bluuebunny/crossref_metadata_2025 huggingface dataset:
RAS/TP53 Co-mutation is Associated With Worse Survival After Concurrent Resection of Colorectal Liver Metastases and Extrahepatic Disease
Authors: Lillemoe Heather A. , Passot Guillaume , Kawaguchi Yoshikuni , DeBellis Mario , Glehen Olivier , Chun Yun Shin , Tzeng Ching-Wei D. , Aloia Thomas A. , Lopez Jonathan , Vauthey Jean-Nicolas
Published: December 2020

Objective:

To determine if tumor genetics are associated with overall survival (OS) after concurrent resection of colorectal liver metastases (CLM) and extrahepatic disease (EHD).

Summary Background Data:

The prognosis for patients who undergo concurrent resection of CLM/EHD is unclear and the impact of somatic mutations has not been reported.

Methods:

Patients undergoing concurrent resection of CLM and EHD from 2007 to 2017 were identified from 2 academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytore-ductive surgery with hyperthermic intraperitoneal chemotherapy. The Kaplan-Meier method was used to construct survival curves, compared using the log-rank test. Multivariable Cox analysis for OS was performed.

Results:

One hundred nine patients were included. Most common EHD sites included lung (33 patients), peritoneum (32), and portal lymph nodes (14). TP53 mutation was the most common mutation, identified in 75 patients (69%), and RAS/TP53 co-mutation was identified in 31 patients (28%). The median OS was 49 months (interquartile range, 24–125), and 3- and 5-year OS rates were 66% and 44%, respectively. Compared to patients without RAS/ TP53 co-mutation, patients with RAS/TP53 co-mutation had lower median OS: 39 vs. 51 months (P = 0.02). On multivariable analysis, lung EHD [hazard ratio (HR), 0.7; 95% confidence intervals (CI), 0.3–1.4], peritoneal EHD (HR, 2.2; 95% CI, 1.1–4.2) and RAS/TP53 co-mutation (HR, 2.8; 95% CI, 1.1–7.2) were independently associated with OS.

Conclusions:

RAS/TP53 co-mutation is associated with worse OS after concurrent CLM/EHD resection. Mutational status and site of EHD should be included in the evaluation of patients considered for concurrent resection.
The Impact of Burn Size on Community Participation
Authors: Ryan Colleen M. , Shapiro Gabriel D. , Rencken Camerin A. , Griggs Cornelia L. , Jeng James C. , Hickerson William L. , Marino Molly , Goverman Jeremy , Kazis Lewis E. , Schneider Jeffrey C. ,   the LIBRE Advisory Board
Published: December 2020

Objective:

To assess the association of burn size and community participation as measured by the LIBRE Profile.

Summary of Background Data:

Burn size is an established clinical predictor of survival after burn injury. It is often a factor in guiding decisions surrounding early medical interventions; however, literature is inconclusive on its relationship to quality of life outcomes.

Methods:

This is a secondary data analysis of a cross-sectional survey of adult burn survivors. Self-reported data were collected between October 2014 and December 2015 from 601 burn survivors aged ≥18 years with ≥5% total body surface area (TBSA) or burns to critical areas. Sociodemographic characteristics were compared between participants with small burns (≤40% TBSA burned) and large burns (>40% TBSA burned). Ordinary least squares regression models examined associations between burn size and LIBRE Profile scale scores with adjustments for sex, current work status, burns to critical areas, and time since burn injury.

Results:

The analytic sample comprised 562 participants with data available for burn size. 42% of respondents had large burns (>40% TBSA burned) and 58% reported smaller burns (TBSA ≤40%). In adjusted regression models, patients with large burns tended to score lower on the Social Activities and Work & Employment scales (P < 0.05) and higher on the Family & Friends scale (P < 0.05). Participants with burns >40% TBSA scored lower for several individual items in the Social Activities scale and one item in the Work & Employment scale (P < 0.05).

Conclusions:

Increasing burn size was found to be negatively associated with selected items of Work & Employment and Social Activities, but positively associated with aspects of Family & Friend Relationships. Future longitudinal studies are necessary to assess and understand the long-term social impact of burn injuries on adult populations.
Comparison of Patient Outcomes Among Integrated Residency Versus Fellowship-trained Vascular Surgeons
Authors: Smith Brigitte K. , Finlayson Samuel R.G. , Perler Bruce A. , Presson Angela P. , Allen Chelsea M. , Brooke Benjamin S.
Published: December 2020

Objective:

This study aims to evaluate whether graduates of integrated vascular surgery residency (IVSR) programs achieve similar surgical outcomes in clinical practice as compared to graduates of vascular surgery fellowships (VSF).

Summary of Background Data:

Early sub-specialization through IVSR programs decreases the total years of surgical training. However, it is unclear whether IVSR graduates achieve comparable outcomes to fellowship-trained surgeons once in clinical practice.

Methods:

We identified all vascular surgeons who finished IVSR and VSF programs between 2013–2017 using American Board of Surgery data, which was linked to the Vascular Quality Initiative registry (2013–2019) to evaluate provider-specific clinical outcomes following carotid, lower extremity, and aortic aneurysm repair procedures. The association between training models and the composite outcome of 1-year mortality, major adverse cardiac events and/or other major complications were analyzed using mixed-effects logistic regression models.

Results:

A total of 338 surgeons (31% IVSR, 69% VSF) submitted cases into the Vascular Quality Initiative registry, including 8155 carotid, 21,428 lower extremity, and 5800 aortic aneurysm repair procedures. Composite 1-year outcome rates were comparable between IVSR and VSF-trained surgeons following carotid endarterectomy (8%-IVSR vs 7%-VSF), lower extremity revascularization (19%-IVSR vs 16%-VSF), and aortic aneurysm repair (13%-IVSR vs 13%-VSF) procedures. These findings among IVSR-trained surgeons persisted following risk adjustment for severity of patient disease and indications for undertaking carotid [aOR: 1.04 (0.84–1.28)], lower extremity [aOR: 1.03 (0.84–1.26)], and aortic [aOR: 0.96 (0.76–1.21)] procedures when compared to VSF-trained surgeons.

Conclusions:

Despite fewer total years of training, graduates of IVSR programs achieve equivalent surgical outcomes as fellowship-trained vascular surgeons once in practice. These results suggest that concerns about differential competence among integrated residency graduates are not warranted.
Postoperative Work and Activity Restrictions After Abdominal Surgery
Authors: Loor Michele M. , Shah Puja , Olavarria Oscar A. , Dhanani Naila , Franz Michael G. , Trautner Barbara W. , Liang Mike K.
Published: December 2020

Objective:

This systematic review aims to assess what is known about convalescence following abdominal surgery. Through a review of the basic science and clinical literature, we explored the effect of physical activity on the healing fascia and the optimal timing for postoperative activity.

Background:

Abdominal surgery confers a 30% risk of incisional hernia development. To mitigate this, surgeons often impose postoperative activity restrictions. However, it is unclear whether this is effective or potentially harmful in preventing hernias.

Methods:

We conducted 2 separate systematic reviews using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The first assessed available basic science literature on fascial healing. The second assessed available clinical literature on activity after abdominal surgery.

Results:

Seven articles met inclusion criteria for the basic science review and 22 for the clinical studies review. The basic science data demonstrated variability in maximal tensile strength and time for fascial healing, in part due to differences in layer of abdominal wall measured. Some animal studies indicated a positive effect of physical activity on the healing wound. Most clinical studies were qualitative, with only 3 randomized controlled trials on this topic. Variability was reported on clinician recommendations, time to return to activity, and factors that influence return to activity. Interventions designed to shorten convalescence demonstrated improvements only in patient-reported symptoms. None reported an association between activity and complications, such as incisional hernia.

Conclusions:

This systematic review identified gaps in our understanding of what is best for patients recovering from abdominal surgery. Randomized controlled trials are crucial in safely optimizing the recovery period.
Pathways to Clinical Cardiac Xenotransplantation
Authors: Reichart Bruno , Längin Matthias , Denner Joachim , Schwinzer Reinhard , Cowan Peter J. , Wolf Eckhard
Published: December 2020

Heart transplantation is the only long-lasting lifesaving option for patients with terminal cardiac failure. The number of available human organs is however far below the actual need, resulting in substantial mortality of patients while waiting for a human heart. Mechanical assist devices are used to support cardiac function but are associated with a high risk of severe complications and poor quality of life for the patients. Consistent success in orthotopic transplantation of genetically modified pig hearts into baboons indicates that cardiac xenotransplantation may become a clinically applicable option for heart failure patients who cannot get a human heart transplant. In this overview, we project potential paths to clinical cardiac xenotransplantation, including the choice of genetically modified source pigs; associated requirements of microbiological, including virological, safety; optimized matching of source pig and recipient; and specific treatments of the donor heart after explantation and of the recipients. Moreover, selection of patients and the regulatory framework will be discussed.
Physiological Effects of Exercising at Different Intensities Wearing TNT or Double-layer Cotton Facemasks Compared to Not Wearing a Mask
Authors: Braga Fabrício , Espinosa Gabriel , Monteiro Amanda , Marinho Beatriz , Drummond Eduardo
Published: December 2020

We compared the physiological differences between exercising wearing a TNT or a double-layer-cotton (DLC) facemask (FM) and not wearing a mask (NM). Sixteen volunteers underwent 4 sets (S) of 2 sequential bouts (B). B1 and B2 corresponded to light and moderate intensity cycling, respectively. FMs were used as follows: S1: NM; S2: TNT or DLC; S3: DLC or TNT; and S4: NM. Metabolic, pulmonary, and perceptual variables were collected. The main results are expressed as effect sizes and confidence intervals (ES [95%CI]) for TNT and DLC unless otherwise indicated. Compared to NM, FM increased the duty cycle (B1=1.11[0.58-1.61] and 1.53[0.81-2.18]; B2=1.27[0.63-1.84] and 1.93[0.97-2.68]) and decreased breath frequency (B1=0.59[0.23-0.94] and 1.43[0.79-2.07], B2=0.39[0.05-0.71] and 1.33[0.71-1.94]). Only B1 tidal volume increased (0.33[0.09-0.56] and 0.62[0.18-1.05]) enough to avoid a ventilation reduction with TNT but not with DLC (B1=0.52[0.23-0.79]; B2=0.84[0.44-1.22]). Both FMs reduced oxygen saturation in B1 (0.56 [0.07-1.03] and 0.69 [0.09-1.28]) but only DLC did so in B2 (0.66 [0.11-1.13]). Both end tidal CO2(B1=0.23[0.05-0.4] and 0.71[0.38-1.02]; B2=0.56[0.2-0.9] and 1.20[0.65-1.68]) and mixed-expired-CO2(B1=0.74[0.38-1.08] 1.71[1.03-2.37], B2=0.94[0.45-1.38] and 1.78[0.97-2.42]) increased with FMs. Ventilatory adaptations imposed during FM exercising influenced blood-lung gas exchange. Larger ESs were seen with DLC. No adverse changes to human health were observed.

Novelty Bullets

Facemasks affect the breathing pattern by changing the frequency and amplitude of pulmonary ventilation.

The augmented ventilatory work increases VO2, VCO2, and RPE and promotes non-concerning drops in SpO2 and CO2 retention.

Increased inspiratory and expiratory pressure can account for the reduction in pulmonary physiological dead space.
2-mercaptoethanol (2-ME)-based IATs or polybrene method mitigates the interference of anti-CD38 immunotherapy on blood compatibility tests
Authors: Zhou Ye , Chen Leiyu , Jiang Tianshu , Fan Liangfeng , Lei Hang , Wang Yuqing , Heililahong Hasiyati , Mi Jianqing , Du Danxin , Miao Tianhong , Xia Rong , Wang Xuefeng , Xiang Dong , Cai Xiaohong , Tang Xiaofeng
Published: December 2020

Background

Treating red blood cells (RBCs) with dithiothreitol (DTT) is a wildly-recommended to overcome the interference of anti-CD38 immunotherapy with blood compatibility testing. Nevertheless, DTT can be hard to obtain in clinical laboratory, while its use in routine practice may be time-consuming. In the following study, we explored the feasibility of using a commercial 2-mercaptoethanol (2-ME) working solution or the time-saving polybrene method to mitigate the daratumumab (DARA) interference.

Materials and Methods

Antibody screening and cross-matching were performed using 2-ME or DTT-based indirect antiglobulin tests (IATs) and polybrene method (human IgG anti-E same IATs titer as DARA as positive control) on 37 samples, and these samples were from patients enrolled in the “Several methods resolve the interference of anti-CD38 monoclonal antibody on blood compatibility tests” clinical trial (www.chictr.org.cn identifier: ChiCTR2000040761). Most clinically important blood group antigens on RBCs were detected after treatment with 2-ME or DTT. Hemoglobin values were compared after 69 units RBCs were transfused with compatible cross-matching results by a 2-ME-based method or polybrene test.

Results

Treating RBCs with 2-ME eliminates the DARA interference with the antibody screening or cross-matching; yet, K antigen is denatured during treatment. DARA with 2+ agglutinations of anti-E control does not interfere with antibody screening and cross-matching via polybrene method. After RBCs transfusion with a negative cross-matching test by 2-ME-based IATs or polybrene method, hemoglobin significantly increased without adverse transfusion reactions.

Conclusion

2-ME-based IATs or polybrene method could be used to mitigate DARA interference as DTT.
SIREN protocol: Impact of detectable anti-SARS-CoV-2 on the subsequent incidence of COVID-19 in 100,000 healthcare workers: do antibody positive healthcare workers have less reinfection than antibody negative healthcare workers?
Authors: Wallace S. , Hall V. , Charlett A. , Kirwan P.D. , Cole M.J. , Shrotri M. , Rokadiya S. , Oguti B. , Vusirikala A. , Zambon M. , Brooks T. , Ramsay M. , Brown C.S. , Chand M.A. , Hopkins S.
Published: December 2020

Background

The overall risk of reinfection in individuals who have previously had COVID-19 is unknown. To determine if prior SARS-CoV-2 infection (as determined by at least one positive commercial antibody test performed in a laboratory) in healthcare workers confers future immunity to reinfection, we are undertaking a large-scale prospective longitudinal cohort study of healthcare staff across the United Kingdom.

Methods

Population and Setting: staff members of healthcare organisations working in hospitals in the UK

At recruitment, participants will have their serum tested for anti-SARS-CoV-2 at baseline and using these results will be initially allocated to either antibody positive or antibody negative cohorts. Participants will undergo antibody and viral RNA testing at 1-4 weekly intervals throughout the study period, and based on these results may move between cohorts. Any results from testing undertaken for other reasons (e.g. symptoms, contact tracing etc.) or prior to study entry will also be included. Individuals will complete enrolment and fortnightly questionnaires on exposures and symptoms. Follow-up will be for at least 12 months from study entry.

Outcome

The primary outcome of interest is a reinfection with SARS -CoV-2 during the study period. Secondary outcomes will include incidence and prevalence (both RNA and antibody) of SARS-CoV-2, viral genomics, viral culture, symptom history and antibody/neutralising antibody titres.

Conclusion

This large study will help us to understand the impact of the presence of antibodies on the risk of reinfection with SARS-CoV-2; the results will have substantial implications in terms of national and international policy, as well as for risk management of contacts of COVID-19 cases.

Trial Registration

IRAS ID 284460, HRA and Health and Care Research Wales approval granted 22 May 2020.
Creating an e-cohort of individuals with lived experience of homelessness and subsequent mortality in Wales, UK
Authors: Song Jiao , Grey Charlotte N.B. , Davies Alisha R.
Published: December 2020

Background

Homelessness is an extreme form of social exclusion, with homeless people experiencing considerable social and health inequities. Estimates of morbidity and mortality amongst homeless populations is limited due to the lack of recording of housing status across health datasets. The aim of this study is to: (1) identify a homelessness e-cohort by linking routine health data, and (2) explore whether a period of reported past homelessness, places this population at greater risk of morbidity and mortality.

Methods

Homelessness identified through linkage across primary, secondary care, and substance misuse datasets in the Secure Anonymised Information Linkage (SAIL) Databank. Mortality was examined through linkage to the Office for National Statistics mortality data.

Results

E-cohort of 15,472 individuals with lived experience of homelessness identified. Of those, 21 individuals died between February and July 2020 from COVID-19. Those with lived experience of homelessness had increased mortality from many causes including COVID-19, i.e. accidents, liver diseases and suicides.

Conclusion

Linking multiple routine datasets provides a more comprehensive dataset of a marginalised population. Application of the cohort demonstrated that individuals with lived experience of homelessness have increased mortality from COVID-19 and other causes. The underlying reasons, health needs, and causes of death warrant further exploration.
Novel echocardiographic markers of elevated left ventricular filling pressure during diastolic stress testing
Authors: Verwerft Jan , Verbrugge Frederik H. , Claessen Guido , Herbots Lieven , Dendale Paul , Gevaert Andreas B.
Published: December 2020

Aims

Diastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but algorithms lack sensitivity. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST.

Methods and Results

We analyzed 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. We identified candidate parameters in patients with exPAWP ≥25 mmHg. Elevated exPAWP was present in 14 patients, and was best identified by peak septal systolic annular velocity on color Doppler (exS’, area under the receiver operating characteristic curve (AUC) 0.97, 95% confidence interval 0.92-1.0) and mean pulmonary artery pressure/cardiac output slope (mPAP/CO, AUC 0.88 [0.72-1.0]). We propose a three-step decision tree to identify patients with elevated exPAWP. Applying this decision tree to 376 patients in an independent non-invasive DST cohort showed that patients labeled as ‘high probability of HFpEF’ had reduced peak oxygen uptake (12.8 (10.5-15.9) mL/kg/min, p<.001 vs intermediate/low probability), high H2FPEF score (55 (44-75)%, p<.007 vs intermediate/low probability), and typical clinical characteristics. The amount of inconclusive DST decreased from 80% using current recommendations, to 29% using the decision tree.

Conclusion

In DST for suspected HFpEF, exS’ was the most accurate echocardiographic parameter to identify elevated PAWP. We propose a decision tree including exS’ and mPAP/CO for interpretation of DST. Application of this decision tree revealed typical HFpEF characteristics in patients labeled as high probability of HFpEF, and substantially reduced the amount of inconclusive results.
COVID19 is a seasonal climate-driven disease across both hemispheres
Authors: Fontal Alejandro , Bouma Menno J. , José Adrià San , Pascual Mercedes , Rodó Xavier
Published: December 2020

The role of climate in the population dynamics of COVID-19 remains poorly understood, and a true seasonal signature has remained elusive. Data from both hemispheres and the second wave provide opportunities to further examine climatic drivers. With a statistical method designed to detect transitory associations, we show consistent negative effects of temperature and absolute humidity at large spatial scales. At finer spatial resolutions we substantiate these connections during the seasonal rise and fall of COVID-19. Strong disease responses are identified between 12-18°C for Temperature and 4-12 g/m3for Absolute Humidity. These results classify COVID-19 as a seasonal low-temperature infection, and point to the airborne pathway as an important contribution to transmission for SARS-CoV-2, with implications for control measures we discuss.
Household bubbles and COVID-19 transmission: insights from percolation theory
Authors: Danon Leon , Lacasa Lucas , Brooks-Pollock Ellen
Published: December 2020

Background

In the era of social distancing to curb the spread of COVID-19, bubbling is the combining of two or more households to create an exclusive larger group. The impact of bubbling on COVID-19 transmission is challenging to quantify because of the complex social structures involved.

Methods

We developed a network description of households in the UK, using the configuration model to link households. We explored the impact of bubbling scenarios by joining together households of various sizes. For each bubbling scenario, we calculated the percolation threshold, that is, the number of connections per individual required for a giant component to form, numerically and theoretically. We related the percolation threshold to the household reproduction number.

Results

We find that bubbling scenarios in which single-person households join with another household has a minimal impact on network connectivity and transmission potential. Ubiquitous scenarios where all households form a bubble are likely to lead to extensive transmission that is hard to control. The impact of plausible scenarios, with variable uptake and heterogeneous bubble sizes, can be mitigated with reduced numbers of contacts outside the household.

Conclusions

Bubbling of households comes at an increased risk of transmission, however under certain circumstances risks can be modest and could be balanced by other changes in behaviours.
A Composite Index to Measure Family Planning Performance with Application to India
Authors: Chaurasia Aalok Ranjan
Published: December 2020

This paper develops a composite family planning performance index that takes into account the met demand for modern family planning methods and the structure of the met demand or the method mix. Application of the index to India suggests that, although, there has been an improvement in India’s family planning performance, yet it has remained poor throughout the period 1992 through 2016 and there are significant variation in the performance across states/Union Territories and across districts. The classification modelling exercise reveals that districts in India can be grouped into eight clusters in terms of family planning performance and both met demand for modern family planning methods and the structure of the met demand are essentially different in different clusters. The paper emphasises that family planning in the country must be promoted as a development strategy rather than an intervention to limit births.
The Wood Image Analysis and Dataset (WIAD): open-access visual analysis tools to advance the ecological data revolution
Authors: Rademacher Tim , Seyednasrollah Bijan , Basler David J. , Cheng Jian , Mandra Tessa , Miller Elise , Lin Zuid , Orwig David A. , Pederson Neil , Pfister Hanspeter , Wei Donglai , Yao Li , Richardson Andrew D.
Published: December 2020

Ecological data is collected and shared at an increasingly rapid pace, but it is often shared in inconsistent and untraceable processed forms. Images of wood contain a wealth of information such as colours and textures but are most commonly reduced to ring-width measurements before they can be shared in various common file formats. Archiving digital images of wood samples in libraries, that have been developed for ecological analysis and are publicly available, remains the exception.

We developed the Wood Image Analysis and Dataset (WIAD) an open-source application including a web-interface to integrate basic visual analysis of wood samples, such as increment cores, thin sections or x-ray films, basic data processing, and archiving of the images and derived data to facilitate transparency and reproducibility in studies using visual characteristics of wood.

WIAD provides user-friendly tools to manipulate images of wood samples, mark and measure wood characteristics such as growth increments, density fluctuations, early- and latewood widths, and fire scars, and to visualise, process, and archive images, metadata, and the derived data.

WIAD constitutes a step towards the reproducible automation of tree-ring analysis, while establishing an open-source foundation to create improved community developed repositories which would enable novel ecological studies harnessing the wealth of existing visual data.
Biomarkers of Length of Stay on an Inpatient Eating Disorder Unit
Authors: Breiner Courtney E. , Qi Baiyu , Thornton Laura M. , Brownley Kimberly A. , Foreman Tonya , Bardone-Cone Anna M. , Bulik Cynthia M. , Baker Jessica H.
Published: December 2020

Length of stay on an inpatient unit for treatment of anorexia nervosa (AN) is widely variable. Although previous research has used anthropometric and clinical variables and duration of illness to predict length of stay, there has been limited investigation of the predictive ability of biomarkers. Biomarkers, including those collected through a comprehensive metabolic panel (CMP) and appetite hormones, such as ghrelin and leptin, are impacted by disease presence and may play an etiological role in AN. Using a series of regression models, we evaluated the associations of these putative biomarkers with length of inpatient stay in 46 females receiving treatment on an inpatient eating disorder unit. Active ghrelin levels at inpatient admission positively predicted length of stay and alkaline phosphatase at discharge was significantly positively correlated with length of stay. This research provides further evidence supporting both biological and psychological components of AN, identifying potential biomarkers that could aid in prospective prediction of treatment needs. Further research is necessary to replicate and extend these findings across treatment settings.
Detection of SARS-CoV2 antigen in human saliva may be a reliable tool for large scale screening
Authors: Kannian Priya , Lavanya Chandra , Ravichandran Krittika , Jayaraman Bagavad Gita , Mahanathi Pasuvaraj , Ashwini Veeraraghavan , Kumarasamy Nagalingeswaran , Rajan Gunaseelan , Ranganathan Kannan , Challacombe Stephen J. , Webster-Cyriaque Jennifer , Johnson Newell W.
Published: December 2020

Introduction

SARS-CoV2, the aetiological agent of the current COVID-19 pandemic, has been detected in saliva and recently implicated in several oral diseases. Collection of nasopharyngeal swabs (NPS) and detection by reverse transcriptase-polymerase chain reaction (RT-PCR) requires medical / technical expertise. A reliable and easy to handle point-of-care (POC) test is highly desirable, especially to curb transmission. Therefore, in this study, we evaluated a commercially available POC rapid antigen test (RAT) for the detection of SARS-CoV2 antigens in the saliva of RT-PCR confirmed positive and negative patients.

Methods

Thirty saliva samples of 10 saliva RT-PCR negative and 20 saliva RT-PCR positive patients were tested by RAT.

Results

RAT was negative in 10/10 (100%) RT-PCR-negative samples; positive in 9/20 (45%) RT-PCR-positive samples; concordance was 63% (p=0.001). Patients with positive RAT had higher virus copies in their NPS samples compared to the RAT-negative patients. This difference was also statistically significant (p=0.01).

Conclusion

Thus, the POC RAT may be used to detect SARS-CoV2 as a reliable tool for self-testing, large-scale population screening and emergency medical/dental screening. Patients negative by RAT should be confirmed by RT-PCR.
Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers
Authors: Eugene Andy R.
Published: December 2020

Background

Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pathogen and one clinical study reported fluoxetine exposure at a median dose of 20mg in patients with the SARS-Cov-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-Cov-2 as reported in Calu-3 human lung cells.

Methods

Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption was used to simulate fluoxetine concentration-time data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20mg/day, 40mg/day, and 60mg/day) to estimate the percentage of the patients achieving a trough level for the EC90 SARS-Cov-2 inhibitory concentration at each day throughout a 10-day treatment period. All analyses were conducted via statistical programming in R.

Results

Standard fluoxetine antidepressant doses resulted in a range of 79% to 97% of the patient population achieving a trough target plasma concentration of 25.1 ng/ml which translates to lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 μM). At a dose of 40mg per day, at least 85% of patients will reach the trough target EC90 concentration within 3-days. The findings of this pharmacokinetic dosing study corroborate both in vitro and observational clinical study findings showing fluoxetine inhibits the SARS-Cov-2 pathogen at commonly treated doses in the practice of psychiatry.
Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages
Authors: Forman Ruth , Logunova Larisa , Smith Hannah , Wemyss Kelly , Mair Iris , Boon Louis , Allen Judith E. , Muller Werner , Pennock Joanne L. , Else Kathryn J.
Published: December 2020

The balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4Rα. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELMα, CD206 and Ym1, associated with activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using aTrichuris murisinfection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELMα and Ym1 expressing cell type during type 2 inflammation, does not require IL4Rα expression on macrophages. Thus, upregulation of RELMα and Ym1 post infection is independent of macrophage IL4Rα expression. Further, this independence is maintained even when the mice are treated with anti-IFNγ antibody to create a strongly polarised Th2 environment. In contrast to RELMα and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELMα and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.
A Theory of Synaptic Transmission
Authors: Wang Bin , Dudko Olga K.
Published: December 2020

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters into the synaptic cleft within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we formulate an analytic theory of the action-potential-triggered neurotransmitter release at a chemical synapse. The theory captures general principles of synaptic transmission while generating concrete predictions for particular synapses. A universal scaling in synaptic transmission is established, and demonstrated through a collapse of experimental data from different synapses onto a universal curve. The theory shows how key characteristics of synaptic function – plasticity, fidelity, and efficacy – emerge from molecular mechanisms of neurotransmitter release machinery.
Human hippocampal neurons track moments in a sequence of events
Authors: Reddy Leila , Zoefel Benedikt , Possel Jessy K. , Peters Judith C. , Dijksterhuis Doris , Poncet Marlene , van Straaten Elisabeth C.W. , Baayen Johannes C. , Idema Sander , Self Matthew W.
Published: December 2020

An indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal “time cells” – neurons that represent temporal information – may play a critical role in this process. While these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10-second gap periods between trials, while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.

Significance Statement

Episodic memory refers to our ability to remember the “what, where, and when” of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.
Sensory modulation of gait characteristics in human locomotion: a neuromusculoskeletal modeling study
Authors: Di Russo Andrea , Stanev Dimitar , Armand Stéphane , Ijspeert Auke
Published: December 2020

The central nervous system of humans and animals is able to modulate the activity in the spinal cord to achieve several locomotion behaviors. Previous neuromechanical models investigated the modulation of human gait changing selected parameters belonging to the CPGs (Central Pattern Generators) feedforward oscillatory structures or to the feedback reflex circuits. CPG-based models could replicate slow and fast walking by changing only the oscillation’s properties. On the other hand, reflex-based models could achieve different behaviors mainly through optimizations of a large dimensional parameter space, but could not identify effectively individual key reflex parameters responsible for the modulation of gait characteristics. This study, investigates which reflex parameters modulate the gait characteristics through neuromechanical simulations. A recently developed reflex-based model is used to perform optimizations with different target behaviors on speed, step length and step duration in order to analyse the correlation between reflex parameters and their influence on these gait characteristics. We identified 9 key parameters that influence the target speed ranging from slow to fast walking (0.48 and 1.71 m/s) as well as a large range of step lengths (0.43 and 0.88 m) and step duration (0.51, 0.98 s). The findings show that specific reflexes during stance have a major effect on step length regulation mainly given by the contribution of positive force feedback on the ankle plantarflexors’ group. On the other hand, stretch reflexes active during swing of iliopsoas and gluteus maximus regulate all the gait characteristics under analysis. Additionally, the results show that the stretch reflex of the hamstring’s group during landing phase is responsible for modulating the step length and step duration. Additional validation studies in simulations demonstrated that the identified reflexes are sufficient to modulate gait in human locomotion. Thus, this study provides an overview of the possible reflexes to control the gait characteristics.

Author summary
A unified theory of E/I synaptic balance, quasicritical neuronal avalanches and asynchronous irregular spiking
Authors: Girardi-Schappo Mauricio , Galera Emilio F. , Carvalho Tawan T. A. , Brochini Ludmila , Kamiji Nilton L. , Roque Antonio C. , Kinouchi Osame
Published: December 2020

Neuronal avalanches and asynchronous irregular (AI) firing patterns have been thought to represent distinct frameworks to understand the brain spontaneous activity. The former is typically present in systems where there is a balance between the slow accumulation of tension and its fast dissipation, whereas the latter is accompanied by the balance between synaptic excitation and inhibition (E/I). Here, we develop a new theory of E/I balance that relies on two homeostatic adaptation mechanisms: the short-term depression of inhibition and the spike-dependent threshold increase. First, we turn off the adaptation and show that the so-called static system has a typical critical point commonly attributed to self-organized critical models. Then, we turn on the adaptation and show that the network evolves to a dynamic regime in which: (I) E/I synapses balance regardless of any parameter choice; (II) an AI firing pattern emerges; and (III) neuronal avalanches display power laws. This is the first time that these three phenomena appear simultaneously in the same network activity. Thus, we show that the once thought opposing frameworks may be unified into a single dynamics, provided that adaptation mechanisms are in place. In our model, the AI firing pattern is a direct consequence of the hovering close to the critical line where external inputs are compensated by threshold growth, creating synaptic balance for any E/I weight ratio.

Highlights

Asynchronous irregular (AI) firing happens together with power-law neuronal avalanches under self-organized synaptic balance.

Self-organization towards the critical and balanced state (with AI and power-law avalanches) occur via short-term inhibition depression and firing threshold adaptation.

The avalanche exponents match experimental findings.

The adaptation time scales drive the self-organized dynamics towards different firing regimes.

Author summary

Two competing frameworks are employed to understand the brain spontaneous activity, both of which are backed by computational and experimental evidence: globally asynchronous and locally irregular (AI) activity arises in excitatory/inhibitory balanced networks subjected to external stimuli, whereas avalanche activity emerge in excitable systems on the critical point between active and inactive states. Here, we develop a new theory for E/I networks and show that there is a state where synaptic balance coexists with AI firing and power-law distributed neuronal avalanches. This regime is achieved through the introducing of short-term depression of inhibitory synapses and spike-dependent threshold adaptation. Thus, the system self-organizes towards the balance point, such that its AI activity arises from quasicritical fluctuations. The need for two independent adaptive mechanisms explains why different dynamical states are observed in the brain.
Dynamic positioning and precision of bistable gene expression boundaries through diffusion and morphogen decay
Authors: Perkins Melinda Liu
Published: December 2020

1

Traditional models for how morphogen gradients guide embryonic patterning fail to account for experimental observations of temporal refinement in gene expression domains. Dynamic positional information has recently emerged as a framework to address this shortcoming. Here, we explore two central aspects of dynamic positional information—the precision and placement of gene expression boundaries—in bistable genetic networks driven by morphogen gradients. First, we hypothesize that temporal morphogen decay may increase the precision of a boundary by compensating for variation in initial conditions that would otherwise lead neighboring cells with identical inputs to diverge to separate steady states. Second, we explore how diffusion of gene products may play a key role in placing gene expression boundaries. Using an existing model for Hb patterning in embryonic fruit flies, we show that diffusion permits boundaries to act as near-traveling wavefronts with local propagation speed determined by morphogen concentration. We then harness our understanding of near-traveling fronts to propose a method for achieving accurate steady-state boundary placement independent of initial conditions. Our work posits functional roles for temporally varying inputs and cell-to-cell coupling in the regulation and interpretation of dynamic positional information, illustrating that mathematical theory should serve to clarify not just our quantitative, but also our intuitive understanding of patterning processes.

2

Author Summary

In many developmental systems, cells interpret spatial gradients of chemical morphogens to produce gene expression boundaries in exact positions. The simplest mathematical models for “positional information” rely on threshold detection, but such models are not robust to variations in the morphogen gradient or initial protein concentrations. Furthermore, these models fail to account for experimental results showing dynamic shifts in boundary placement and increased boundary precision over time. Here, we propose two theoretical mechanisms for enhancing boundary precision and placement using a bistable toggle switch. Distinct from existing research in “dynamic positional information”, this work posits a functional role for temporal decay in morphogen concentration and for diffusion of gene expression products, the latter of which is often omitted in quantitative models. We suggest that future research into dynamic positional information would benefit from perspectives that link local (cellular) and global (patterning) behaviors, as well as from mathematical theory that builds our intuitive understanding alongside more data-driven approaches.
Considerations for performance metrics of metagenomic next generation sequencing analyses
Authors: Kralj Jason G. , Servetas Stephanie L. , Forry Samuel P. , Jackson Scott A.
Published: December 2020

Evaluating the performance of metagenomics analyses has proven a challenge, due in part to limited ground-truth standards, broad application space, and numerous evaluation methods and metrics. Application of traditional clinical performance metrics (i.e. sensitivity, specificity, etc.) using taxonomic classifiers do not fit the “one-bug-one-test” paradigm. Ultimately, users need methods that evaluate fitness-for-purpose and identify their analyses’ strengths and weaknesses. Within a defined cohort, reporting performance metrics by taxon, rather than by sample, will clarify this evaluation. An estimated limit of detection, positive and negative control samples, and true positive and negative true results are necessary criteria for all investigated taxa. Use of summary metrics should be restricted to comparing results of similar cohorts and data, and should employ harmonic means and continuous products for each performance metric rather than arithmetic mean. Such consideration will ensure meaningful comparisons and evaluation of fitness-for-purpose.
Poly(ADP-ribose) potentiates ZAP antiviral activity
Authors: Xue Guangai , Braczyk Klaudia , Gonçalves-Carneiro Daniel , Dawidziak Daria M. , Zawada Katarzyna , Ong Heley , Wan Yueping , Zadrozny Kaneil K. , Ganser-Pornillos Barbie K. , Bieniasz Paul D. , Pornillos Owen
Published: December 2020

Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens such as hepatitis B virus and type 1 human immunodeficiency virus (HIV-1). ZAP selectively binds CpG dinucleotides through its N-terminal RNA-binding domain, which consists of four zinc fingers. ZAP also contains a central region that consists of a fifth zinc finger and two WWE domains. Through structural and biochemical studies, we found that the fifth zinc finger and tandem WWEs of ZAP combine into a single integrated domain that binds to poly(ADP-ribose) (PAR), a cellular polynucleotide. PAR binding is mediated by the second WWE module of ZAP and likely involves specific recognition ofiso(ADP-ribose), a repeating structural unit of PAR. Mutation of the putativeiso(ADP-ribose) binding site in ZAP abrogates the interactionin vitroand diminishes ZAP activity against a CpG-rich HIV-1 reporter virus. In cells, PAR facilitates formation of non-membranous sub-cellular compartments such as DNA repair foci, spindle poles and cytosolic RNA stress granules. Our results suggest that ZAP-mediated viral mRNA degradation is facilitated by PAR, and provides a biophysical rationale for the reported association of ZAP with RNA stress granules.