous years.
ConclusionThe prospective audit and feedback component of AMSP provides insights into the use of restricted antimicrobials. This component should be considered by hospitals for inclusion in their program on an ongoing basis even if limited for a few drugs and in few areas of the hospital. | infectious diseases |
10.1101/2021.01.28.21250675 | Age significantly influences the sensitivity of SARS-CoV-2 rapid antibody assays | BACKGROUNDPoint of care serological assays are a promising tool in COVID-19 diagnostics but do have limitations. This study evaluated the sensitivity of five rapid antibody assays and explored factors influencing their sensitivity to detect SARS-CoV-2-specific IgG and IgM antibodies.
METHODSFinger-prick blood samples from 102 participants, within two to six weeks of PCR-confirmed COVID-19 diagnosis, were tested for IgG and IgM on five rapid serological assays. The assay sensitivities were compared, and patient factors evaluated in order to investigate potential associations with assay sensitivity.
RESULTSSensitivity ranged from 36% to 69% for IgG and 13% to 67% for IgM. Age was the only factor significantly influencing the likelihood of a detectable IgG or IgM response. Individuals aged 40 years and older had an increased likelihood of a detectable IgG or IgM antibody response by rapid antibody assay.
CONCLUSIONRapid serological assays demonstrate significant variability when used in a real-world clinical context. There may be limitations in their use for COVID-19 diagnosis amongst the young. | infectious diseases |
10.1101/2021.01.28.21250577 | Effect of RBD (Y453F) mutation in spike glycoprotein of SARS-CoV-2 on neutralizing IgG affinity. | BackgroundCertain mutant strains of SARS-CoV-2 are known to spread widely among humans, including the receptor binding domain (RBD) mutant, Y453F, from farmed minks, and the RBD mutant, N501Y, a mutation common to three major SARS-CoV-2 subspecies (B.1.1.7, B.1.351, and B.1.1.248).
MethodsWe investigated the characteristics of the RBD mutants, Y453F and N501Y, using three-dimensional structural analysis. We also investigated the effect of Y453F and N501Y on neutralizing antibodies in serum derived from COVID-19-positive patients.
ResultsOur results suggest that SARS-CoV-2 subspecies with the RBD mutations Y453F or N501Y partially escaped detection by 4 neutralizing monoclonal antibodies and 21 neutralizing antibodies in serums derived from COVID-19-positive patients.
ConclusionsInfection with SARS-CoV-2 subspecies that cause serious symptoms in humans may spread globally. | infectious diseases |
10.1101/2021.01.28.21250577 | Effect of RBD mutations in spike glycoprotein of SARS-CoV-2 on neutralizing IgG affinity | BackgroundCertain mutant strains of SARS-CoV-2 are known to spread widely among humans, including the receptor binding domain (RBD) mutant, Y453F, from farmed minks, and the RBD mutant, N501Y, a mutation common to three major SARS-CoV-2 subspecies (B.1.1.7, B.1.351, and B.1.1.248).
MethodsWe investigated the characteristics of the RBD mutants, Y453F and N501Y, using three-dimensional structural analysis. We also investigated the effect of Y453F and N501Y on neutralizing antibodies in serum derived from COVID-19-positive patients.
ResultsOur results suggest that SARS-CoV-2 subspecies with the RBD mutations Y453F or N501Y partially escaped detection by 4 neutralizing monoclonal antibodies and 21 neutralizing antibodies in serums derived from COVID-19-positive patients.
ConclusionsInfection with SARS-CoV-2 subspecies that cause serious symptoms in humans may spread globally. | infectious diseases |
10.1101/2021.01.28.21250713 | Resource Allocation for Different Types of Vaccines against COVID-19: Tradeoffs and Synergies between Efficacy and Reach | ObjectiveVaccine shortage and supply-chain challenges have caused limited access by many resource-limited countries during the COVID-19 pandemic. One of the primary decisions for a vaccine-ordering decision-maker is how to allocate the limited resources between different types of vaccines effectively. We studied the tradeoff between efficacy and reach of the two vaccine types that become available at different times.
MethodsWe extended a Susceptible-Infected-Recovered-Deceased (SIR-D) model with vaccination, ran extensive simulations with different settings, and compared the level of infection attack rate (IAR) under different reach ratios between two vaccine types under different resource allocation decisions.
ResultsWe found that when there were limited resources, allocating resources to a vaccine with high efficacy that became available earlier than a vaccine with lower efficacy did not always lead to a lower IAR, particularly if the former could vaccinate less than 42.5% of the population (with the selected study parameters) who could have received the latter. Sensitivity analyses showed that this result stayed robust under different study parameters.
ConclusionsOur results showed that a vaccine with lower resource requirements (wider reach) can significantly contribute to reducing IAR, even if it becomes available later in the pandemic, compared to a higher efficacy vaccine that becomes available earlier but requires more resources. Limited resource in vaccine distribution is significant challenge in many parts of the world that needs to be addressed to improve the global access to life-saving vaccines. Understanding the tradeoffs between efficacy and reach is critical for resource allocation decisions between different vaccine types for improving health outcomes. | infectious diseases |
10.1101/2021.01.28.21250713 | Resource Allocation for Different Types of Vaccines against COVID-19: Tradeoffs and Synergies between Efficacy and Reach | ObjectiveVaccine shortage and supply-chain challenges have caused limited access by many resource-limited countries during the COVID-19 pandemic. One of the primary decisions for a vaccine-ordering decision-maker is how to allocate the limited resources between different types of vaccines effectively. We studied the tradeoff between efficacy and reach of the two vaccine types that become available at different times.
MethodsWe extended a Susceptible-Infected-Recovered-Deceased (SIR-D) model with vaccination, ran extensive simulations with different settings, and compared the level of infection attack rate (IAR) under different reach ratios between two vaccine types under different resource allocation decisions.
ResultsWe found that when there were limited resources, allocating resources to a vaccine with high efficacy that became available earlier than a vaccine with lower efficacy did not always lead to a lower IAR, particularly if the former could vaccinate less than 42.5% of the population (with the selected study parameters) who could have received the latter. Sensitivity analyses showed that this result stayed robust under different study parameters.
ConclusionsOur results showed that a vaccine with lower resource requirements (wider reach) can significantly contribute to reducing IAR, even if it becomes available later in the pandemic, compared to a higher efficacy vaccine that becomes available earlier but requires more resources. Limited resource in vaccine distribution is significant challenge in many parts of the world that needs to be addressed to improve the global access to life-saving vaccines. Understanding the tradeoffs between efficacy and reach is critical for resource allocation decisions between different vaccine types for improving health outcomes. | infectious diseases |
10.1101/2021.01.28.21250486 | PCR assay to enhance global surveillance for SARS-CoV-2 variants of concern | With the emergence of SARS-CoV-2 variants that may increase transmissibility and/or cause escape from immune responses1-3, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant first detected in the UK4,5 could be serendipitously detected by the ThermoFisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike {Delta}69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern that lack spike {Delta}69-70, such as B.1.351 (also 501Y.V2) detected in South Africa6 and P.1 (also 501Y.V3) recently detected in Brazil7. We identified a deletion in the ORF1a gene (ORF1a {Delta}3675-3677) in all three variants, which has not yet been widely detected in other SARS-CoV-2 lineages. Using ORF1a {Delta}3675-3677 as the primary target and spike {Delta}69-70 to differentiate, we designed and validated an open source PCR assay to detect SARS-CoV-2 variants of concern8. Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence spread of B.1.1.7, B.1.351, and P.1. | infectious diseases |
10.1101/2021.01.28.21250486 | PCR assay to enhance global surveillance for SARS-CoV-2 variants of concern | With the emergence of SARS-CoV-2 variants that may increase transmissibility and/or cause escape from immune responses1-3, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant first detected in the UK4,5 could be serendipitously detected by the ThermoFisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike {Delta}69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern that lack spike {Delta}69-70, such as B.1.351 (also 501Y.V2) detected in South Africa6 and P.1 (also 501Y.V3) recently detected in Brazil7. We identified a deletion in the ORF1a gene (ORF1a {Delta}3675-3677) in all three variants, which has not yet been widely detected in other SARS-CoV-2 lineages. Using ORF1a {Delta}3675-3677 as the primary target and spike {Delta}69-70 to differentiate, we designed and validated an open source PCR assay to detect SARS-CoV-2 variants of concern8. Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence spread of B.1.1.7, B.1.351, and P.1. | infectious diseases |
10.1101/2021.01.28.21250365 | Differences in detected viral loads guide use of SARS-CoV-2 antigen-detection assays towards symptomatic college students and children. | Limitations in timely testing for SARS-CoV-2 drive the need for new approaches in suspected COVID-19 disease. We queried whether viral load (VL) in the upper airways at presentation could improve the management and diagnosis of patients. This study was conducted in a 9 hospital system in Allegheny County, Pennsylvania between March 1-August 31 2020. Viral load was determined by PCR assays for patients presenting to the Emergency Departments (ED), community pediatrics practices and college health service. We found that for the ED patients, VL did not vary substantially between those admitted and not. VL was relatively equivalent across ages, except for the under 25 age groups that tended to present with higher loads. To determine if rapid antigen testing (RAT) could aid diagnosis in certain populations, we compared BD Veritor and Quidel Sofia to SOC PCR-based tests. The antigen assay provided a disease-detection sensitivity of >90% in a selection of 32 positive students and was modeled to have an 80% sensitivity in all positive students. In the outpatient pediatric population, the antigen assay detected 70% of PCR-positives. Extrapolating these findings to viral loads in older hospitalized patients, a minority would be detected by RAT (40%). Higher loads did correlate with death, though the prognostic value was marginal (ROC AUC of only 0.66). VL did not distinguish between those needing mechanical ventilation and routine inpatients. We conclude that VL in upper airways, while not prognostic for disease management, may aid in selecting proper testing methodologies for certain patient populations. | infectious diseases |
10.1101/2021.01.28.21250280 | Unmet need of essential treatments for critical illness in Malawi | BackgroundCritical illness is common throughout the world and has been the focus of a dramatic increase in attention in the COVID-19 pandemic. Severely deranged vital signs can identify critical illness, are simple to check and treatments that aim to correct derangements are established, basic and low-cost. The aim of the study was to estimate the unmet need of essential treatments for severely deranged vital signs in all adults admitted to hospitals in Malawi.
MethodsWe conducted a cross-sectional study with follow-up of adult hospitalized patients in Malawi. All in-patients aged [≥]18 on single days Queen Elizabeth Central Hospital (QECH) and Chiradzulu District Hospital (CDH) were screened.. Patients with hypoxia (oxygen saturation <90%), hypotension (systolic blood pressure <90mmHg) and reduced conscious level (Glasgow Coma Score <9) were included in the study. The a-priori defined essential treatments were oxygen therapy for hypoxia, intravenous fluid for hypotension and an action to protect the airway for reduced consciousness (placing the patient in the lateral position, insertion of an oropharyngeal airway or endo-tracheal tube or manual airway protection).
ResultsOf the 1135 hospital in-patients screened, 45 (4.0%) had hypoxia, 103 (9.1%) had hypotension, and 17 (1.5%) had a reduced conscious level. Of those with hypoxia, 40 were not receiving oxygen (88.9%). Of those with hypotension, 94 were not receiving intravenous fluids (91.3%). Of those with a reduced conscious level, nine were not receiving an action to protect the airway (53.0%).
ConclusionThere was a large unmet need of essential treatments for critical illness in two hospitals in Malawi. | intensive care and critical care medicine |
10.1101/2021.01.29.21250407 | 12-lead Electrocardiogram in Hospitalized COVID 19 Patients | COVID-19 pandemic resulted in considerable morbidity and mortality. We analyzed 345 Electrocardiograms of 100 COVID-19 patients admitted to our tertiary care center in Detroit, during the initial month of Covid-19. Findings were correlated with mortality, cardiac injury and inflammatory markers. Our cohort included 61% males and 77% African Americans. The median age and BMI were 66 years (57-74) and 31 kg/m2 (26.1-39), respectively. We observed atrial arrhythmias in 29% of the patients (17% new onset), First degree heart block in 12%, ST-T segment changes in 17%, S1Q3T3 pattern in 19%, premature ventricular complexes in 23%, premature atrial complexes in 13%, Q waves in 27%, T wave inversion in 42% of the cases. While presence of premature atrial complexes or left atrial abnormality correlated with mortality (P = 0.02 & 0.03, respectively), other findings did not show significant correlation in this small cohort of patients. | cardiovascular medicine |
10.1101/2021.01.28.21250129 | Application of a 27-protein candidate cardiovascular surrogate endpoint to track risk ascendancy and resolution in COVID-19. | BackgroundThere is an urgent need for tools allowing the early prognosis and subsequent monitoring of individuals with heterogeneous COVID-19 disease trajectories. Pre-existing cardiovascular (CV) disease is a leading risk factor for COVID-19 susceptibility and poor outcomes, and cardiac involvement is prevalent in COVID-19 patients both during the acute phase as well as in convalescence. The utility of traditional CV risk biomarkers in mild COVID-19 disease or across disease course is poorly understood. We sought to determine if a previously validated 27-protein predictor of CV outcomes served a purpose in COVID-19.
MethodsThe 27-protein test of residual CV (RCV) risk was applied without modification to n=860 plasma samples from hospitalized and non-hospitalized SARS-CoV-2 infected individuals at disease presentation from three independent cohorts to predict COVID-19 severity and mortality. The same test was applied to an additional n=991 longitudinal samples to assess sensitivity to change in CV risk throughout the course of infection into convalescence.
ResultsIn each independent cohort, RCV predictions were significantly related to maximal subsequent COVID-19 severity and to mortality. At the baseline blood draw, the mean protein-predicted likelihood of an event in subjects who died during the study period ranged from 88-99% while it ranged from 8-36% in subjects who were not admitted to hospital. Additionally, the test outperformed existing risk predictors based on commonly used laboratory chemistry values or presence of comorbidities. Application of the RCV test to sequential samples showed dramatic increases in risk during the first few days of infection followed by risk reduction in the survivors; a period of catastrophically high cardiovascular risk (above 50%) typically lasted 8-12 days and had not resolved to normal levels in most people within that timescale.
ConclusionsThe finding that a 27-protein candidate CV surrogate endpoint developed in multi-morbid patients prior to the pandemic is both prognostic and acutely sensitive to the adverse effects of COVID-19 suggests that this disease activates the same biologic risk-related mechanisms. The test may be useful for monitoring recovery and drug response. | cardiovascular medicine |
10.1101/2021.01.29.21250703 | Using simulated infectious disease outbreaks to guide the design of individually randomized vaccine trials | Background/AimsNovel strategies are needed to make vaccine efficacy trials more robust given the uncertain epidemiology of outbreaks. Spatially resolved mathematical and statistical models can help investigators identify sites at highest risk of future transmission and prioritize these for inclusion in trials. Models can also characterize the uncertainty in whether transmission will occur at a site, and how nearby or connected sites may have correlated outcomes. A structure is needed for how trials can use models to address key design questions, including how to prioritize sites, the optimal number of sites, and how to allocate participants across sites.
MethodsWe illustrate the added value of models using the motivating example of Zika vaccine trial planning during the 2015-2017 Zika epidemic. We used a stochastic, spatially resolved, agent-based transmission model (GLEAM) to generate 1,142 epidemics and site-level incidence at 100 high-risk sites in the Americas. We considered several strategies for prioritizing sites (average site-level incidence of infection across epidemics, median incidence, probability of exceeding 1% incidence), selecting the number of sites, and allocating sample size across sites (equal enrollment, proportional to average incidence, proportional to rank). To evaluate each design, we stochastically simulated trials in each hypothetical epidemic by drawing observed cases from site-level incidence data.
ResultsWhen constraining the overall trial sample size, the optimal number of sites represents a balance between prioritizing highest-risk sites and having enough sites to reduce the chance of observing too few endpoints. The optimal number of sites remained roughly constant despite varying the targeted number of events, although it is necessary to increase the total sample size to achieve the desired power. Though different ranking strategies returned different site orders, they performed similarly with respect to trial power. Instead of enrolling participants equally from each site, investigators can allocate participants proportional to projected incidence, though this did not provide an advantage in our example because the top sites had a roughly similar risk profile. Sites from the same geographic region may have similar outcomes, so optimal combinations of sites may be those that are more geographically dispersed, even when these are not the highest ranked sites.
ConclusionsMathematical and statistical models may assist in the design of successful vaccination trials by capturing uncertainty and correlation in future transmission. Although many factors affect site selection, such as logistical feasibility, models can help investigators optimize site selection and the number and size of participating sites. | epidemiology |
10.1101/2021.01.29.21250334 | Birhan Maternal and Child Health Cohort: a study protocol | IntroductionReliable estimates on maternal and child morbidity and mortality are essential for health programs and policies. Data are needed in populations which have the highest burden of disease but also have the least evidence and research, to design and evaluate health interventions to prevent illnesses and deaths that occur worldwide each year.
Methods and analysisThe Birhan Maternal and Child Health (MCH) cohort is an open prospective pregnancy and birth cohort nested within the Birhan health and demographic surveillance system (HDSS). An estimated 2500 pregnant women are enrolled each year and followed through pregnancy, birth, and the postpartum period. Newborns are followed through two years of life to assess growth and development. Baseline medical data, signs and symptoms, laboratory test results, anthropometrics, and pregnancy and birth outcomes (stillbirth, preterm birth, low birthweight) are collected from both home and health facility visits. We will calculate the period prevalence and incidence of primary morbidity and mortality outcomes.
Ethics and DisseminationThe cohort has received ethical approval. Findings will be disseminated at scientific conferences, peer-reviewed journals, and to relevant stakeholders including the ministry of health.
Strengths and limitations of this studyO_LIThis cohort collects longitudinal data at multiple time points from pregnancy through birth and childhood in a setting where there are limited data.
C_LIO_LIData from this study provide estimates for birth outcomes such as stillbirths, preterm birth, and low birth weight.
C_LIO_LIResults will inform risk profiles for maternal, neonatal, and child morbidity and mortality.
C_LIO_LISimilar to all observational studies, there are potential confounders that are unmeasurable.
C_LIO_LIEvidence from this study will support policies and programs to improve maternal and child health.
C_LI | epidemiology |
10.1101/2021.01.29.20248797 | High variability in transmission of SARS-CoV-2 within households and implications for control | BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a high risk of transmission in close-contact indoor settings, which may include households. Prior studies have found a wide range of household secondary attack rates and may contain biases due to simplifying assumptions about transmission variability and test accuracy.
MethodsWe compiled serological SARS-CoV-2 antibody test data and prior SARS-CoV-2 test reporting from members of 9,224 Utah households. We paired these data with a probabilistic model of household importation and transmission. We calculated a maximum likelihood estimate of the importation probability, mean and variability of household transmission probability, and sensitivity and specificity of test data. Given our household transmission estimates, we estimated the threshold of non-household transmission required for epidemic growth in the population.
ResultsWe estimated that individuals in our study households had a 0.41% (95% CI 0.32% - 0.51%) chance of acquiring SARS-CoV-2 infection outside their household. Our household secondary attack rate estimate was 36% (27% - 48%), substantially higher than the crude estimate of 16% unadjusted for imperfect serological test specificity and other factors. We found evidence for high variability in individual transmissibility, with higher probability of no transmissions or many transmissions compared to standard models. With household transmission at our estimates, the average number of non-household transmissions per case must be kept below 0.41 (0.33 - 0.52) to avoid continued growth of the pandemic in Utah.
ConclusionsOur findings suggest that crude estimates of household secondary attack rate based on serology data without accounting for false positive tests may underestimate the true average transmissibility, even when test specificity is high. Our finding of potential high variability (overdispersion) in transmissibility of infected individuals is consistent with characterizing SARS-CoV-2 transmission being largely driven by superspreading from a minority of infected individuals. Mitigation efforts targeting large households and other locations where many people congregate indoors might curb continued spread of the virus. | epidemiology |
10.1101/2021.01.29.20248797 | High variability in transmission of SARS-CoV-2 within households and implications for control | BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a high risk of transmission in close-contact indoor settings, which may include households. Prior studies have found a wide range of household secondary attack rates and may contain biases due to simplifying assumptions about transmission variability and test accuracy.
MethodsWe compiled serological SARS-CoV-2 antibody test data and prior SARS-CoV-2 test reporting from members of 9,224 Utah households. We paired these data with a probabilistic model of household importation and transmission. We calculated a maximum likelihood estimate of the importation probability, mean and variability of household transmission probability, and sensitivity and specificity of test data. Given our household transmission estimates, we estimated the threshold of non-household transmission required for epidemic growth in the population.
ResultsWe estimated that individuals in our study households had a 0.41% (95% CI 0.32% - 0.51%) chance of acquiring SARS-CoV-2 infection outside their household. Our household secondary attack rate estimate was 36% (27% - 48%), substantially higher than the crude estimate of 16% unadjusted for imperfect serological test specificity and other factors. We found evidence for high variability in individual transmissibility, with higher probability of no transmissions or many transmissions compared to standard models. With household transmission at our estimates, the average number of non-household transmissions per case must be kept below 0.41 (0.33 - 0.52) to avoid continued growth of the pandemic in Utah.
ConclusionsOur findings suggest that crude estimates of household secondary attack rate based on serology data without accounting for false positive tests may underestimate the true average transmissibility, even when test specificity is high. Our finding of potential high variability (overdispersion) in transmissibility of infected individuals is consistent with characterizing SARS-CoV-2 transmission being largely driven by superspreading from a minority of infected individuals. Mitigation efforts targeting large households and other locations where many people congregate indoors might curb continued spread of the virus. | epidemiology |
10.1101/2021.01.29.21250660 | Correlation of SARS-CoV-2 serology and clinical phenotype amongst hospitalised children in a tertiary children's hospital in India | IntroductionChildren usually present with minimal or no symptoms of SARS-CoV-2 infection. Antibody responses to SARS-CoV-2 in children from low- and middle-income countries (LMIC) have not been well described. We describe the prevalence of anti-SARS-CoV-2 antibodies and clinical phenotype of seropositive children admitted to a tertiary childrens hospital in South India.
MethodsTo determine the seropositivity and describe the clinical characteristics of SARS-CoV-2 infection amongst hospitalised children, we performed a prospective clinical data collection and blood sampling of children admitted to Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India over 4 months of the COVID-19 pandemic. In seropositive children, we compared antibody titres between children with and without PIMS-TS.
ResultsOf 463 children, 91 (19.6%) were seropositive. The median (range) age of seropositive children was 5 years (1 month - 17 years). Clinical presentation was consistent with Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) in 48% (44/91) of seropositive children. The median (range) antibody titre was 54.8 (11.1-170.9) AU/ml among all seropositive children. The median antibody titre among the children with PIMS-TS (60.3 AU/mL) was significantly (p=0.01) higher when compared to the children without PIM-TS (54.8 AU/mL).
ConclusionWe describe the antibody responses to SARS-CoV-2 amongst hospitalised children in a LMIC tertiary childrens hospital. Almost half of the seropositive children had PIMS-TS. Antibody levels may be helpful in the diagnosis and disease stratification of PIMS-TS.
Lay summaryChildren usually present with minimal or no symptoms of SARS-CoV-2 infection. However, Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) has emerged as a distinctive paediatric illness related to SARS-CoV-2. Recently, antibody testing for SARS-CoV-2 is being used increasingly as a diagnostic test for PIMS-TS. However, data on the antibody responses to SARS-CoV-2 in children is sparse. We therefore, attempted to identify the seropositivity and describe the clinical spectrum of SARS-CoV-2 infection amongst infants and children getting hospitalised in a childrens hospital in south India. Nearly one-fifth of the hospitalised children tested serology positive over 4 months. Antibody levels in children with PIMS-TS were significantly higher in comparison to the other two groups (acute SARS-CoV-2 infection and children without PIMS-TS). Results from our study suggest that all children are at risk of SARS-CoV-2 infection though they may present with mild illness or no symptoms. We also observed that antibody testing may have a possible role in diagnosis of PIMS-TS. | pediatrics |
10.1101/2021.01.29.21250740 | Illusory social agents within and beyond voices: a computational linguistics analysis of the experience of psychosis | AimsPsychosis has a strong social component and often involves the experience of being affected by illusory social agents. However, this experience remains under-characterised, particularly for social agents in delusions and non-vocal hallucinations. One useful approach is a form of computational linguistics called corpus linguistics that studies texts to identify patterns of meaning encoded in both the semantics and linguistic structure of the text.
MethodsTwenty people living with psychosis were recruited from community and inpatient services. They participated in open-ended interviews on their experiences of social agents in psychosis and completed a measure of psychotic symptoms. Corpus linguistics analysis was used to identify key phenomenological features of vocal and non-vocal social agents in psychosis.
ResultsSocial agents are i) represented with varying levels of richness in participants experiences, ii) are attributed with different kinds of identities including physical characteristics and names, iii) are perceived to have internal states and motivations that are different from those of the participants, and iv) interact with participants in various ways including through communicative speech acts, affecting participants bodies and moving through space. These representation were equally rich for agents associated with hallucinated voices and those associated with non-vocal hallucinations and delusions.
ConclusionsWe show that the experience of illusory social agents is a rich and complex social experience reflecting many aspects of genuine social interaction and is not solely present in auditory hallucinations, but also in delusions and non-vocal hallucinations. | psychiatry and clinical psychology |
10.1101/2021.01.30.21250083 | Increasing but inadequate intention to receive Covid-19 vaccination over the first 50 days of impact of the more infectious variant and roll-out of vaccination in UK: indicators for public health messaging | ObjectivesTo inform critical public health messaging by determining how changes in Covid-19 vaccine hesitancy, attitudes to the priorities for administration, the emergence of new variants and availability of vaccines may affect the trajectory and achievement of herd immunity.
Methods>9,000 respondents in an ongoing cross-sectional participatory longitudinal epidemiology study (LoC-19, n=18,581) completed a questionnaire within their personal electronic health record in the week reporting first effective Covid-19 vaccines, and then again after widespread publicity of the increased transmissibility of a new variant (November 13th and December 31st 2020 respectively). Questions covered willingness to receive Covid-19 vaccination and attitudes to prioritisation. Descriptive statistics, unadjusted and adjusted odds ratios (ORs) and natural language processing of free-text responses are reported, and how changes over the first 50 days of both vaccination roll-out and new-variant impact modelling of anticipated transmission rates and the likelihood and time to herd immunity.
FindingsCompared with the week reporting the first efficacious vaccine there was a 15% increase in acceptance of Covid-19 vaccination, attributable in one third to the impact of the new variant, with 75% of respondents "shielding" - staying at home and not leaving unless essential - regardless of health status or tier rules. 12.5% of respondents plan to change their behaviour two weeks after completing vaccination compared with 45% intending to do so only when cases have reduced to a low level. Despite the increase from 71% to 86% over this critical 50-day period, modelling of planned uptake of vaccination remains below that required for rapid effective herd immunity - now estimated to be 90 percent in the presence of a new variant escalating R0 to levels requiring further lockdowns. To inform the public messaging essential therefore to improve uptake, age and female gender were, respectively, strongly positively and negatively associated with wanting a vaccine. 22.7% disagreed with the prioritisation list, though 70.3% were against being able to expedite vaccination through payment. Teachers (988, 12.6%) and Black, Asian and Minority Ethnic (BAME) (837, 10.7%) groups were most cited by respondents for prioritisation.
InterpretationIn this sample, the growing impact of personal choice among the increasingly informed public highlights a decrease in Covid-19 vaccine hesitancy over time, with news of a new variant motivating increased willingness for vaccination but at levels below what may be required for effective herd immunity. We identify public preferences for next-in-line priorities, headed by teachers and BAME groups, consideration of which will help build trust and community engagement critical for maximising compliance with not only the vaccination programme but also all other public health measures. | public and global health |
10.1101/2021.01.29.21250789 | Relative humidity predicts day-to-day variations in COVID-19 cases in the city of Buenos Aires | Possible links between the transmission of COVID-19 and meteorology have been investigated by comparing positive cases across geographical regions or seasons. Little is known, however, about the degree to which environmental conditions modulate the daily dynamics of COVID-19 spread at a given location. One reason for this is that individual waves of the disease are typically too abrupt, making it hard to isolate the contribution of meteorological cycles. To overcome this shortage, we here present a case study of the first wave of the outbreak in the city of Buenos Aires, which had a slow evolution of the case load extending along most of 2020. We found that humidity plays a prominent role in modulating the variation of COVID-19 positive cases through a negative-slope linear relationship, with an optimal lag of 9 days between the meteorological observation and the positive case report. This relationship is specific to winter months, when relative humidity predicts up to half of the variance in positive cases. Our results provide a tool to anticipate local surges in COVID-19 cases after events of low humidity. More generally, they add to accumulating evidence pointing to dry air as a facilitator of COVID-19 transmission. | public and global health |
10.1101/2021.01.29.21250789 | Relative humidity predicts day-to-day variations in COVID-19 cases in the city of Buenos Aires | Possible links between the transmission of COVID-19 and meteorology have been investigated by comparing positive cases across geographical regions or seasons. Little is known, however, about the degree to which environmental conditions modulate the daily dynamics of COVID-19 spread at a given location. One reason for this is that individual waves of the disease are typically too abrupt, making it hard to isolate the contribution of meteorological cycles. To overcome this shortage, we here present a case study of the first wave of the outbreak in the city of Buenos Aires, which had a slow evolution of the case load extending along most of 2020. We found that humidity plays a prominent role in modulating the variation of COVID-19 positive cases through a negative-slope linear relationship, with an optimal lag of 9 days between the meteorological observation and the positive case report. This relationship is specific to winter months, when relative humidity predicts up to half of the variance in positive cases. Our results provide a tool to anticipate local surges in COVID-19 cases after events of low humidity. More generally, they add to accumulating evidence pointing to dry air as a facilitator of COVID-19 transmission. | public and global health |
10.1101/2021.01.29.21250749 | COVID-19 vaccine uptake among healthcare workers in the fourth country to authorize BNT162b2 during the first month of rollout | BackgroundThe Kingdom of Saudi Arabia (KSA) was the fourth country in the world to authorize the BNT162b2 coronavirus disease 2019 (COVID-19) vaccine, which it rolled out on December 17, 2020 and first targeted at healthcare workers (HCWs). This study assesses vaccine uptake among this group during the first month of its availability.
MethodsA national cross-sectional, pilot-validated, self-administered survey was conducted among HCWs in the KSA between December 27, 2020 and January 3, 2021. The survey included sociodemographic details, previous contact with COVID-19 patients, previous infection with COVID-19, receiving (or registering with the Ministry of Health website to receive) the COVID-19 vaccine, sources of HCWs information on vaccines, awareness of emerging variants of concern, and anxiety level using the 7-item Generalized Anxiety Disorder assessment. A descriptive bivariate analysis and multivariate logistic binary regression analysis were performed. The primary evaluated outcome was vaccine uptake.
ResultsOf the 1,058 participants who completed the survey, 704 (66.5%) were female, and 626 (59.2%) were nurses. Of all the respondents, 352 (33.27%) were enrolled to receive or had already received the vaccine, while 706 (66.73%) had not registered. In a bivariate analysis, not enrolling for vaccination was more likely in females than males (78.5% vs. 21.5%, P < 0.001), HCWs between the ages of 20 and 40 years than those > 40 years (70.4% vs. 29.6%, P = 0.005), Saudi HCWs than expatriates (78% vs 22%, P < 0.001), and among HCWs who used social media as a source of information than those who did not (69.8% vs. 38.6%, P < 0.001). In a multivariate analysis, independent factors for not enrolling to receive the vaccine included being female (aOR = 0.287, 95%CI = 0.206-0.401, P < 0.001), being less than 40 years of age (aOR = 1.021, 95%CI = 1.002-1.040, P = 0.032), and using social media as a source of information (aOR = 0.207, 95%CI = 0.132-1.354, P = 0.001). Factors associated with uptake were being a Saudi national (aOR = 1.918, 95%CI = 1.363-2.698, P < 0.001), working in an intensive care unit (aOR = 1.495, 95%CI = 1.083-2.063, P = 0.014), and working at a university hospital (aOR = 1.867, 95%CI = 1.380-2.525, P < 0.001).
ConclusionsA low level of vaccine uptake was observed especially in female HCWs, those younger than 40 years old, and those who used social media as their source of vaccine information. This survey provides important information for public health authorities in order to scale up vaccination campaigns targeting these HCWs to increase vaccine enrollment and uptake. | public and global health |
10.1101/2021.01.29.21250794 | COVID-19 Prevention Beliefs and Practices in College Students | BackgroundAs college students in the United States return to university campuses, it is important to understand their beliefs and practices on coronavirus disease 2019 (COVID-19) prevention.
PurposeTo assess beliefs and practices regarding COVID-19 prevention among college students in the United States
MethodsAn online, self-administered survey was developed that collected information on COVID-19 preventative practice and beliefs. Survey responses were collected between July 13, 2020 and July 31, 2020.
ResultsA total of 4,834 college students participated in the survey with a response rate of 22.9%. Compared to males, more female college students practiced COVID-19 preventative measures, including always wearing masks or face coverings in public (52% vs. 44%, p<0.001) and always or often observing social distancing (70% vs. 63%, p<0.001). In contrast to students from larger population areas, fewer college students from rural areas reported practicing prevention measures, such as always wearing a mask (24% rural v. 45% towns vs. 55% cities, p<0.001) and always social distancing (20% rural vs. 21% towns vs. 29% cities, p<0.001). Additionally, more students from rural areas have become much less worried about personally contracting COVID-19 over the last 3 months when compared to students from towns and cities (21% vs. 16% vs. 11%, p<0.001). Fewer white college students compared to other racial groups thought it was very important to wear masks (55% white vs. 76% Black vs. 82% Asian vs. 63% American Indian or Alaskan native (AIAN) & Native Hawaiian or Other Pacific Islander (NHOPI), p<0.001) and very important to practice social distancing (29% white vs. 50% Black vs. 53% Asian vs. 36% AIAN/NHOPI, p <0.001). Compared to Non-Hispanic students, more Hispanic students thought it was very important to practice preventative measures, including wearing a mask (71% vs. 58%, p<0.001), social distancing (37% vs. 32%, p=0.017), and good hand hygiene (77% vs. 67%, p=0.013).
ConclusionCOVID-19 prevention beliefs and practices differ between sexes, the size of town one lives, race, and ethnicity. In general, female students followed Center for Disease Control and Prevention (CDC) COVID-19 prevention guidelines more closely than male students. Students who reside in areas of larger populations have more strict COVID-19 prevention beliefs and practices than students from areas with smaller populations. Asian and Black/African American students adhered closer to CDC COVID-19 prevention guidelines and had stronger beliefs for infection prevention measures than white or AIAN/NHOPI students. Hispanic/Latino students were more stringent in COVID-19 prevention beliefs and practices than non-Hispanic/Latino students. | public and global health |
10.1101/2021.01.29.21250730 | How best do we engage the general population in testing for COVID-19? | The UK Scientific Advisory Group for Emergencies (SAGE) emphasises the need for high levels of engagement with communities and individuals to ensure the effectiveness of any COVID-19 testing programme. A novel pilot health surveillance programme to assess the feasibility of weekly mass RT-LAMP testing for the SARS-CoV-2 virus using saliva samples collected at home was developed and piloted by the University of Southampton and Southampton City Council. Rapid qualitative evaluation was conducted to explore experiences of those who took part in the programme, of those who declined and of those in the educational and healthcare organisations involved in the pilot testing who were responsible for roll-out. This included 77 interviews and 20 focus groups with 223 staff, students, pupils and household members from four schools, one university, and one community healthcare NHS trust. Conversations revealed that high levels of communication, trust and convenience were necessary to ensure peoples engagement with the programme. This suggests community leaders and stakeholder organisations should be involved throughout programme development and implementation to optimise these features of the testing. Participants and stakeholders motivations, challenges and concerns need to be understood and these insights used to modify the programme in a continuous, real-time process to ensure and sustain engagement with testing over the extended period necessary. | public and global health |
10.1101/2021.01.28.21250163 | Ultra-short-wave diathermy shortens the course of moderate and severe COVID-19: a randomized controlled trial | QuestionIs ultra-short-wave diathermy (USWD) safe and effective in coronavirus disease 2019 (COVID-19) ?
DesignSingle-centre, evaluator-blinded, two-arm, parallel design, randomized controlled clinical trial.
ParticipantsModerate and severe COVID-19 patients with acute respiratory syndrome.
InterventionUSWD for 10 minutes twice daily for 12 consecutive days along with standard medical treatment (USWD group, n = 25), versus standard medical treatment alone (control group, n = 25).
Outcome measuresThe primary outcomes were the duration of recovery and negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on days 7, 14, 21, and 28. Secondary outcomes included clinical status (seven-category ordinal and systemic inflammatory response syndrome (SIRS) scores), computed tomography (CT), routine blood tests, and adverse events.
ResultsTime to clinical recovery (USWD 36.84{+/-}9.93 vs. control 43.56{+/-}12.15, P = 0.037) was significantly shortened with a between-group difference of 6.72 days. Clinical status was improved with significant between-group differences on day 28 (SIRS, P = 0.011; seven-category scale, P = 0.003). The rate of RNA negative conversion at days 7 (P = 0.066), 14 (P = 0.239), 21 (P = 0.269), and 28 (P = 0.490) was statistically insignificant. Moreover, insignificant differences were observed in the artificial intelligence-assisted CT analysis. No treatment-associated adverse events or worsening of pulmonary fibrosis were observed.
ConclusionUSWD, as adjunctive therapy, shortened the recovery course and improved clinical status of patients with COVID-19 without aggravating pulmonary fibrosis. the findings are limited due to the small sample size and early termination.
RegistrationChiCTR2000029972 | rehabilitation medicine and physical therapy |
10.1101/2021.01.28.21250163 | Ultra-short-wave diathermy shortens the course of moderate and severe COVID-19: a randomized controlled trial | QuestionIs ultra-short-wave diathermy (USWD) safe and effective in coronavirus disease 2019 (COVID-19) ?
DesignSingle-centre, evaluator-blinded, two-arm, parallel design, randomized controlled clinical trial.
ParticipantsModerate and severe COVID-19 patients with acute respiratory syndrome.
InterventionUSWD for 10 minutes twice daily for 12 consecutive days along with standard medical treatment (USWD group, n = 25), versus standard medical treatment alone (control group, n = 25).
Outcome measuresThe primary outcomes were the duration of recovery and negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on days 7, 14, 21, and 28. Secondary outcomes included clinical status (seven-category ordinal and systemic inflammatory response syndrome (SIRS) scores), computed tomography (CT), routine blood tests, and adverse events.
ResultsTime to clinical recovery (USWD 36.84{+/-}9.93 vs. control 43.56{+/-}12.15, P = 0.037) was significantly shortened with a between-group difference of 6.72 days. Clinical status was improved with significant between-group differences on day 28 (SIRS, P = 0.011; seven-category scale, P = 0.003). The rate of RNA negative conversion at days 7 (P = 0.066), 14 (P = 0.239), 21 (P = 0.269), and 28 (P = 0.490) was statistically insignificant. Moreover, insignificant differences were observed in the artificial intelligence-assisted CT analysis. No treatment-associated adverse events or worsening of pulmonary fibrosis were observed.
ConclusionUSWD, as adjunctive therapy, shortened the recovery course and improved clinical status of patients with COVID-19 without aggravating pulmonary fibrosis. the findings are limited due to the small sample size and early termination.
RegistrationChiCTR2000029972 | rehabilitation medicine and physical therapy |
10.1101/2021.01.29.21250773 | Targeted screening for Alzheimer's disease clinical trials using data-driven disease progression models | Heterogeneity in Alzheimers disease progression contributes to the ongoing failure to demonstrate efficacy of putative disease-modifying therapeutics that have been trialled over the past two decades. Any treatment effect present in a subgroup of trial participants (responders) can be diluted by non-responders who ideally should have been screened out of the trial. How to identify (screen-in) the most likely potential responders is an important question that is still without an answer. Here we pilot a computational screening tool that leverages recent advances in data-driven disease progression modelling to improve stratification. This aims to increase the sensitivity to treatment effect by screening out non-responders, which will ultimately reduce the size, duration, and cost of a clinical trial. We demonstrate the concept of such a computational screening tool by retrospectively analysing a completed double-blind clinical trial of donepezil in people with amnestic mild cognitive impairment (clinicaltrials.gov: NCT00000173), identifying a data-driven subgroup having more severe cognitive impairment who showed clearer treatment response than observed for the full cohort. | neurology |
10.1101/2021.01.28.21250322 | Caspase-6-cleaved tau is relevant in Alzheimer's disease but not in 4-repeat tauopathies: diagnostic and therapeutic implications | AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimers disease (AD) and other tauopathies remains unclear.
MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.
ResultsCasp-6 activation was strongest in AD, followed by Picks disease (PiD), but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD lacked p-tau aggregates.
ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that not all neurons that are vulnerable to tau pathology are detected by a conventional p-tau Ser 202 antibody and that AD has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could be necessary to modulate tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD supports the investigation of biofluid biomarkers against N-terminus tr-tau, which could detect AD and differentiate it from 4R tauopathies at a single patient level.
3 - sentence summaryTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation, but the relationship between aCasp-6, tr-tau, and hyperphosphorylated tau (p-tau) accumulation in Alzheimers disease (AD) and other tauopathies remains unclear. We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6 and used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in brains from healthy controls, AD, and primary tauopathies. We detected relatively high Casp-6 activation in AD, followed by Picks disease (PiD). aCasp-6 was almost absent in 4-repeat (4R) tauopathies, suggesting that early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy in AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. | neurology |
10.1101/2021.01.28.21250322 | Caspase-6-cleaved tau is relevant in Alzheimer's disease but not in 4-repeat tauopathies: diagnostic and therapeutic implications | AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimers disease (AD) and other tauopathies remains unclear.
MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.
ResultsCasp-6 activation was strongest in AD, followed by Picks disease (PiD), but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD lacked p-tau aggregates.
ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that not all neurons that are vulnerable to tau pathology are detected by a conventional p-tau Ser 202 antibody and that AD has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could be necessary to modulate tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD supports the investigation of biofluid biomarkers against N-terminus tr-tau, which could detect AD and differentiate it from 4R tauopathies at a single patient level.
3 - sentence summaryTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation, but the relationship between aCasp-6, tr-tau, and hyperphosphorylated tau (p-tau) accumulation in Alzheimers disease (AD) and other tauopathies remains unclear. We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6 and used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in brains from healthy controls, AD, and primary tauopathies. We detected relatively high Casp-6 activation in AD, followed by Picks disease (PiD). aCasp-6 was almost absent in 4-repeat (4R) tauopathies, suggesting that early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy in AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. | neurology |
10.1101/2021.01.29.21250725 | The effects of time-restricted eating vs. standard dietary advice on weight, metabolic health and the consumption of processed food: A pragmatic randomised controlled trial in community-based adults | Weight loss is key to control the increasing prevalence of metabolic syndrome (MS) and its components, i.e. central obesity, hypertension, prediabetes, and dyslipidaemia. We characterised the relationships between eating duration, unprocessed and processed food consumption, and metabolic health. During 4 weeks of observation, 213 adults used a smartphone application to record food and drink consumption, which was annotated for food processing levels following the NOVA classification. Consumption of unprocessed food items showed the highest number of significant associations with MS components after age and sex. In a pragmatic randomised controlled trial, we compared the metabolic benefits of 12h time-restricted eating (TRE) to standard dietary advice (SDA) in 54 adults with an eating duration >14h and at least one MS component. After 6 months, those randomised to TRE lost 1.6% of initial body weight (SD 2.9, p=0.01), compared to the absence of weight loss with SDA (-1.1%, SD 3.5, p=0.19). There was no significant difference in weight loss between TRE and SDA (between-group difference -0.88%, 95% confidence interval -3.1 to 1.3, p=0.43). Our results show the potential of smartphone records to predict metabolic health and highlight that further research is needed to understand individual responses to TRE. | nutrition |
10.1101/2021.01.29.21250725 | The effects of time-restricted eating vs. standard dietary advice on weight, metabolic health and the consumption of processed food: A pragmatic randomised controlled trial in community-based adults | Weight loss is key to control the increasing prevalence of metabolic syndrome (MS) and its components, i.e. central obesity, hypertension, prediabetes, and dyslipidaemia. We characterised the relationships between eating duration, unprocessed and processed food consumption, and metabolic health. During 4 weeks of observation, 213 adults used a smartphone application to record food and drink consumption, which was annotated for food processing levels following the NOVA classification. Consumption of unprocessed food items showed the highest number of significant associations with MS components after age and sex. In a pragmatic randomised controlled trial, we compared the metabolic benefits of 12h time-restricted eating (TRE) to standard dietary advice (SDA) in 54 adults with an eating duration >14h and at least one MS component. After 6 months, those randomised to TRE lost 1.6% of initial body weight (SD 2.9, p=0.01), compared to the absence of weight loss with SDA (-1.1%, SD 3.5, p=0.19). There was no significant difference in weight loss between TRE and SDA (between-group difference -0.88%, 95% confidence interval -3.1 to 1.3, p=0.43). Our results show the potential of smartphone records to predict metabolic health and highlight that further research is needed to understand individual responses to TRE. | nutrition |
10.1101/2021.01.29.21250806 | Pelvic Pain: what are the symptoms and predictors for surgery, endometriosis and endometriosis severity? | BackgroundChronic pelvic pain (CPP) is a common condition which significantly impacts the quality of life and wellbeing of many women.
Laparoscopy with histopathology is recommended for investigation of pelvic pain and identification of endometriosis with concurrent removal. Never-the-less, the association between endometriosis and pelvic pain is challenging, with endometriosis identified in only 30-50% of women with pain.
AimsTo explore the predictors for undergoing surgery, for identifying endometriosis and endometriosis severity in a cohort of women with CPP.
Materials and MethodsThis study forms part of the Persistent Pelvic Pain project, a prospective observational cohort study (ANZCTR:ACTRN12616000150448). Women referred to a public gynaecology clinic with pain were randomised to one of 2 gynaecology units for routine care and followed for 36-months with 6-monthly surveys assessing demographics, medical history, quality of life, and pain symptoms measured on a Likert scale. Operative notes were reviewed, and endometriosis staged.
ResultsOf 471 women recruited, 102 women underwent laparoscopy or laparotomy, of whom 52 had endometriosis (n=37 stage I-II; n=15 stage III-IV). Gynaecology unit, pelvic pain intensity and lower parity were all predictors of surgery (Odds ratio (OR) 0.342; 95%CI 0.209-0.561; OR 1.303; 95%CI: 1.079-1.573; OR 0.767; 95%CI: 0.620-0.949 respectively). There were no predictors identified for endometriosis diagnosis and the only predictor of severity was increasing age (OR 1.155; 95%CI: 1.047-1.310).
ConclusionsPain intensity and gynaecology unit were key predictors of undergoing laparoscopy, however, pain severity did not predict endometriosis diagnosis or staging. These findings indicate the need to review current frameworks guiding practice towards surgery for pelvic pain. | obstetrics and gynecology |
10.1101/2021.01.29.21250381 | Cholesterol-lowering Decreased mTOR Complex 2 Signaling and Enhanced Antitumor Immunity | Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease. Cholesterol may have complex and opposing effects on immunity. We lowered serum cholesterol to clinically relevant levels in mice and evaluated the final adaptive immune response. Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and enhanced central CD8+ T cell memory. In both mice and patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. Lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In a prospective clinical trial, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. Here, we show that lowering serum cholesterol may be an effective strategy to decrease signaling through mTORC2 and enhance antitumor CD8+ T cell memory. | oncology |
10.1101/2021.01.29.21250757 | Updated SARS-CoV-2 Single Nucleotide Variants and Mortality Association | Since its outbreak in December 2019, COVID-19 has caused 100,5844,555 cases and 2,167,313 deaths as of Jan 27, 2021. Comparing our previous study of SARS-CoV-2 single nucleotide variants (SNVs) before June 2020, we found out that the SNV clustering had changed considerably since June 2020. Apart from that the group SNVs represented by two non-synonymous mutations A23403G (S: D614G) and C14408T (ORF1ab: P4715L) became dominant and carried by over 95% genomes, a few emerging groups of SNVs were recognized with sharply increased monthly occurrence ratios up to 70% in November 2020. Further investigation revealed that several SNVs were strongly associated with the mortality, but they presented distinct distribution in specific countries, e.g., Brazil, USA, Saudi Arabia, India, and Italy. SNVs including G25088T, T25A, G29861T and G29864A were adopted in a regularized logistic regression model to predict the mortality status in Brazil with the AUC of 0.84. Protein structure analysis showed that the emerging subgroups of non-synonymous SNVs and those mortality-related ones in Brazil were located on protein surface area. The clashes in protein structure introduced by these mutations might in turn affect virus pathogenesis through conformation changes, leading to the difference in transmission and virulence. Particularly, we found that SNVs tended to occur in intrinsic disordered regions (IDRs) of Spike (S) and ORF1ab, suggesting a critical role of SNVs in protein IDRs to determine protein folding and immune evasion. | health informatics |
10.1101/2021.01.29.21250753 | Discontinuation of isolation for persons with COVID-19: Is 10 days really safe? | BackgroundThe detection of SARS-CoV-2 RNA by real-time polymerase chain reaction (PCR) in respiratory samples from COVID-19 patients is not a direct indication of the presence of viable viruses. The isolation of SARS-CoV-2 in cell culture system however, can acts as surrogate marker of infectiousness. Cell culture based studies performed mostly with hospitalized and moderate/severe COVID-19 claims that no replication competent virus is found after 9 days of the symptoms onset in respiratory samples. Therefore, it is now recommended 10 days isolation before patient discharge.
MethodsWe cell-cultured 29 SARS-COV-2 RT-PCR positive respiratory samples at the 10th day after the illness in Vero E6 cells. After two passages, cytopathic effect and cycle threshold (CT) lower than the obtained in the original sample were used to determine positivity.
FindingsWe found viable particles in (7/29) 24% of samples tested. The positivity in cell culture was strongly associated (p<0.0001) to the low cycle thresholds in clinical samples (Ct <21).
ConclusionThis data adds important knowledge to the current protocols for de-isolation of patients with non-hospitalized mild COVID-19. | health policy |
10.1101/2021.01.29.21250771 | Persistent COVID-19 symptoms minimally impact the development of SARS-CoV-2 specific cellular immunity | SARS-CoV-2 represents an unprecedented public health challenge with many unknowns remaining regarding the factors that impact viral pathogenicity and the development of immunity after infection. While the majority of SARS-CoV-2 infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, a significant number of individuals experienced prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, especially within the cellular immune compartment. However, it is unclear if persistent mild-to-moderate COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed the development of SARS-CoV-2 specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms, or symptoms persisting for 18 days or more. We observed that the duration of COVID-19 symptoms minimally impacts the magnitude, antigen specificity, and transcriptional profile of SARS-CoV-2 specific cellular immunity within both the CD4+ and CD8+ T cell compartments. Furthermore, we observed that reactivity against the structural N protein from SARS-CoV-2 in convalescent COVID-19 patients correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide additional insight into the complex processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses. | infectious diseases |
10.1101/2021.01.29.21250804 | A mathematical model to estimate percentage secondary infections from margin of error of diagnostic sensitivity: Useful tool for regulatory agencies to assess the risk of propagation due to false negative outcome of diagnostics | False negative outcome of a diagnosis is one the major reasons for the dissemination of the diseases with high risk of propagation. Diagnostic sensitivity and the margin of error determine the false negative outcome of the diagnosis. A mathematical model had been developed to estimate the mean % secondary infections based on the margin of error of diagnostic sensitivity, % prevalence and R0 value. This model recommends a diagnostic test with diagnostic sensitivity [≥] 96% and at least 92% lower bound limit of the 95% CI or [≤] 4% margin of error for a highly infectious diseases like COVID-19 to curb the secondary transmission of the infection due to false negative cases. Positive relationship was found between mean % secondary infection and margin of error of sensitivity suggesting greater the margin of error of a diagnostic test sensitivity, higher the number of secondary infections in a population due to false negative cases. Negative correlation was found between number of COVID-19 test kits (>90% sensitivity) with regulatory approval and margin of error (R= -0.92, p=0.023) suggesting lesser the margin of error of a diagnostic test, higher the chances of getting approved by the regulatory agencies. However, there are no specific regulatory standards available for margin of error of the diagnostic sensitivity of COVID-19 diagnostic tests. Highly infectious disease such as COVID-19, certainly need specific regulatory standards on margin of error or 95% CI of the diagnostic sensitivity to curb the dissemination of the disease due to false negative cases and our model can be used to set the standards such as sensitivity, margin of error or lower bound limit of 95% CI. | infectious diseases |
10.1101/2021.01.29.21250712 | MOATAI-VIR - an AI algorithm that predicts severe adverse events and molecular features for COVID-19's complications | Following SARS-CoV-2 infection, some COVID-19 patients experience severe adverse events caused by pathogenic host responses. To treat these complications, their underlying etiology must be identified. Thus, a novel AI-based methodology, MOATAI-VIR, which predicts disease-protein-pathway relationships for 22 clinical manifestations attributed to COVID-19 was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure associated risk genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. Three uncharacterized manifestation categories are found: neoplasms, mental and behavioral disorders, and congenital malformations, deformations, and chromosomal abnormalities. The prevalence of neoplasms suggests a possible association between COVID-19 and cancer, whether by shared molecular mechanisms between oncogenesis and viral replication, or perhaps, SARS-CoV-2 is an oncovirus. To assess the molecular basis of each manifestation, the proteins shared across each group of comorbidities were prioritized and subject to global pathway analysis. From these most frequent pathways, the molecular features associated with hallmark COVID-19 phenotypes, such as loss of sense of smell/taste, unusual neurological symptoms, cytokine storm, and blood clots were explored. Results of MOATAI-VIR are available for academic users at: http://pwp.gatech.edu/cssb/MOATAI-VIR/. | infectious diseases |
10.1101/2021.01.30.21250844 | Retinol Depletion in Severe COVID-19 | Background and PurposeVitamin A is depleted during infections. Vitamin A has been used successfully in measles, RSV and AIDS patients and is an effective vaccine adjuvant. In this study, low retinol levels were found in patients with severe COVID-19. Retinoid signaling impairment in COVID-19 disrupts Type-I interferon synthesis.
Material and MethodTwo groups were formed in the study. The patient group consisted of 27 (Group 1) severe COVID-19 patients hospitalized in the intensive care unit with respiratory failure, and the control group consisted of 23 (Group 2) patients without COVID-19 symptoms. Serum retinol levels were analyzed by ELIZA and HPLC in both groups.
FindingsRetinol levels were found to be significantly lower in the patient group (P <0.001). There was no difference in retinol between two different age groups in the patient group (P> 0.05). There was no significant difference in retinol between men and women (P> 0.05). Comorbidity did not affect serum retinol levels (P >0.05).
ConclusionSerum retinol levels were low in patients with severe COVID-19. Drugs preventing retinol excretion were not stopped in the patient group. Some patients took vitamin A externally. Despite this, retinol was low in COVID-19 patients. Retinol depletion impairs Type-I interferon synthesis by impairing retinoid signaling. Retinoid signaling may be the main pathogenetic disorder in COVID-19. This pathogenesis can serve as a guide for adjuvants, drug targets, and candidate drugs. Retinol, retinoic acid derivatives, and some CYP450 inhibitors may work on COVID-19. | infectious diseases |
10.1101/2021.01.29.21250790 | Sensitive extraction-free SARS-CoV-2 RNA virus detection using a novel RNA preparation method | Current conventional detection of SARS-CoV-2 involves collection of a patient sample with a nasopharyngeal swab, storage of the swab during transport in a viral transport medium, extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). We developed a simplified and novel preparation method using a Chelex resin that obviates RNA extraction during viral testing. Direct detection RT-qPCR and digital-droplet PCR was compared to the current conventional method with RNA extraction for simulated samples and patient specimens. The heat-treatment in the presence of Chelex markedly improved detection sensitivity as compared to heat alone, and lack of RNA extraction shortens the overall diagnostic workflow. Furthermore, the initial sample heating step inactivates SARS-CoV-2 infectivity, thus improving workflow safety. This fast RNA preparation and detection method is versatile for a variety of samples, safe for testing personnel, and suitable for standard clinical collection and testing on high throughput platforms. | infectious diseases |
10.1101/2021.01.29.21250317 | Differential Cytokine Signatures of SARS-CoV-2 and Influenza Infection Highlight Key Differences in Pathobiology | BackgroundSeveral inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease.
MethodsThirty-seven cytokines and chemokines were measured in plasma from 145 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI on disease severity.
ResultsIL-18, IL-1{beta}, IL-6, and TNF- were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-{gamma}, IFN-{lambda}1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF- were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-{lambda}1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity.
ConclusionsThese findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.
SummarySevere COVID-19 is marked by dysregulated inflammation and is associated with elevated BMI. By comparing cytokines and chemokines in patients with either COVID-19 or influenza, we identified distinct inflammatory pathways and a cytokine mediator of the effect of BMI. | infectious diseases |
10.1101/2021.01.30.21250843 | Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2 | Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list. | infectious diseases |
10.1101/2021.01.30.21250843 | Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2 | Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list. | infectious diseases |
10.1101/2021.01.30.21250843 | Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2 | Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list. | infectious diseases |
10.1101/2021.01.30.21250843 | Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2 | Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list. | infectious diseases |
10.1101/2021.01.30.21250843 | Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2 | Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list. | infectious diseases |