bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand
Authors: Yao Ming , Watanabe Masaaki , Sun Sune , Tokodai Kazuaki , Cerami Anthony , Brines Michael , Östenson Claes-Göran , Ericzon Bo-Göran , Lundgren Torbjörn , Kumagai-Braesch Makiko
Published: April 2020

Background.

During intraportal pancreatic islet transplantation (PITx), early inflammatory reactions cause an immediate loss of more than half of the transplanted graft and potentiate subsequent allograft rejection. Previous findings suggest that cibinetide, a selective innate repair receptor agonist, exerts islet protective and antiinflammatory properties and improved transplant efficacy in syngeneic mouse PITx model. In a stepwise approach toward a clinical application, we have here investigated the short- and long-term effects of cibinetide in an allogeneic mouse PITx model.

Methods.

Streptozotocin-induced diabetic C57BL/6N (H-2b) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2d) mice via the portal vein. Recipients were treated perioperative and thereafter daily during 14 d with cibinetide (120 µg/kg), with or without tacrolimus injection (0.4 mg/kg/d) during days 4–14 after transplantation. Graft function was assessed using nonfasting glucose measurements. Relative gene expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by quantitative polymerase chain reaction. Cibinetide’s effects on dendritic cell maturation were investigated in vitro.

Results.

Cibinetide ameliorated the local inflammatory responses in the liver and improved glycemic control immediately after allogeneic PITx and significantly delayed the onset of allograft loss. Combination treatment with cibinetide and low-dose tacrolimus significantly improved long-term graft survival following allogeneic PITx. In vitro experiments indicated that cibinetide lowered bone-marrow-derived-immature-dendritic cell maturation and subsequently reduced allogeneic T-cell response.

Conclusions.

Cibinetide reduced the initial transplantation–related severe inflammation and delayed the subsequent alloreactivity. Cibinetide, in combination with low-dose tacrolimus, could significantly improve long-term graft survival in allogeneic PITx.
Social Inequalities in Life Expectancy and Mortality in People With Dementia in the United Kingdom
Authors: Vestergaard Anne H.S. , Sampson Elizabeth L. , Johnsen Søren P. , Petersen Irene
Published: April 2020

Introduction:

Inequalities in life expectancy and mortality by social deprivation in the general population of the United Kingdom are widening. For people with dementia, data on potential gradients in life expectancy and mortality by social deprivation are sparse. This study aimed to explore potential differentials in life expectancy and mortality in people with dementia according to social deprivation.

Methods:

Using The Health Improvement Network (THIN) primary care database, we included people with a diagnosis of dementia in the United Kingdom in 2000 to 2016 and obtained data on age at death and mortality. Comparisons were made according to social deprivation quintiles adjusting for age at diagnosis.

Results:

Among 166,268 people with dementia there were no differences in life expectancy and mortality in the most deprived compared with the least deprived. This pattern has been stable during the study period, as no increasing inequalities in life expectancy and mortality according to social deprivation were found.

Discussion:

Contrary to the general population, there were limited inequalities in life expectancy and mortality according to social deprivation for people with dementia.
Association of maternal hepatitis B virus infection with adverse pregnancy outcomes and prenatal screening result of second-trimester: a retrospective cohort study
Authors: He Quanze , Zhou You , Wu Xiaojuan , Xue Ying , Zhang Chunhua , Lu Lu , Liu Hankui , Zhang Jianguo , Dang Xiao , Wang Ting , Li Hong
Published: April 2020

Objective

The association between maternal HBV infection and adverse pregnancy outcomes remains controversial and the prenatal screening features was not investigated though they strongly indicate adverse pregnancy outcomes. We conducted a retrospective cohort study to determine the association between maternal HBV infection and adverse pregnancy outcomes and the result of prenatal screening.

Design

The information from 65,257 pregnant women who performed non-invasive prenatal screening (NIPS) in second-trimester from July 2015 to Nov 2019 in Suzhou, China were collected. The participants were divided into the group of “control” (n = 63,591) and “exposure” (n = 1,666). Meanwhile, eight types of adverse pregnancy outcomes in history and twelve prenatal screening results in the second-trimester of current pregnancy were investigated by estimating and adjusting their risk ratios (aRR) for women between HBV infected and uninfected using multivariate logic regression.

Result

Our results suggested that women infected with HBV have higher risks on the biochemical pregnancy, extrauterine pregnancy and three kinds of screen result for fetal Down’s syndrome (DS) than women with HBV un-infected. Meanwhile, the diagnostic result for the positive result of fetal Down syndrome in NIPS suggested the 98% additional risk in women with HBV infected than uninfected and supported by all adjusted models.

Conclusion

Taken together, maternal HBV infection is an independent risk factor of biochemical pregnancy, extrauterine pregnancy, and fetal Down’s syndrome. It also indicates the influence of maternal HBV infection way across all gestation.
A follow-up study of children infected with SARS-CoV-2 from Western China
Authors: Xu Hongmei , Liu Enmei , Xie Jun , Smyth Rosalind , Zhou Qi , Zhao Ruiqiu , Zang Na , Long Xiaoru , Tang Yuyi , Estill Janne , Yang Shu , Zhu Jing , Yan Xiaofeng , Gong Fang , Tian Wenguang , Zhou Xiaqia , Mo Yunbo , Xiao Hongzhou , Tang Zhengzhen , Chen Yanni , Wang Yi , Cui Yuxia , Fang Xiuling , Li Feiyu , Tian Yong , Li Peibo , Deng Quanmin , Ren Chongsong , He Ronghui , Li Yi , Qin Hong , Wang Aiguo , Deng Hongli , Wu Jianguo , Meng Wenbo , Li Weiguo , Zhao Yao , Luo Zhengxiu , Wang Zijun , Chen Yaolong , Wong Gary , Li Qiu
Published: April 2020

Background

To clarify the characteristic and the duration of positive nucleic acid in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including asymptomatic children.

Methods

A total of 32 children confirmed with SARS-CoV-2 infection between January 24 and February 12, 2020 from four provinces in Western China were enrolled in this study and followed up until discharge and quarantine 14 days later.

Results

Eleven children (34%) were asymptomatic, among whom six children had normal computed tomographic (CT) scan images. Age and gender were not associated with clinical symptoms or the results of CT scan in children infected with SARS-CoV-2. The concentrations of white blood cells and neutrophils were higher in children with asymptomatic infection than in children with clinical symptoms or CT abnormalities. Patients who presented with CT abnormalities had lower D-dimer or lower total bilirubin than those who had normal CT scan but clinical symptoms. All children recovered and no one died or was admitted to the pediatric intensive care unit (PICU). The mean duration of positive SARS-CoV-2 nucleic acid was 15.4 (SD=7.2) days and similar for both asymptomatic children and children with symptoms or CT abnormalities. We found a significant negative correlation between the lymphocyte count and the duration of positive nucleic acid test.

Conclusions

Children with asymptomatic infection should be quarantined for the same duration as symptomatic patients infected with SARS-CoV-2. The clinical significance and mechanism behind the negative correlation between the number of lymphocytes and the duration of positive SARS-CoV-2 needs further study.
The impact of changes in diagnostic testing practices on estimates of COVID-19 transmission in the United States
Authors: Pitzer Virginia E. , Chitwood Melanie , Havumaki Joshua , Menzies Nicolas A. , Perniciaro Stephanie , Warren Joshua L. , Weinberger Daniel M. , Cohen Ted
Published: April 2020

Estimates of the reproductive number for novel pathogens such as SARS-CoV-2 are essential for understanding the potential trajectory of the epidemic and the level of intervention that is needed to bring the epidemic under control. However, most methods for estimating the basic reproductive number (R0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explore the impact of secular changes in diagnostic testing and reporting on estimates ofR0andRtusing simulated data. We then compare these patterns to data on reported cases of COVID-19 and testing practices from different United States (US) states. We find that changes in testing practices and delays in reporting can result in biased estimates ofR0andRt. Examination of changes in the daily number of tests conducted and the percent of patients testing positive may be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of COVID-19.
A web-based Diagnostic Tool for COVID-19 Using Machine Learning on Chest Radiographs (CXR)
Authors: Kana E.B. Gueguim , Kana M.G. Zebaze , Kana A.F. Donfack , Kenfack R.H Azanfack
Published: April 2020

This paper reports the development and web deployment of an inference model for Coronavirus COVID-19 using machine vision on chest radiographs (CXR). The transfer learning from the Residual Network (RESNET-50) was leveraged for model development on CXR images from healthy individuals, bacterial and viral pneumonia, and COVID-19 positives patients. The performance metrics showed an accuracy of 99%, a recall valued of 99.8%, a precision of 99% and an F1 score of 99.8% for COVID-19 inference. The model was further successfully validated on CXR images from an independent repository. The implemented model was deployed with a web graphical user interface for inference (https://medics-inference.onrender.com) for the medical research community; an associated cron job is scheduled to continue the learning process when novel and validated information becomes available.
Conspiracy beliefs are associated with lower knowledge and higher anxiety levels regarding COVID-19 among students at the University of Jordan
Authors: Sallam Malik , Dababseh Deema , Yaseen Alaa’ , Al-Haidar Ayat , Ababneh Nidaa A. , Bakri Faris G. , Mahafzah Azmi
Published: April 2020

Background

The world has been afflicted heavily by the burden of coronavirus disease 2019 (COVID-19) that overwhelmed health care systems and caused severe economic and educational deficits, in addition to anxiety among the public. The main aim of this study was to evaluate the mutual effects of belief that the pandemic was the result of a global conspiracy on knowledge and anxiety levels among students at the University of Jordan (UJ).

Methods

An electronic-based survey was conducted between March 29th 2020 and March 31st 2020. The targeted population involved all undergraduate and postgraduate students from Health, Scientific and Humanities Schools at UJ. Survey sections included 26 items on: socio-demographic information, knowledge and sources of information about the disease, attitude towards the false notion that COVID-19 stemmed from a global conspiracy and items to assess the anxiety level among students during the quarantine period.

Results

The total number of participants was 1540 students. The majority of participants perceived the disease as moderately dangerous (n=1079, 70.1%), with males, Jordanians and participants with lower income being more inclined to feel that the disease is very dangerous (p<0.001, 0.020, and <0.001, respectively). Lower level of knowledge and higher level of anxiety about COVID-19 were associated with the belief that the disease is part of a global conspiracy (p<0.001 and p=0.004, respectively). Females and participants with lower income were more likely to believe that the disease is related to conspiracy (p=0.001 and p<0.001, respectively). Belief in global conspiracy regarding the origin of COVID-19 was associated with misinformation about the availability of vaccine and the therapeutic use of antibiotics for COVID-19 treatment (p=0.001 and p<0.001, respectively). Ministry of Health in Jordan was the most common source of information about COVID-19 reported by the participants (n=1018).

Conclusions

The false belief that COVID-19 was the result of a global conspiracy could be the consequence of lower level of knowledge about the virus and could lead to higher level of anxiety, which should be considered in the awareness tools of various media platforms about the current pandemic.
High prevalence of putative invasive pulmonary aspergillosis in critically ill COVID-19 patients
Authors: Alanio Alexandre , Dellière Sarah , Fodil Sofiane , Bretagne Stéphane , Mégarbane Bruno
Published: April 2020

We are currently facing a frightening increase in COVID-19 patients admitted to the ICU. Aiming at screening for fungal secondary pneumonia, we collected the data of our first 27 ICU patients, who underwent bronchoalveolar lavage or bronchial aspirates. We classified the patients based on the recently published study on invasive aspergillosis in influenza patients (Schauwvlinghe et al., 2018.) and found 33% of our COVID-19 patients with putative invasive pulmonary aspergillosis. Observing such a high prevalence in COVID-infected patients was somehow unexpected since the 30% prevalence of invasive aspergillosis in influenza patients has been attributed to the action of oseltamivir on anti-Aspergillus immunity. Almost all critically ill COVID-19 patients develop ARDS and are likely to receive high-dose steroids or immunomodulatory therapies to prevent worsening as suggested by reports from China. In the COVID-19 patients with putative invasive aspergillosis, antifungal prophylactic therapy may be questioned to avoid increased lung inflammation that may compromise the outcome. This issue remains to be addressed in future clinical trials. We are strongly convinced that testing deep lung specimens for Aspergillus in severe COVID-19 patients should be recommended.
No Clear Benefit to the Use of Corticosteroid as Treatment in Adult Patients with Coronavirus Disease 2019 : A Retrospective Cohort Study
Authors: Wang Dan , Wang Juan , Jiang Qunqun , Yang Juan , Li Jun , Gao Chang , Jiang Haiwei , Ge Lintong , Liu Yongming
Published: April 2020

Background

Coronavirus disease 2019 (COVID-19) is becoming an increasing global health issue which has spread across the globe. We aimed to study the effect of corticosteroids in the treatment of adult inpatients with COVID-19.

Methods

A retrospective cohort of 115 consecutive adult COVID-19 patients admitted to The Third People’s Hospital of Hubei Province between Jan 18, 2020, and Feb 28, 2020 was analysed to study the effectiveness of corticosteroid. They were categorized according to whether or not corticosteroid therapy was given, and compared in terms of demographic characteristics, clinical features, laboratory indicators and clinical outcomes. The primary endpoint was defined as either mortality or intensive care unit (ICU) admission. Known adverse prognostic factors were used as covariates in multiple logistic regressions to adjust for their confounding effects on outcomes.

Results

Among 115 patients, 73 patients (63.5%) received corticosteroid. The levels of age, C-reactive protein, D-dimer and albumin were similar in both groups. The corticosteroid group had more adverse outcomes (32.9% vs. 11.9%) and statistically significant differences were observed (p=0.013). In multivariate analysis, corticosteroid treatment was associated with a 2.155-fold increase in risk of either mortality or ICU admission, although not statistically significant.

Conclusion

No evidence suggests that adult patients with COVID-19 will benefit from corticosteroids, and they might be more likely to be harmed with such treatment.
Prognostic significance of compound combined peri-operative biomarkers in gastric cancer
Authors: Powell Arfon , Coxon Alexandra , Robinson David , James Osian , Christian Adam , Roberts Ashley , Lewis Wyn
Published: April 2020

Background

Survival after gastric cancer surgery is largely attributed to tumor biology, neoadjuvant chemotherapy (NAC), and surgical approach, yet other prognostic factors have been reported, including pre-operative systemic inflammatory response (SIR), and Morbidity Severity Score (MSS). The hypothesis tested was that a SIR, MMS, and pathological composite score, would be associated with disease-free (DFS) and overall survival (OS).

Methods

Consecutive 358 patients undergoing potentially curative gastrectomy for adenocarcinoma were studied. Complications were defined as a MSS of Clavien-Dindo classification (CDSC) >1. Serum SIR measurements were performed on the day before surgery, and a composite score (CIMpN) (0-3) was developed based on CRP, morbidity, and pN-stage. Primary outcome measures were DFS and OS.

Results

Post-operative complications occurred in 138 (38.5%) patients, (8 (2.2%) deaths), and was associated with higher CRP (28.3% vs. 15.5%, p=0.003), vascular invasion (55.8% vs. 36.8%, p<0.001), and R1 status (26.1% vs. 9.5%, p=0.001). Five-year DFS and OS were 32.9% and 33.3% for patients with post-operative complications compared with 62.5% and 64.0% in controls (p<0.001). Five-year DFS and OS were 31.4% and 37.3% in patients with raised CRPs compared with 58.5% and 59.5% in controls (p=0.005, p=0.001, respectively). Five-year DFS for CIMpN scores of 0, 1, 2, and 3 were 85.9%, 50.0%, 26.2%, and 15.4% (p<0.001) respectively. On multivariable analysis CIMpN score was independently associated with DFS [HR 3.00, 95% Confidence Interval (CI) 1.90-4.73, p<0.001] and OS [1.93 (1.43-2.59), p<0.001].

Conclusion

A novel composite score, CIMpN, based on SIR, MSS and pN-stage, offers important prognostic signals.
Risk assessment of drug-induced Long QT Syndrome for some COVID-19 repurposed drugs
Authors: Michaud Veronique , Dow Pamela , Al Rihani Sweilem B. , Deodhar Malavika , Arwood Meghan , Cicali Brian , Turgeon Jacques
Published: April 2020

The risk-benefit ratio associated with the use of repurposed drugs to treat 2019 SARS-CoV-2 related infectious disease (COVID-19) is complicated since benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID-19. A risk assessment of drug-induced Long QT Syndrome (LQTS) associated with COVID-19 repurposed drugs was performed and compared to 23 well-known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID-19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.
Association of infected probability of COVID-19 with ventilation rates in confined spaces: a Wells-Riley equation based investigation
Authors: Dai Hui , Zhao Bin
Published: April 2020

Background

A growing number of epidemiological cases are proving the possibility of airborne transmission of coronavirus disease 2019 (COVID-19). Ensuring adequate ventilation rate is essential to reduce the risk of infection in confined spaces.

Methods

We obtained the quantum generation rate by a COVID-19 infector with a reproductive number based fitting approach, and then estimated the association between infected probability and ventilation rate with the Wells-Riley equation.

Results

The estimated quantum generation rate of COVID-19 is 14-48 /h. To ensure infected probabolity less than 1%, ventilation rate lareger than common values (100-350 m3/h and 1200-4000 m3/h for 15 minutes and 3 hours exposure, respectively) is required. If both the infector and susceptibles wear masks, the ventilation rate ensuring less than 1% infected probability is reduced to 50-180 m3/h and 600-2000 m3/h correspondingly, which is easier to be achieved by normal ventilation mode applied in some typical scenarios, including offices, classrooms, buses and aircraft cabins.

Interpretation

The risk of potential airborne transmission in confined spaces cannot be ignored. Strict preventive measures that have been widely adopted should be effective in reducing the risk of airborne transmitted infection.
The effect of short-graft preparation with tape suspension and screw fixation on loss of knee extension following anterior cruciate ligament reconstruction: A retrospective cross-sectional analysis of public hospital cases from 2015 - 2017
Authors: Bell Christopher , Scholes Corey , Jegatheesan Maha , Tuckerman Kirby
Published: April 2020

Introduction

The short graft with tape suspension (SGTS) is a technique for ACL reconstruction that has gained popularity in recent years. Though the construct utilises a hamstring tendon, its biomechanical properties more closely resemble a stiffer graft such as bone-patella-bone. Due to these properties, there are concerns this technique may increase the likelihood of postoperative loss of extension (LOE), particularly if the surgeon does not modify their tensioning technique. This study compared LOE in patients undergoing ACLR with the SGTS technique, versus other ACLR techniques. We hypothesised that with appropriate technique modifications, the SGTS technique would not be inferior to long hamstring graft techniques with respect to LOE observed clinically during supervised rehabilitation.

Materials and Methods

We retrospectively reviewed 138 patients who received primary ACLR at one of two hospitals between January 2015 and December 2017 and elected to participate in a rehabilitation program with the hospital physiotherapy department. Postoperative knee extension was assessed by a department physiotherapist until satisfactory function was achieved. Patients were classified as SGTS ACLR or non-SGTS ACLR during chart review and LOE compared at initial assessment and at the time of maximum extension, via a noninferiority analysis.

Results

The grafts for the SGTS group (N=44) were significantly larger in diameter (median 8.5mm vs. 8.0mm, P <0.001) and less incidence of notchplasties (17.8% vs. 44.7%, P <0.001) compared with the non-SGTS group (N=94). The upper 95% confidence interval for the difference in proportions between groups did not exceed the non-inferiority margin (0.3 or 30%) at either Initial or Maximum timepoints.

Conclusions

The SGTS technique was not inferior to other hamstring-graft ACLR techniques with respect to postoperative LOE. Surgeons using or considering using the SGTS construct can rule out increased incidence of LOE as a factor in their decision-making, providing the grafts are prepared according to existing guidance and tensioned in full extension. Further studies are recommended to assess longer term functional outcomes and ultimately treatment success.
COVID-19 epidemic in Sri Lanka: A mathematical and computational modelling approach to control
Authors: Wickramaarachchi WPTM , Perera SSN , Jayasignhe S
Published: April 2020

The ongoing COVID19 outbreak originated in the city of Wuhan, China has caused a significant damage to the world population and the global economy. It has claimed more than 50,000 lives worldwide and more than one million of people have been infected as of 04th April 2020.

In Sri Lanka, the first case of COVI19 was reported late January 2020 was a Chinese national and the first local case was identified in the second week of March. Since then, the government of Sri Lanka introduced various sequential measures to improve social distancing such as closure of schools and education institutes, introducing work from home model to reduce the public gathering, introducing travel bans to international arrivals and more drastically, imposed island wide curfew expecting to minimize the burden of the disease to the Sri Lankan health system and the entire community. Currently, there are 159 cases with five fatalities and also reported that 24 patients are recovered and discharged from hospitals.

In this study, we use the SEIR conceptual model and its modified version by decomposing infected patients into two classes; patients who show mild symptoms and patients who tend to face severe respiratory problems and are required to treat in intensive care units. We numerically simulate the models for about five months period considering three critical parameters of COVID transmission mainly in the Sri Lankan context; efficacy of control measures, rate of overseas imported cases and time to introduce social distancing measures by the respective authorities.
Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
Authors: Hathazi Denisa , Griffin Helen , Jennings Matthew J. , Giunta Michele , Powell Christopher , Pearce Sarah F. , Munro Benjamin , Wei Wei , Boczonadi Veronika , Poulton Joanna , Pyle Angela , Calabrese Claudia , Gomez-Duran Aurora , Schara Ulrike , Pitceathly Robert D.S. , Hanna Michael G. , Joost Kairit , Cotta Ana , Paim Julia Filardi , Navarro Monica Machado , Duff Jennifer , Mattmann Andre , Chapman Kristine , Servidei Serenella , Uusimaa Johanna , Roos Andreas , Mootha Vamsi , Hirano Michio , Tulinius Mar , Giri Manta , Hoffmann Eric P. , Lochmüller Hanns , DiMauro Salvatore , Minczuk Michal , Chinnery Patrick F. , Müller Juliane S. , Horvath Rita
Published: April 2020

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6 months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation, however only ∼1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGluincludingEARS2andTRMUin the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. The spontaneous recovery in infants with digenic mutations is modulated by changes in amino acid availability in a multi-step process. First, the integrated stress-response associated with increasedFGF21andGDF15expression enhances catabolism via β-oxidation and the TCA cycle increasing the availability of amino acids. In the second phase mitochondrial biogenesis increases via mTOR activation, leading to improved mitochondrial translation and recovery. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
Collateral damage: the impact on cancer outcomes of the COVID-19 pandemic
Authors: Sud Amit , Jones Michael , Broggio John , Loveday Chey , Torr Bethany , Garrett Alice , Nicol David L. , Jhanji Shaman , Boyce Stephen A. , Ward Phillip , Handy Jonathan M. , Yousaf Nadia , Larkin James , Suh Yae-Eun , Scott Stephen , Pharoah Paul D.P. , Swanton Charles , Abbosh Christopher , Williams Matthew , Lyratzopoulos Georgios , Houlston Richard , Turnbull Clare
Published: April 2020

Background

Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival.

Methods

We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations.

Findings

Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of six months would cause attributable death of 10,555 of these individuals with loss of 205,024 life years. For cancer surgery, average life years gained (LYGs) per patient are 18·1 under standard conditions and 15·9 with a delay of six months (a loss of 2·3 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2·25 resource-adjusted life years gained (RALYGs) under standard conditions and 1·98 RALYGs following delay of six months. For 94,912 hospital COVID-19 admissions, there are 474,505 LYGs requiring of 1,097,937 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5·0 LYG and 0·43 RALYGs.

Interpretation

Delay of six months in surgery for incident cancers would mitigate 43% of life years gained by hospitalisation of an equivalent volume of admissions for community acquired COVID-19. This rises to 62% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued.

Funding

Breast Cancer Now, Cancer Research UK, Bobby Moore Fund for Cancer Research, National Institute for Health Research (NIHR)
Biased and unbiased estimation of the average length of stay in intensive care units in the COVID-19 pandemic
Authors: Lapidus Nathanael , Zhou Xianlong , Carrat Fabrice , Riou Bruno , Zhao Yan , Hejblum Gilles
Published: April 2020

Background

The average length of stay (LOS) in the intensive care unit (ICU_ALOS) is a helpful parameter summarizing critical bed occupancy. During the outbreak of a novel virus, estimating early a reliable ICU_ALOS estimate of infected patients is critical to accurately parameterize models examining mitigation and preparedness scenarios.

Methods

Two estimation methods of ICU ALOS were compared: the average LOS of already discharged patients at the date of estimation (DPE), and a standard parametric method used for analyzing time-to-event data which fits a given distribution to observed data and includes the censored stays of patients still treated in the ICU at the date of estimation (CPE). Methods were compared on a series of all COVID-19 consecutive cases (n=59) admitted in an ICU devoted to such patients. At the last follow-up date, 99 days after the first admission, all patients but one had been discharged. A simulation study investigated the generalizability of the methods’ patterns. CPE and DPE estimates were also compared to COVID-19 estimates reported to date.

Findings

LOS ≥ 30 days concerned 14 out of the 59 patients (24%), including 8 of the 21 deaths observed. Two months after the first admission, 38 (64%) patients had been discharged, with corresponding DPE and CPE estimates of ICU_ALOS (95%CI) at 13.0 days (10.4–15.6) and 23.1 days (18.1–29.7), respectively. Series’ true ICU_ALOS was greater than 21 days, well above reported estimates to date.

Interpretation

Discharges of short stays are more likely observed earlier during the course of an outbreak. Cautious unbiased ICU_ALOS estimates suggest parameterizing a higher burden of ICU bed occupancy than that adopted to date in COVID-19 forecasting models.

Funding

Support by the National Natural Science Foundation of China (81900097 to Dr. Zhou) and the Emergency Response Project of Hubei Science and Technology Department (2020FCA023 to Pr. Zhao).
Optimal strategies for quarantine stopping in France – General expected patterns of strategies focusing on contact between age groups
Authors: Roche Benjamin , Garchitorena Andres , Roiz David
Published: April 2020

Due to the COVID-19 pandemic, many countries have implemented a complete lockdown of their population that may not be sustainable for long. To identify the best strategy to replace this full lockdown, sophisticated models that rely on mobility data have been developed. In this study, using the example of France as a case-study, we develop a simple model considering contacts between age classes to derive the general impact of partial lockdown strategies targeted at specific age groups. We found that epidemic suppression can only be achieved by targeting isolation of young and middle age groups with high efficiency. All other strategies tested result in a flatter epidemic curve, with outcomes in (e.g. mortality and health system over-capacity) dependent of the age groups targeted and the isolation efficiency. Targeting only the elderly can decrease the expected mortality burden, but in proportions lower than more integrative strategies involving several age groups. While not aiming to provide quantitative forecasts, our study shows the benefits and constraints of different partial lockdown strategies, which could help guide decision-making.
Association between DNA Methylation Levels in Brain Tissue and Late-Life Depression in Community-Based Participants
Authors: Hüls Anke , Robins Chloe , Conneely Karen N. , Jager Philip L. De , Bennett David A. , Epstein Michael P. , Wingo Thomas S. , Wingo Aliza P.
Published: April 2020

Objective

Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.

Methods

We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC) generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately.

Results

We found epigenome-wide significant associations between brain-tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p-value=2.55 × 10−11; cg03899372, p-value=3.12 × 10−09; cg12796440, p-value=1.51 × 10−08, cg23982678, p-value=7.94 × 10−08). Analysis of differentially methylated regions (DMR, p-value=5.06 × 10−10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p-value=1.75 × 10−08), FNDC3B (cg20367479, p-value=4.97 × 10−08) and SLIT2 (cg10946669, p-value=8.01 × 10−08). Notably, brain-tissue based methylation levels were strongly associated with late-life MDD in men more than in women.

Conclusions

We identified altered methylation in the YOD1, UGT8, FNDC3B and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.
Effect of a one-month lockdown on the epidemic dynamics of COVID-19 in France
Authors: Roques Lionel , Klein Etienne , Papaïx Julien , Sar Antoine , Soubeyrand Samuel
Published: April 2020

The COVID-19 epidemic started in the Hubei province in China in December 2019 and then spread around the world reaching the pandemic stage at the beginning of March 2020. Since then, several countries went into lockdown. We estimate the effect of the lockdown in France on the contact rate and the effective reproduction number Re of the COVID-19. We obtain a reduction by a factor 7 (Re = 0.47, 95%-CI: 0.45-0.50), compared to the estimates carried out in France at the early stage of the epidemic. We also estimate the fraction of the population that would be infected by the beginning of May, at the official date at which the lockdown should be relaxed. We find a fraction of 3.7% (95%-CI: 3.0-4.8%) of the total French population, without taking into account the number of recovered individuals before April 1st, which is not known. This proportion is seemingly too low to reach herd immunity. Thus, even if the lockdown strongly mitigated the first epidemic wave, keeping a low value of Re is crucial to avoid an uncontrolled second wave (initiated with much more infectious cases than the first wave) and to hence avoid the saturation of hospital facilities. Our approach is based on the mechanistic-statistical formalism, which uses a probabilistic model to connect the data collection process and the latent epidemiological process, which is described by a SIR-type differential equation model.
An Adaptive, Interacting, Cluster-Based Model Accurately Predicts the Transmission Dynamics of COVID-19
Authors: Ravinder R. , Singh Sourabh , Bishnoi Suresh , Jan Amreen , Sinha Abhinav , Sharma Amit , Kodamana Hariprasad , Krishnan N. M. Anoop
Published: April 2020

The SARS-CoV-2 driven disease, COVID-19, is presently a pandemic with increasing human and monetary costs. COVID-19 has put an unexpected and inordinate degree of pressure on healthcare systems of strong and fragile countries alike. In order to launch both containment and mitigation measures, each country requires accurate estimates of COVID-19 incidence as such preparedness allows agencies to plan efficient resource allocation and design control strategies. Here, we have developed a new adaptive, interacting, and cluster-based mathematical model to predict the granular trajectory COVID-19. We have analyzed incidence data from three currently afflicted countries of Italy, the United States of America, and India, and show that our approach predicts state-wise COVID-19 spread for each country with high accuracy. We show that R0 as the basic reproduction number exhibits significant spatial and temporal variation in these countries. However, by including a new function for temporal variation of R0 in an adaptive fashion, the predictive model provides highly reliable estimates of asymptomatic and undetected COVID-19 patients, both of which are key players in COVID-19 transmission. Our dynamic modeling approach can be applied widely and will provide a new fillip to infectious disease management strategies worldwide.
Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD
Authors: Peyre Hugo , Schoeler Tabea , Liu Chaoyu , Williams Camille Michèle , Hoertel Nicolas , Havdahl Alexandra , Pingault Jean-Baptiste
Published: April 2020

Background

Several lines of evidence point toward the presence of shared genetic factors underlying Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, Genome-Wide Association Studies (GWAS) have yet to identify risk variants (i.e. Single-Nucleotide Polymorphisms, SNPs) shared by ADHD and ASD.

Methods

Two complementary multivariate analyses – genomic structural equation modelling (SEM) and colocalization analysis – were exploited to identify the shared SNPs for ASD and ADHD, using summary data from two independent GWAS of ASD (N=46,350) and ADHD individuals (N=55,374).

Results

Genomic SEM identified 7 novel SNPs shared between ASD and ADHD (pgenome-wide<5e-8), including three SNPs that were not identified in any of the original univariate GWAS of ASD and ADHD (rs227378, rs2391769 and rs325506). We also mapped 4 novel genes (MANBA, DPYD, INSM1, and PAX1) to SNPs shared by ASD and ADHD, as well as 4 genes that had already been mapped to SNPs identified in either ASD or ADHD GWAS (SORCS3, XRN2, PTBP2 and NKX2-4). All the shared genes between ADHD and ASD were more prominently expressed in the brain than the genes mapped to SNPs specific to ASD or ADHD. Colocalization analyses revealed that 44% percent of the SNPs associated with ASD (p<1e-6) colocalized with ADHD SNPs and 26% of the SNPs associated with ADHD (p<1e-6) colocalized with ASD SNPs.

Conclusions

Using multivariate genomic analyses, the present study reveals the shared genetic pathways that underlie ASD and ADHD. Further investigation of these pathways may help identify new targets for treatment of these disorders.
Micro-community associated with ectomycorrhizalRussulasymbiosis and sporocarp-producingRussulain Fagaceae dominant nature areas in southern China
Authors: Yu Wen Ying , Peng Ming Hui , Wang Jia Jia , Ye Wen Yu , Wang Zong Hua , Lu Guo Dong , Bao Jian Dong
Published: April 2020

Russula griseocarnosa, an ectomycorrhizal (ECM) fungus, is a species of precious wild edible mushrooms with very high market value in southern China. Its yield is affected by many factors including the tree species and environmental conditions such as soil microbiome, humidity. How the microbiome promotes the ECM fungus symbiosis with Fagaceae plants and sporocarp-producing has never been studied. In this study, we collected rhizosphere samples from Fujian province, the microbiota in the root and mycorrhizal rhizosphere were identified by Illumina MiSeq high-throughput sequencing. First, we compared three types of fungal communities: root tips infected with ECMRussula(type 1), tips withRussulasporocarp (type 2) and tips without ECM (type 3). Our results showed that the fungal richness was negatively correlated withRussula. Russula, TomentellaandLactariuswere common in Fagaceae ECM roots. As to the mycorrhizal interactions,Boletus may be considered as an indicator species for sporocarp-producingRussula, andAcremonium, Cladophialophorawere associated withRussulasymbiosis. Second, we analyzed the fungal and bacterial communities in rhizosphere soils from the corresponding to previously three types (type 1, 2, 3).DacryobolusandAcidocellamay be considered as an indicator species for sporocarp-producingRussula. FungiTomentella, Saitozyma, Elaphomycesand bacteriaAcidicaldus, Bryobacter, SorangiumandAcidobacteriumoccurred more frequently in the ECMRussularhizosphere. Furthermore, the indicatorsElaphomyces, Tomentella, Sorangiumhad a positive correlation withRussulasymbiosis by network analyses. Overall, our results suggest a relationship between micro-community and ECMRussulaformation andRussulasporocarp, which may provide new strategies for improvingRussulasymbiosis rate and sporocarp production.
CT in relation to RT-PCR in diagnosing COVID-19 in the Netherlands: a prospective study
Authors: Gietema Hester A , Zelis Noortje , Nobel J. Martijn , Lambriks Lars J.G. , van Alphen Lieke B , Oude Lashof Astrid M.L. , Wildberger Joachim E , Nelissen Irene C , Stassen Patricia M
Published: April 2020

Introduction
Early differentiation between emergency department (ED) patients with and without corona virus disease (COVID-19) is very important. Chest CT scan may be helpful in early diagnosing of COVID-19. We investigated the diagnostic accuracy of CT using RT-PCR for SARS-CoV-2 as reference standard and investigated reasons for discordant results between the two tests.

Methods
In this prospective single centre study in the Netherlands, all adult symptomatic ED patients had both a CT scan and a PCR upon arrival at the ED. CT results were compared with PCR test(s). Diagnostic accuracy was calculated. Discordant results were investigated using discharge diagnoses.

Results
Between March 13th and March 24th 2020, 193 symptomatic ED patients were included. In total, 43.0% of patients had a positive PCR and 56.5% a positive CT, resulting in a sensitivity of 89.2%, specificity 68.2%, likelihoodratio (LR) + 2.81 and LR- 0.16. Sensitivity was higher in patients with high risk pneumonia (CURB-65 score ≥3; n=17, 100%) and with sepsis (SOFA score ≥2; n=137, 95.5%).

Of the 35 patients (31.8%) with a suspicious CT and a negative PCR, 9 had another respiratory viral pathogen, and in 7 patients, COVID-19 was considered likely. One of nine patients with a non-suspicious CT and a positive PCR had developed symptoms within 48 hours before scanning.

Discussion
The accuracy of chest CT in symptomatic ED patients is high, but used as a single diagnostic test, CT can not safely diagnose or exclude COVID-19. However, CT can be used as a quick first screening tool.
COVID-19: Public Compliance with and Public Support for Stay-at-Home Mitigation Strategies
Authors: Czeisler Mark É. , Howard Mark E. , Robbins Rebecca , Barger Laura K. , Facer-Childs Elise R. , Rajaratnam Shantha M. W. , Czeisler Charles A.
Published: April 2020

Abstract

Objectives

Governments worldwide have recommended unprecedented measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic. As pressure mounts to scale back these measures, understanding public compliance with and priorities for COVID-19 mitigation is critical. The main aim of this study was to assess public compliance with and support for government-imposed stay-at-home orders in nations and cities with different COVID-19 infection and death rates.

Design

In this cross-sectional study, questionnaires were administered to nationally representative respondents from April 2-8, 2020.

Setting

Regions with different disease prevalence included two nations [the United States (US—high) and Australia (AU—low)] and two cities [New York (NY—high) and Los Angeles (LA—low)].

Participants

For adults 18 years or older residing in specified regions, eligible respondents were empaneled until representative quotas were reached for age, gender, and either race and ethnicity (US, NY, LA) or ancestry (AU), matching the 2010 US or 2016 AU census. Of 8718 eligible potential respondents, 5573 (response rate, 63.9%) completed surveys (US: 3010; NY: 507; LA: 525; AU: 1531). The median age was 47 years (range, 18-89); 3039 (54.5%) were female.

Exposure

The prevalence of COVID-19 in each region (cumulative infections, deaths) as of April 8, 2020: US (458610, 15659), AU (5956, 45),1 NY (81803, 4571), LA (7530, 198).2

Main Outcomes Measures

Public compliance with and attitudes regarding government-imposed stay-at-home orders were evaluated and compared between regions.

Results

Of 5573 total respondents, 4560 (81.8%) reported compliance with recommended quarantine or stay-at-home policies (range of samples, 75.5%-88.2%). Despite significant disruptions of social and work life, health, and behavior, 5022 respondents (90.1%) supported government-imposed stay-at-home orders (range of samples, 88.9%-93.1%). Of these, 90.8% believe orders should last at least three more weeks or until public health or government officials recommend, with such support spanning the political spectrum.

Conclusions

Public compliance with stringent quarantine and stay-at-home policies was very high, in both highly-affected (US, NY) and minimally-affected regions (AU, LA). Despite extensive disruption of respondents’ lives, the vast majority supported continuation of long-term government-imposed stay-at-home orders. These findings have important implications for policymakers grappling with the decision as to when to lift restrictions.