bluuebunny/crossref_metadata_2025 huggingface dataset:
A precise score for the regular monitoring of COVID-19 patients condition validated within the first two waves of the pandemic
Authors: Bakin Evgeny A. , Stanevich Oksana V. , Belash Vassily A. , Belash Anastasia A. , Savateeveva Galina A. , Bokinova Veronika A. , Arsentieva Natalia A. , Sayenko Ludmila F. , Korobenkov Evgeny A. , Lioznov Dmitry A. , Totolian Areg A. , Polushin Yury S. , Kulikov Alexander N.
Published: February 2021

Purpose

The sudden outbreak of COVID-19 pandemic has shown that the medical community needs an accurate and interpretable aggregated score not only for an outcome prediction but also for a daily patient’s condition assessment. Due to a continuously changing pandemic landscape, robustness becomes a crucial additional requirement for the score.

Patients and methods

In this research, real-world data collected within the first two waves of the COVID-19 pandemic was used. The first wave data (1349 cases collected from 27.04.2020 to 03.08.2020) was used as a training set for the score development, while the second wave data (1453 cases collected from 01.11.2020 to 19.01.2021) was used as a validating set. For all the available patients’ features we tested their association with an outcome using robust linear regression. Statistically significant features were taken to the further analysis for each of which their partial sensitivity, specificity and promptness were estimated. The sensitivity and the specificity were further combined into a feature informativeness index.

Results

The developed score was derived as a weighted sum of the following 9 features showed the best trade-off between informativeness and promptness: APTT (> 42 sec, 4 points), CRP (> 146 mg/L, 3 points), D-dimer (> 2149 mkg/L, 4 points), Glucose (> 9 mmol/L, 4 points), Hemoglobin (< 115 g/L, 3 points), Lymphocytes (< 0,7*10^9/L, 3 points), Total protein (< 61 g/L, 6 points), Urea (> 11 mmol/L, 5 points) and WBC (> 13,5*10^9/L, 4 points). Thus, the proposed score ranges between 0 and 36 points. Internal and temporal validation showed that sensitivity and specificity over 90% may be achieved with an expected prediction range >7 days. Moreover, we demonstrated a high robustness of the score to the varying peculiarities of the pandemic. For the additional simplicity of application we split the full range of the score into five grades delimited with 9, 14, 19 and 24 points which determine expected death:discharge odds 1:100, 1:25, 1:5 and 1:1 correspondingly.

Conclusions

An extensive application of the score within the second wave of the COVID-19 pandemic showed its potential for the optimization of patients management as well as improvement of medical staff attentiveness during high workload stress. The transparent structure of the score, as well as tractable cut-off bounds, simplified its implementation into clinical practice.
Results of an early second PCR test performed on SARS-CoV-2 positive patients may indicate risk for severe COVID-19
Authors: Mizrahi Barak , Bivas-Benita Maytal , Kalkstein Nir , Akiva Pinchas , Yanover Chen , Yehezkelli Yoav , Kessler Yoav , Alon Sharon Hermoni , Rubin Eitan , Chodick Gabriel
Published: February 2021

Identifying patients at increased risk for severe COVID-19 is of high priority during the pandemic as it could affect clinical management and shape public health guidelines. In this study we assessed whether a second PCR test conducted 2-7 days after a SARS-CoV-2 positive test could identify patients at risk for severe illness. Analysis of a nationwide electronic health records data of 1,683 SARS-CoV-2 positive individuals indicated that a second negative PCR test result was associated with lower risk for severe illness compared to a positive result. This association was seen across different age groups and clinical settings. More importantly, it was not limited to recovering patients but also observed in patients who still had evidence of COVID-19 as determined by a subsequent positive PCR test. Our study suggests that an early second PCR test may be used as an additional risk-assessment tool to improve disease management and patient care.
Penalized regression for left-truncated and right-censored survival data
Authors: McGough Sarah F. , Incerti Devin , Lyalina Svetlana , Copping Ryan , Narasimhan Balasubramanian , Tibshirani Robert
Published: February 2021

High-dimensional data are becoming increasingly common in the medical field as large volumes of patient information are collected and processed by high-throughput screening, electronic health records (EHRs), and comprehensive genomic testing. Statistical models that attempt to study the effects of many predictors on survival typically implement feature selection or penalized methods to mitigate the undesirable consequences of overfitting. In some cases survival data is also left-truncated which can give rise to an immortal time bias, but penalized survival methods that adjust for left truncation are not commonly implemented. To address these challenges, we apply a penalized Cox proportional hazards model for left-truncated and right-censored survival data and assess implications of left truncation adjustment on bias and interpretation. We use simulation studies and a high-dimensional, real-world clinico-genomic database (CGDB) to highlight the pitfalls of failing to account for left truncation in survival modeling.
Temporal trends of SARS-CoV-2 seroprevalence in transfusion blood donors during the first wave of the COVID-19 epidemic in Kenya
Authors: Adetifa Ifedayo M.O. , Uyoga Sophie , Gitonga John N. , Mugo Daisy , Otiende Mark , Nyagwange James , Karanja Henry K. , Tuju James , Wanjiku Perpetual , Aman Rashid , Mwangangi Mercy , Amoth Patrick , Kasera Kadondi , Ng’ang’a Wangari , Rombo Charles , Yegon Christine , Kithi Khamisi , Odhiambo Elizabeth , Rotich Thomas , Orgut Irene , Kihara Sammy , Bottomley Christian , Kagucia Eunice W. , Gallagher Katherine E. , Etyang Anthony , Voller Shirine , Lambe Teresa , Wright Daniel , Barasa Edwine , Tsofa Benjamin , Bejon Philip , Ochola-Oyier Lynette I. , Agweyu Ambrose , Scott J. Anthony G. , Warimwe George M.
Published: February 2021

Observed SARS-CoV-2 infections and deaths are low in tropical Africa raising questions about the extent of transmission. We measured SARS-CoV-2 IgG by ELISA in 9,922 blood donors across Kenya and adjusted for sampling bias and test performance. By 1st September 2020, 577 COVID-19 deaths were observed nationwide and seroprevalence was 9.1% (95%CI 7.6-10.8%). Seroprevalence in Nairobi was 22.7% (18.0-27.7%). Although most people remained susceptible, SARS-CoV-2 had spread widely in Kenya with apparently low associated mortality.
Accounting for imported cases in estimating the time-varying reproductive number of COVID-19
Authors: Tsang Tim K. , Wu Peng , Lau Eric H. Y. , Cowling Benjamin J.
Published: February 2021

Background

Estimating the time-varying reproductive number, Rt, is critical for monitoring transmissibility of an emerging infectious disease during outbreaks. When local transmission is effectively suppressed, imported cases could substantially impact transmission dynamics.

Methods

We developed methodology to estimate separately the Rt for local cases and imported cases, since certain public health measures aim only to reduce onwards transmission from imported cases. We applied the framework to data on COVID-19 outbreaks in Hong Kong.

Results

We estimated that the Rt for local cases decreased from above one in the early phase of outbreak to below one after tightening of public health measures. Assuming the same infectiousness of local and imported cases underestimated Rt for local cases due to control measures targeting travelers.

Conclusions

When a considerable proportion of all cases are imported, the impact of imported cases in estimating Rt is critical. The methodology described here can allow for differential infectiousness of local imported cases.
The global distribution of COVID-19 vaccine: The role of macro-socioeconomics measures
Authors: Roghani Ali , Panahi Samin
Published: February 2021

Since coronavirus disease 2019 (covid-19) has continued to spread globally, many countries have progressed clinical trials and started vaccinations at the end of December 2020. This report aims to analyze the association of COVID-19 vaccine distribution and two macro-socioeconomics measures, including human development index (HDI) and Gross domestic product (GDP), among 25 countries till the first week of February 2021. Our results indicate that a higher GDP per Capita is positively associated with higher COVID-19 vaccine distribution. In addition, the result shows HDI does not have a significant relationship with vaccine distribution. Although these macro-socioeconomic measures may be counted as a vital indicator for vaccine distribution, other factors may play roles in vaccine distribution, including well-developed health infrastructure, a centralized political system, and population size.
Quantifying the preventive effect of wearing face masks
Authors: Britton Tom
Published: February 2021

An important task in combating the ongoing covid-19 effect lies in estimating the effect of different preventive measures. Here we focus on the preventive effect of enforcing the use of face masks. Several publications study this effect, however often using different measures such as: the relative attack rate in case-control studies, the effect on incidence growth/decline in a specific time-frame, the effect on the number of infected in a given time-frame. These measures all depend on community-specific features and are hence not easily transferred to other community settings. We argue that a more universal measure is the relative reduction in the reproduction number, which we call the face mask effect, EFM. It is shown how to convert the other measures to EFM. We also apply the methodology on three publications using different other measures (two of them resulting in two different estimates each, and all five estimates of EFM lie between 20-40%, suggesting that mandatory face masks reduce the reproduction number by 20-40% as compared to no individuals wearing face masks.
Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis
Authors: Ma Hui , Wang Lin , Wen Zilu , Chen Xinchun , Liu Haiying , Zhang Shulin , Xu Jianqing , Song Yanzheng , Wong Ka-Wing
Published: February 2021

Metabolic activity in pulmonary lesion is associated with disease severity and relapse risk in tuberculosis. However, the nature of the metabolic activity associated with tuberculosis in humans remains unclear. Previous works indicate that tuberculosis bears resemblance transcriptionally with systemic lupus erythematosus in peripheral blood, except that the plasma cell component was absent in tuberculosis. Here we reported that the missing transcriptional component was present within the metabolic active tissues in the lung of patients with sputum culture-negative tuberculosis, within which increased levels of circulating immune complexes and anti-dsDNA antibodies were found relative to nearby non-metabolic active tissues. Histological examination revealed specific vascular deposition of immune complexes, neutrophil extracellular traps, and vascular necrosis in the metabolic-active tissue. Thus, tuberculosis-initiated metabolic activity was associated with hyperactive antibody responses and vascular pathology, and shared features with systemic lupus erythematosus and other autoimmune diseases. We discussed these observations in the context of earlier literatures demonstrating that similar effects could be induced in humans and animal models by complete freund’s adjuvant, the most potent antibody response inducer ever reported. Our small case series, if verified in a larger size study, might help inform host-directed therapies to alleviate disease progression and augment treatment efficacy.

IMPORTANCE

In patients with pulmonary tuberculosis, lung tissues were destroyed by a hyperactive inflammatory response towardsM. tuberculosis. The mechanisms underlying the inflammatory response are still poorly understood. Using 18F-FDG avidity as a surrogate marker of inflammation, we have identified that hyper-inflamed tissues possessed features associated with systemic lupus erythematosus: gene expression signatures of plasma cell and immunoglobulins and increased levels of anti-dsDNA antibodies, immune deposits, and vasculopathy. This observation might suggest an explanation to why patients with tuberculosis share more gene expression signatures with autoimmune diseases than infectious diseases and why they are more likely to develop autoimmune diseases. Defining the inflammatory responses at the lesion could help inform host-directed therapies to intervene disease progression or even accelerate cure.
Seroprevalence of SARS-CoV-2, symptom profiles and seroneutralization during the first COVID-19 wave in a suburban area, France
Authors: Gégout petit Anne , Jeulin Hélène , Legrand Karine , Bochnakian Agathe , Vallois Pierre , Schvoerer Evelyne , Guillemin Francis
Published: February 2021

Background

The World Health Organisation recommends monitoring the circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to estimate anti–SARS-CoV-2 total immunoglobulin (IgT) antibody seroprevalence and describe symptom profiles and in vitro seroneutralization in Nancy, France, in spring 2020.

Methods

Individuals were randomly sampled from electoral lists and invited with household members over 5 years old to be tested for anti–SARS-CoV-2 (IgT, i.e. IgA/IgG/IgM) antibodies by ELISA (Bio-rad). Serum samples were classified according to seroneutralization activity >50% (NT50) on Vero CCL-81 cells. Age- and sex-adjusted seroprevalence was estimated. Subgroups were compared by chi-square or Fisher exact test and logistic regression.

Results

Among 2006 individuals, 43 were SARS-CoV-2–positive; the raw seroprevalence was 2.1% (95% confidence interval 1.5 to 2.9), with adjusted metropolitan and national standardized seroprevalence 2.5% (1.8 to 3.3) and 2.3% (1.7 to 3.1). Seroprevalence was highest for 20-to 34-year-old participants (4.7% [2.3 to 8.4]), within than out of socially deprived area (2.5% vs 1%, P=0.02) and with than without intra-family infection (p<10−6). Moreover, 25% (23 to 27) of participants presented at least one COVID-19 symptom associated with SARS-CoV-2 positivity (p<10−13), with anosmia or ageusia highly discriminant (odds ratio 27.8 [13.9 to 54.5]), associated with dyspnea and fever. Among the SARS-CoV-2-positives, 16.3% (6.8 to 30.7) were asymptomatic. For 31 of these individuals, positive seroneutralization was demonstrated in vitro.

Conclusions

In this population of very low anti-SARS-CoV-2 antibody seroprevalence, a beneficial effect of the lockdown can be assumed, with frequent SARS-CoV-2 seroneutralization among IgT-positive patients.

Key Messages

Total immunoglobulin antibody (IgT) measurement is an accurate tool to monitor the circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a key biological feature to assume the spread of COVID-19 later after the appearance of symptoms.

IgT seroprevalence was 2.1% in the Grand Nancy Metropolitan area, France; was highest for young adults; in socially deprived area, but this was not confirmed at the individual level; and was associated with high intra-family viral transmission.

About two thirds of IgT-positive individuals exhibited SARS-CoV-2–positive seroneutralization.

Trial registration

NCT04448769
ImplemeNting SARS-CoV-2 Rapid antigen testing in the Emergency wArd of a Swiss univErsity hospital: the INCREASE study
Authors: Caruana Giorgia , Croxatto Antony , Kampouri Eleftheria , Kritikos Antonios , Opota Onya , Foerster Marylin , Brouillet René , Senn Laurence , Lienhard Reto , Egli Adrian , Pantaleo Giuseppe , Carron Pierre-Nicolas , Greub Gilbert
Published: February 2021

Background

While facing a second wave in SARS-CoV-2 pandemic, in November 2020 the Swiss Federal Office of Public Health (FOPH) authorized the use of rapid antigen tests (RATs) in addition to the gold-standard reverse transcription-polymerase chain reaction (RT-PCR).

Methods

We implemented the use of RAT in the emergency ward of our university hospital for rapid patients’ triaging and compared performances of four different antigen tests. All results were compared to SARS-CoV-2 specific RT-PCR (reference standard).

Results

Triaging patients using RAT in association with RT-PCR allowed us to isolate promptly positive patients and to save resources, in a context of rapid RT-PCR reagents shortage. Among 532 patients with valid results, overall sensitivities were 48.3% for One Step Exdia and 41.2% for Standard Q®, Panbio−and BD Veritor. All four antigen tests exhibited specificity above 99%. Sensitivity increased up to 74.6%, 66.2%, 66.2% and 64.8% for One Step Exdia, Standard Q, Panbio, and BD Veritor respectively, when considering viral loads above 105copies/ml, up to 100%, 97.8%, 96.6% and 95.6% for viral loads above 106 copies/ml and 100% (for all tests) when considering viral loads above 107 copies/ml. Sensitivity was significantly higher for patients presenting with symptoms onset within 4 days (74.3%, 69.2%, 69.2% and 64%, respectively) versus patients with evolution of symptoms for more than 4 days (36.8%, 21.1%, 21.1% and 23.7%, respectively). Sensitivities of all RAT assays were of only 33% among hospitalized patients without COVID-19 symptoms.

Conclusion

RAT might represent a useful epidemiological resource in selected clinical settings as a complementary tool to the molecular tests for rapid patients triaging, but the lower sensitivity compared to RT-PCR, especially in late presenters and subjects without COVID-19 symptoms, must be taken into account in order to correctly use RAT for triaging.
Response to Whole-Lung Low-Dose Radiation Therapy (LD-RT) Predicts Freedom from Intubation in Patients Receiving Dexamethasone and/or Remdesevir for COVID-19-Related Acute Respiratory Distress Syndrome (ARDS)
Authors: Hess Clayton B. , Eng Tony Y. , Nasti Tahseen H. , Dhere Vishal R. , Kleber Troy J. , Switchenko Jeffrey M. , Weinberg Brent D. , Rouphael Nadine , Tian Sibo , Rudra Soumon , Taverna Luisa S. , Perez Alvaro , Ahmed Rafi , Khan Mohammad K.
Published: February 2021

Background

Phase I/II clinical trials have explored whole-lung low-dose radiotherapy (LD-RT) as a potential treatment for patients with COVID-19-related acute respiratory distress syndrome (ARDS). Initial findings require reproduction. Concomitant LD-RT administration with existing therapies requires safety evaluation.

Methods

Patients with COVID-19-related pneumonia receiving dexamethasone and/or remdesevir were treated with 1.5 Gy whole-lung LD-RT, followed for 28 days or until hospital discharge, and compared to controls blindly matched by age, comorbidity, and disease severity. Eligible patients were hospitalized, SARS-CoV-2 positive, had radiographic consolidations, and required supplemental oxygen. Endpoints included safety, clinical recovery, intubation, radiographic changes, and biomarker response.

Findings

20 patients received whole-lung LD-RT between Jun 11 and Dec 7, 2020 and were compared to controls. Freedom from intubation improved from 68% in controls to 86% following LD-RT (p=0.09) as did C-reactive protein (CRP) (p=0.02) and creatine kinase (CK) (p<0.01) levels, consistent with prior report. Eighty percent of LD-RT patients experienced rapid decline in CRP within 3 days and were classified as LD-RT responders. Intubation-free survival (100% vs 66%, p=0.01) and oxygenation loads were lower in LD-RT responders compared to matched controls: 32% lower per individual (p=0.03) and 56% lower for the cohort (p=0.06). No patient whose CRP declined following LD-RT died or required intubation, whereas all LD-RT non-responders died. Observed reduction of prolonged recoveries and hospitalization times did not reach significance. Radiographic changes were equivalent.

Interpretation

A cohort of patients with COVID-19-related ARDS treated with LD-RT demonstrated superior freedom from intubation compared to matched controls, especially LD-RT responders (p=0.01). LD-RT appears safe to deliver with concurrent drugs. LD-RT lowered CRP and CK biomarkers. CRP response predicted favorable outcome. Optimal timing for LD-RT after oxygen dependence but before intubation may extinguish immunopathology prior to systemic spread. Confirmatory clinical trials are warranted. Clinical Trial Registration: NCT04366791.

Funding

None
C-reactive protein guided use of procalcitonin in COVID-19
Authors: Houghton Rebecca , Moore Nathan , Williams Rebecca , El-Bakri Fatima , Peters Jonathan , Mori Matilde , Vernet Gabrielle , Lynch Jessica , Lewis Henry , Tavener Maryanna , Durham Tom , Bowyer Jack , Saeed Kordo , Pollara Gabriele
Published: February 2021

Low procalcitonin (PCT) concentrations (<0.5ng/mL) can facilitate exclusion of bacterial co-infection in viral infections, including COVID-19. However, costs associated with PCT measurement preclude universal adoption, indicating a need to identify settings where PCT provides clinical information beyond that offered by other inflammatory markers, such as C-reactive protein (CRP) and white cell count (WCC). In an unselected cohort of 299 COVID-19 patients, we tested the hypothesis that PCT<0.5ng/mL was associated with lower levels of CRP and WCC. We demonstrated that CRP values below the geometric mean of the entire patient population had a negative predictive value for PCT<0.5ng/mL of 97.6% and 100% at baseline and 48 hours into admission respectively, and that this relationship was not confounded by intensive care admission or microbiological findings. CRP-guided PCT testing algorithms can reduce costs and support antimicrobial stewardship strategies in COVID-19.
COVID-19 and Influenza: Vaccination Before and During the Pandemic among the Lebanese Adult Population
Authors: Elia Anthony , Taha Nedal , Tokajian Sima
Published: February 2021

Influenza is a common respiratory tract disease that has been around for years. Vaccination remains the most cost-effective measure to avoid infection. Influenza vaccination rates in Lebanon, like elsewhere in the world, are known to be suboptimal. The emergence and spread of SARS-CoV-2 led to a global health crisis. This study aimed at assessing the impact of the COVID-19 pandemic on the tendency of the general adult population residing in Lebanon to vaccinate against influenza. A quantitative cross-sectional study was conducted between November and December 2020 using a structured questionnaire passed on 1055 individuals to determine factors influencing vaccination habits prior to and during the COVID-19 pandemic. The factors were analyzed using univariate, bivariate, and multivariate analyses. The majority (69.7%) of the study participants never received the influenza vaccine within the last 5 years, 20% vaccinated occasionally, and only 10.3% were yearly vaccinated. Among individuals who never got the influenza vaccine within the last 5 years, 20.7% reported their willingness to vaccinate this winter significantly increasing the vaccination percentage. Participants concerned about the COVID-19 pandemic showed an enhanced willingness to vaccinate against both. Influenza and COVID-19 vaccination rates, nevertheless, are still considerably lower than the recommended coverage. The COVID-19 pandemic caused a significant increase in the tendency to vaccinate against influenza. Yet, urgent vaccination strategies should be implemented to boost vaccine uptake across all demographics to consequently diminish the burden conflicted by influenza, COVID-19, and ultimately other infectious diseases.
Human liver organoid derived intra-hepatic bile duct cells support SARS-CoV-2 infection and replication and its comparison with SARS-CoV
Authors: Lui Vincent Chi-Hang , Hui Kenrie Pui-Yan , Babu Rosanna Ottakandathil , Yue Haibing , Chung Patrick Ho-Yu , Tam Paul Kwong-Hang , Chan Michael Chi-Wai , Wong Kenneth Kak-Yuen
Published: February 2021

Background

Although the main route of infection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the respiratory tract, liver injury is also commonly seen in many patients, as evidenced by deranged parenchymal liver enzymes. Furthermore, patients with severe liver disease have been shown to have higher mortality. Overall, the mechanism behind the liver injury remains unclear.

Approach and results

We showed that intra-hepatic bile duct cells could be grown using a human liver organoid platform. The cholangiocytes were not only susceptible to SARS-CoV-2 infection, they also supported efficient viral replication. We also showed that SARS-CoV-2 replication was much higher than SARS-CoV.

Conclusion

Our findings suggested direct cytopathic viral damage being a mechanism for SARS-CoV-2 liver injury.
Anti-nuclear matrix protein 2 antibody-positive idiopathic inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash
Authors: Ichimura Yuki , Shobo Miwako , Inoue Sae , Okune Mari , Maeda Akemi , Tanaka Ryota , Kubota Noriko , Matsumoto Isao , Ishii Akiko , Tamaoka Akira , Shimbo Asami , Mori Masaaki , Morio Tomohiro , Kishi Takayuki , Miyamae Takako , Tanboon Jantima , Inoue Michio , Nishino Ichizo , Fujimoto Manabu , Nomura Toshifumi , Okiyama Naoko
Published: February 2021

Objective

Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous edema, and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail.

Methods

This multi-center retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs.

Results

The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash and Gottron sign/papules); this was more common in the adults than children (48.9% vs. 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous edema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4).

Conclusion

Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.
A participatory modelling approach for investigating the spread of COVID-19 in countries of the Eastern Mediterranean Region to support public health decision-making
Authors: Adib Keyrellous , Hancock Penelope A. , Rahimli Aysel , Mugisa Bridget , Abdulrazeq Fayez , Farag Noha , Aguas Ricardo , White Lisa , Hajjeh Rana , Ariqi Lubna Al , Nabeth Pierre
Published: February 2021

Early on in the COVID-19 pandemic, the WHO Eastern Mediterranean Regional Office (WHO EMRO) recognised the importance of epidemiological modelling to forecast the progression of the COVID-19 pandemic to support decisions guiding the implementation of response measures. We established a modelling support team to facilitate the application of epidemiological modelling analyses in the Eastern Mediterranean Region (EMR) countries. Here we present an innovative, stepwise approach to participatory modelling of the COVID-19 pandemic that engaged decision-makers and public health professionals from countries throughout all stages of the modelling process. Our approach consisted of first identifying the relevant policy questions, collecting country-specific data, and interpreting model findings from a decision-maker’s perspective, as well as communicating model uncertainty. We used a simple modelling methodology that was adaptable to the shortage of epidemiological data, and the limited modelling capacity, in our region. We discuss the benefits of using models to produce rapid decision-making guidance for COVID-19 control in the WHO Eastern Mediterranean Region (EMR), as well as challenges that we have experienced regarding conveying uncertainty associated with model results, synthesizing and comparing results across multiple modelling approaches, and modelling fragile and conflict-affected states.
Shared genetic aetiology between childhood intelligence and longevity
Authors: Hill W. David , Deary Ian J.
Published: February 2021

Background

Intelligence and longevity are phenotypically and genetically correlated. Whereas molecular genetic data has been used to show that adult intelligence is genetically correlated with longevity, no such analysis has examined the association between childhood intelligence and longevity.

Method and Results

Using genome wide association study data on childhood intelligence (n = 12,441) and on parental longevity (n = 389,166) we found a positive genetic correlation of rg = 0.35 (SE = 0.14, P = 0.01) between childhood intelligence and parental longevity.

Conclusion

These results add to the weight of evidence that the phenotypic link between childhood intelligence and longevity is, partly, accounted for by shared genetic aetiology.
A robust phenomenological approach to investigate COVID-19 data for France
Authors: Griette Q. , Demongeot J. , Magal P.
Published: February 2021

We provide a new method to analyze the COVID-19 cumulative reported cases data based on a two-step process: first we regularize the data by using a phenomenological model which takes into account the endemic or epidemic nature of the time period, then we use a mathematical model which reproduces the epidemic exactly. This allows us to derive new information on the epidemic parameters and to compute the effective basic reproductive ratio on a daily basis. Our method has the advantage of identifying robust trends in the number of new infectious cases and produces an extremely smooth reconstruction of the epidemic. The number of parameters required by the method is parsimonious: for the French epidemic between February 2020 and January 2021 we use only 11 parameters in total.
Identification of high-risk COVID-19 patients using machine learning
Authors: Quiroz-Juárez Mario A. , Torres-Gómez Armando , Hoyo-Ulloa Irma , León-Montiel Roberto de J. , U’Ren Alfred B.
Published: February 2021

The current COVID-19 public health crisis, caused by SARSCoV-2 (severe acute respiratory syndrome coronavirus 2), has produced a devastating toll both in terms of human life loss and economic disruption. In this paper we present a machine-learning algorithm capable of identifying whether a given patient (actually infected or suspected to be infected) is more likely to survive than to die, or vice-versa. We train this algorithm with historical data, including medical history, demographic data, as well as COVID-19-related information. This is extracted from a database of confirmed and suspected COVID-19 infections in Mexico, constituting the official COVID-19 data compiled and made publicly available by the Mexican Federal Government. We demonstrate that the proposed method can detect high-risk patients with high accuracy, in each of four identified treatment stages, thus improving hospital capacity planning and timely treatment. Furthermore, we show that our method can be extended to provide optimal estimators for hypothesis-testing techniques commonly-used in biological and medical statistics. We believe that our work could be of use in the context of the current pandemic in assisting medical professionals with real-time assessments so as to determine health care priorities.
County-Specific, Real-Time Projection of the Effect of Business Closures on the COVID-19 Pandemic
Authors: Yurk Dominic , Abu-Mostafa Yaser
Published: February 2021

Abstract

Public health policies such as business closures have been one of our most effective tools in slowing the spread of COVID-19, but they also impose costs. This has created demand from policy makers for models which can predict when and where such policies will be most effective to head off a surge and where they could safely be loosened. No current model combines data-driven, real-time policy effect predictions with county-level granularity. We present a neural net-based model for predicting the effect of business closures or re-openings on the COVID-19 time-varying reproduction number Rt in real time for every county in California. When trained on data from May through September the model accurately captured relative county dynamics during the October/November California COVID-19 surge (r2 = 0.76), indicating robust out-of-sample performance. To showcase the model’s potential utility we present a case study of various counties in mid-October. Even when counties imposed similar restrictions at the time, our model successfully distinguished counties in need of drastic and immediate action to head off a surge from counties in less dire need of intervention. While this study focuses on business closures in California, the presented model architecture could be applied to other policies around world.
Early introductions and community transmission of SARS-CoV-2 variant B.1.1.7 in the United States
Authors: Alpert Tara , Brito Anderson F. , Lasek-Nesselquist Erica , Rothman Jessica , Valesano Andrew L. , MacKay Matthew J. , Petrone Mary E. , Breban Mallery I. , Watkins Anne E. , Vogels Chantal B.F. , Kalinich Chaney C. , Dellicour Simon , Russell Alexis , Kelly John P. , Shudt Matthew , Plitnick Jonathan , Schneider Erasmus , Fitzsimmons William J. , Khullar Gaurav , Metti Jessica , Dudley Joel T. , Nash Megan , Beaubier Nike , Wang Jianhui , Liu Chen , Hui Pei , Muyombwe Anthony , Downing Randy , Razeq Jafar , Bart Stephen M. , Grills Ardath , Morrison Stephanie M. , Murphy Steven , Neal Caleb , Laszlo Eva , Rennert Hanna , Cushing Melissa , Westblade Lars , Velu Priya , Craney Arryn , Fauntleroy Kathy A. , Peaper David R. , Landry Marie L. , Cook Peter W. , Fauver Joseph R. , Mason Christopher E. , Lauring Adam S. , George Kirsten St. , MacCannell Duncan R. , Grubaugh Nathan D.
Published: February 2021

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2500 COVID-19 cases associated with this variant have been detected in the US since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight the primary ports of entry for B.1.1.7 in the US and locations of possible underreporting of B.1.1.7 cases. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.
A Convex Optimization Solution for the Effective Reproduction NumberRt
Authors: Salas Joaquín
Published: February 2021

COVID-19 is a global infectious disease that has affected millions of people. With new variants emerging with augmented transmission rates, slowing down of vaccine rollouts, and rising new cases threatening sanitary capabilities to the brink of collapse, there is the need to continue studying more effective forms to track its spread. This paper presents a strategy to compute the effective reproduction numberRt. Our method starts with a form of the renewal equation of the birth process specially suitable to computeRt. After showing that one can express it as a linear system, we proceed to solve it, along with appropriate constraints, using convex optimization. We demonstrate the method’s effectiveness using synthetic and real sequences of infections and comparing it with a leading approach.
Virus transmission by ultrasonic scaler and its prevention by antiviral agent
Authors: Fidler Aleš , Steyer Andrej , Gašperšič Rok
Published: February 2021

During an ultrasonic scaler (USS) operation, droplets and aerosol are generated that may contribute to the transmission of viruses contained in saliva and gingival crevicular fluid. The purpose of this research was to develop an experimental model for testing the spread of viruses during USS instrumentation and to examining the prevention of spreading by replacing the coolant with an antiviral agent. In a virus transmission tunnel, USS operation with saline coolant and delivery of a viral suspension to the vicinity of USS tip generated droplets and aerosol containing Equine Arteritis Virus (EAV). Evaluation of droplet transmission was evaluated with adherent 48h cell culture monolayer RK13 cell lines in standard 48-well-plates positioned at a distance from 30 to 55 cm. The aerosol was collected by a cyclone aero-sampler flow of 100l/min. Antiviral activity of 0.25% sodium hypochlorite or electrolyzed water (EOW) was tested by suspension test. The two tested antiviral agents’ transmission prevention ability was evaluated by repeating the same experiment as with saline coolant. All experiments were repeated twice. With saline coolant, the cytopathic effect on cells was found in cells up to the distance of 45 cm, with the number of infected wells decreasing with distance. Viral particles were detected in only one AS in a very low concentration (≤4.2 TCID50/ml). In suspension test of 0.25% NaOCl and EOW, the TCID50/ml was below detection limit after 5s. With both antiviral agents, no cytopathic effect was found. However, the cytotoxic effect of 0.25% NaOCl was evident up to the distance of 35 cm. By USS activity, EAV could be transmitted by droplets up to a distance of 45 cm. Both antiviral agents could prevent virus droplet transmission. The transmission of EAV by aerosol yielded inconclusive results.
Latrophilin GPCR Signaling Mediates Synapse Formation
Authors: Sando Richard , Südhof Thomas C.
Published: February 2021

Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neuronsin vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.
Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis
Authors: Tasneen Rokeya , Mortensen Deborah S. , Converse Paul J. , Urbanowski Michael E. , Upton Anna , Fotouhi Nader , Nuermberger Eric , Hawryluk Natalie
Published: February 2021

Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. BecauseMycobacterium tuberculosismodulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-treated mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.
Plasma pharmacokinetics of high dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial
Authors: Wasserman Sean , Davis Angharad , Stek Cari , Chirehwa Maxwell , Botha Stephani , Daroowala Remy , Bremer Marise , Maxebengula Mpumi , Koekemoer Sonya , Goliath Rene , Jackson Amanda , Crede Thomas , Naude Jonathan , Szymanski Patryk , Vallie Yakoob , Moosa Muhammed S , Wiesner Lubbe , Black John , Meintjes Graeme , Maartens Gary , Wilkinson Robert J
Published: February 2021

Background

Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.

Materials and methods

We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).

Results

Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; IV, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 −253). Geometric mean AUC0-∞ was 47.7 µg·h/mL (90% CI, 33.2 – 68.5) for standard dose; 322.3 µg·h/mL (90% CI,234.6 – 442.7) for high dose; and 214.6 µg·h/mL (90% CI, 176.2 – 261.2) for intravenous. High dose oral dosing achieved higher rifampicin exposure than intravenous: AUC0-∞ GMR 0.67 (90% CI, 0.46 −1.0); however, Cmax GMR was 1.11 (90% CI, 0.81 – 1.59), suggesting equivalence.

Conclusions

Plasma rifampicin exposure was similar with high dose oral and intravenous administration. Findings support oral rifampicin dosing in future tuberculous meningitis trials.
A Method for Machine Learning Generation of Realistic Synthetic Datasets for Validating Healthcare Applications
Authors: Arvanitis Theodoros N. , White Sean , Harrison Stuart , Chaplin Rupert , Despotou George
Published: February 2021

Background

Digital health applications can improve quality and effectiveness of healthcare, by offering a number of tools to patients, professionals, and the healthcare system. Introduction of new technologies is not without risk, and digital health applications are often considered a medical device. Assuring their safe operation requires, amongst others, clinical validation, which needs large datasets to test their application in realistic clinical scenarios. Access to such datasets is challenging, due to concerns about patient privacy. Development of synthetic datasets, which will be sufficiently realistic to test digital applications, is seen as a potential alternative, enabling their deployment.

Objective

The aim of work was to develop a method for the generation of realistic synthetic datasets, statistically equivalent to real clinical datasets, and demonstrate that Generative Adversarial Network based approach is fit for purpose.

Method

A generative adversarial network was implemented and trained, in a series of six experiments, using numerical and categorical variables from three clinically relevant datasets, including ICD-9 and laboratory codes from the MIMIC III dataset. A number of contextual steps provided the success criteria for the synthetic dataset.

Results

The approach created a synthetic dataset that exhibits very similar statistical characteristics with the real dataset. Pairwise association of variables is very similar. A high degree of Jaccard similarity and a successful K-S test further support this.

Conclusions

The proof of concept of generating realistic synthetic datasets was successful, with the approach showing promise for further work.
Inclusion of cycle threshold (CT) values when reporting SARS-CoV-2 RT-PCR results improves clinical Interpretation in suspected and confirmed COVID-19
Authors: Coyle Peter V. , Molawi Naema Hassan Al , Kacem Mohamed Ali Ben Hadj , Kahlout Reham Awni El , Kuwari Einas Al , Khal Abdullatif Al , Gilliani Imtiaz , Jeremijenko Andrew , Saeb Hatoun , Thani Sheikh Mohammad Al , Bertollini Roberto , Rahim Hanan F. Abdul , Chemaitelly Hiam , Tang Patrick , Latif Ali Nizar , Kaabi Saad Al , AlMaslamani Muna A. Rahman S. , Morris Brendan David , Al-Ansari Nasser , Kaleeckal Anvar Hassan , Raddad Laith J. Abu
Published: February 2021

Introduction

The Cycle Threshold (CT) value in Real-time Polymerase Chain Reaction (RT-PCR) is where a target specific amplification signal becomes detectable and can infer viral load, risk of transmission and recovery in SARS-CoV-2 infections. Adoption into routine practice is however uncommon.

Gap Statement

The lack of inclusion of CT values when reporting SARS-CoV-2 RT-PCR results in routine practice.

Aim

To use CT values when reporting SARS-CoV-2 RT-PCR results in Qatar to aid clinical interpretation and patient management.

Methodology

Routine CT values across 3 different RT-PCR platforms were reviewed for concordance at presentation and clearance in patients with COVID-19. An Indicative Threshold of CT 30 based on viral clearance kinetics categorized low and high CT values.

Results

There was very high Correlation and Kappa Score agreement between the different gene targets in each platform (p<0.001). Using the Indicative Threshold it was possible to autoverify and add average CT values and append Interpretive Comments to all RT-PCR reports. The new reporting algorithm impacted immediately and safely on: physician interpretation of SARS-CoV-2 results; patient management; staff surveillance protocols; length of stay in quarantine; a redefinition of patient recovery.

Conclusion

Incorporation of CT values into routine practice is possible across different RT-PCR platforms and adds useful information for patient management. The use of an Indicative Threshold and interpretive comments improves clinical interpretation of the result and could be a model for reporting other respiratory infections. The current accepted practice of withholding CT values should be reviewed by the profession, accreditation bodies and regulators.