bluuebunny/crossref_metadata_2025 huggingface dataset:
The CN Lantern Test and Different Viewing Distances
Authors: Almustanyir Ali , Hovis Jeffery K.
Published: May 2020

SIGNIFICANCE

This research shows that some color-vision–defective patients could identify railway signal lights correctly if they are working in the yard where sighting distances for signal lights are shorter.

PURPOSE

When interpreting railway signal lights, sighting distance can vary depending on the employee's location and job requirements. Individuals with a color-vision-defect may pass railroad employment color vision testing for positions with shorter sighting distances, despite failing to qualify for positions with longer sighting distances. The CN Lantern (CNLan) simulates railway signal lights. We evaluated performance and repeatability on CNLan at different viewing distances in color-normal and color-deficient individuals.

METHODS

Fifty-six subjects with normal color vision and 63 subjects with a red-green color-vision-defect participated. The CNLan test was performed at 4.6-, 2.3-, 1.15-, and 0.57-m viewing distance. The test was repeated after 10 days.

RESULTS

All individuals with normal color vision passed the CNLan at all distances at both visits without errors. For the group with a color-vision-defect, the pass rate increased from 12% at 4.6 m to 62% at 0.57 m. The repeatability of the CNLan between visits for the color-vision–defective group was very good with AC1 agreement values greater than 0.85.

CONCLUSIONS

An increase in retinal illumination was likely responsible for the improved performance as the test distance was decreased. Typical sighting distances in railway yards correspond to the 0.57-m test distance in our study. The results of this study suggest that 62% of the individuals with a red-green color-vision-defect may correctly identify colored signal lights in a railway yard where sighting distances are less than 100 m.
Extracorporeal Membrane Oxygenation for Pediatric Patients With Coronavirus Disease 2019–Related Illness*
Authors: MacGregor Robert M. , Antiel Ryan M. , Najaf Tasnim , Said Ahmed S. , Warner Brad W. , Raval Mehul V. , Shakhsheer Baddr
Published: May 2020

Objective:

To describe current hospital guidelines and the opinions of extracorporeal membrane oxygenation leaders at U.S. children’s hospitals concerning the use of extracorporeal membrane oxygenation for coronavirus disease 2019–positive pediatric patients.

Design:

Confidential, self-administered questionnaire.

Setting:

One hundred twenty-seven U.S. pediatric extracorporeal membrane oxygenation centers.

Subjects:

Extracorporeal membrane oxygenation center program directors and coordinators.

Interventions:

None.

Measurements and Main Results:

In March 2020, a survey was sent to 127 pediatric extracorporeal membrane oxygenation centers asking them to report their current hospital extracorporeal membrane oxygenation guidelines for coronavirus disease 2019–positive patients. Respondents were also asked their opinion on three ethical dilemmas including: prioritization of children over adults for extracorporeal membrane oxygenation use, institution of do-not-resuscitate orders, and the use of extracorporeal cardiopulmonary resuscitation for coronavirus disease 2019–positive patients. Forty-seven extracorporeal membrane oxygenation centers had enacted guidelines including 46 (100%) that offer venovenous-extracorporeal membrane oxygenation and 42 (89%) that offer venoarterial-extracorporeal membrane oxygenation for coronavirus disease 2019–positive pediatric patients. Forty-four centers (94%) stated that the indications for extracorporeal membrane oxygenation candidacy in coronavirus disease 2019 disease were similar to those used in other viral illnesses, such as respiratory syncytial virus or influenza. Most program directors (98%) did not endorse that children hospitalized with coronavirus disease 2019 should be made do-not-resuscitate and had variable opinions on whether children should be given higher priority over adults when rationing extracorporeal membrane oxygenation. Over half of program directors (60%) did not support the use of extracorporeal cardiopulmonary resuscitation for coronavirus disease 2019.

Conclusions:

The majority of pediatric extracorporeal membrane oxygenation centers have proactively established guidelines for the use of extracorporeal membrane oxygenation for coronavirus disease 2019–related illnesses. Further work is needed to help guide the fair allocation of extracorporeal membrane oxygenation resources and to determine the appropriateness of extracorporeal cardiopulmonary resuscitation.
Improving the Timeliness and Safety of Therapeutic Hypothermia for Hypoxic–Ischemic Encephalopathy
Authors: Smith Hannah N. , Hughes Driscoll Colleen A.
Published: May 2020

Introduction:

Therapeutic hypothermia (TH) is a time-sensitive, efficacious treatment for newborns who experience perinatal hypoxic–ischemic encephalopathy. Optimal management of patient temperatures during TH may improve newborn outcomes and reduce side effects. We noted that patients undergoing TH were often outside of the target temperature range during treatment. This project sought to improve the timely initiation of effective treatment and temperature stability during TH through system-based changes in practice.

Methods:

Measures include the time to target temperature, the percentage of core temperatures outside of the target range, and the absolute difference between core and peripheral temperatures over 41 months. System-based changes in the TH protocol included changing from passive to active hypothermia on transport and utilizing a delivery mode that uses more gradual temperature fluctuations during TH. We compared measures of health status and side effects as balancing measures.

Results:

The TH protocol changes resulted in a significant reduction of time to goal temperature from 1.67 to 0.49 hours, in the percentage of temperature readings outside goal range from 12.6% to 6.3%, and the average absolute difference between core and peripheral temperatures from 1.78°C to 1.47°C. No adverse health outcomes were detected. We observed decreases in vasopressor use with each protocol change.

Conclusions:

This study demonstrates that detailed attention to the method of delivery of TH has an impact on ensuring effective delivery of therapy and minimizing the risks of treatment. The protocol changes were not associated with an increase in adverse events and were associated with a reduction in vasopressor use.
Reducing Antacid Use in a Level IV NICU: A QI Project to Reduce Morbidity
Authors: Reinhart Richelle M. , McClary Jacquelyn D. , Zhang Mengqi , Marasch Jaime L. , Hibbs Anna Maria , Nock Mary L.
Published: May 2020

Introduction:

Gastroesophageal reflux is a physiologic occurrence in infants. Clinicians caring for neonates use histamine-2 receptor antagonists (H2As) or proton pump inhibitors (PPIs) for symptomatic reflux, apnea/bradycardia/desaturations, or irritability. Recent studies have shown that there is an increased incidence of infection, fracture, and mortality in neonates who receive antacids.

Methods:

A multidisciplinary team aimed to decrease nonindicated antacid use in the NICU by 50% by April 2019. Outcome measures include the median number of inappropriate antacid prescriptions and patient-days on acid-suppressants. Interventions include education regarding use and risks of antacids, development of a list of indications deemed “appropriate” for starting an H2A or PPI, mandatory discussion on rounds when considering antacids, documentation of treatment goal, and indication, and an automatic drop-off in the electronic medical record.

Results:

Baseline data (June–December 2017) showed 19 prescriptions of H2As or PPIs. Of those, 10 orders were deemed “inappropriate,” according to our indicated uses. There were 407 total patient-days of medication-use (median: 51 patient-days). After the implementation of the interventions (October 2018–May 2019), there were 11 prescriptions of antacid medications, 3 of which were deemed “inappropriate.” There were 206 total days of medication-use (median: 18.5 patient-days).

Conclusions:

A multidisciplinary agreement on indications for antacid use in neonates stimulates discussion and creates more purposeful use. Overall, we successfully decreased nonindicated antacid prescriptions in the NICU. For the next steps, we hope to educate physicians on the risks of antacid use and reduce prescriptions in other areas of the hospital and the outpatient setting.
Ethnic Differences in Resting Total Peripheral Resistance: A Systematic Review and Meta-Analysis
Authors: Brownlow Briana N. , Williams DeWayne P. , Kapuku Gaston , Vasey Michael W. , Anderson Norman B. , Koenig Julian , Thayer Julian F. , Hill LaBarron K.
Published: May 2020

Objective

Decades of research suggest that there may be important ethnic differences in the hemodynamic mechanisms that co-determine arterial blood pressure, the primary diagnostic index of hypertension. In general, studies have observed that, compared with European Americans (EAs), African Americans (AAs) exhibit higher total peripheral resistance (TPR), an important summative index of peripheral vascular constriction. In contrast, EAs have been reliably shown to exhibit greater cardiac output (CO), which is directly linked to left ventricle and overall cardiac blood flow. We have previously proposed that elevated basal TPR, in particular, represents one component of the cardiovascular conundrum, characterized, paradoxically, by elevated resting heart rate variability among AAs relative to EAs. The present meta-analysis and systematic review of the literature sought to extend this previous work by establishing the magnitude of the empirically implied ethnic differences in resting TPR and CO.

Methods

A search of the literature yielded 140 abstracts on differences in TPR between AAs and EAs; 40 were included. Sample sizes, means, and standard deviations for baseline TPR with samples that included EAs and AAs were collected, and Hedgesgwas computed.

Results

Findings indicated that AAs had higher baseline TPR than did EAs (Hedgesg= 0.307, SE = 0.043, confidence interval= 0.224 to 0.391,p< .001). In addition, EAs had higher resting CO than did AAs (Hedgesg= −0.214, SE = 0.056, confidence interval = −0.324 to −0.104,p< .001).

Conclusions

We discuss the present findings in the context of the role of elevated TPR in the deleterious effects of high blood pressure specifically for AAs.
The Effect of Pain Resilience on Experimental Pain Experience Across Different Stimuli
Authors: Ankawi Brett , Slepian P. Maxwell , Himawan Lina , France Christopher R.
Published: May 2020

Objective

Pain resilience, one’s ability to maintain behavioral engagement and adaptively regulate cognitions and emotions despite intense or prolonged pain, has been shown to protect against negative pain-related outcomes in experimental settings. A weakness of this research, and much of experimental pain research in general, has been the lack of rationale behind the selection of noxious stimuli, which can activate different nociceptive fibers. The present study sought to determine if the relationship between pain resilience and pain ratings differed across stimuli based on the stimulated nociceptors.

Methods

Healthy undergraduate students (N= 100; mean [SD] age = 19.4 [1.2] years; 60% female) completed the Pain Resilience Scale and provided continuous pain ratings during exposure to three different tasks, each selected based on their ability to stimulate specific combinations of nociceptive fibers: pinprick (Aδ fibers), cold water immersion (Aδ and C fibers), and ischemic tourniquet (C fibers).

Results

Participants with high pain resilience reported lower pain ratings over time during cold water immersion than did those with low pain resilience (F(1, 39) = 8.526,p= .006); however, there was no relationship between pain resilience and pain ratings during either of the pinprick or ischemic tourniquet stimuli.

Conclusions

This study provides further support for the use of multiple pain stimuli for pain assessment given their unique characteristics and concludes that outcome variables aside from pain ratings may provide additional insight into the role of resilience on pain adaptation.
Recent Trends of Infectious Complications Following Heart Transplantation
Authors: Multani Ashrit , Moayedi Yasbanoo , Puing Alfredo , Henricksen Erik , Garvert Donn W. , Gomez Carlos A. , Tremblay-Gravel Maxime , Bunce Paul E. , Luikart Helen , Ross Heather J. , Khush Kiran K. , Montoya Jose G. , Teuteberg Jeffrey J.
Published: May 2020

Background.

Heart transplantation is a life-saving procedure that has seen improvements in transplant and patient outcomes due to advances in immunosuppression and prevention of posttransplantation infectious episodes (IEps). This study systematically evaluates IEps in the modern era of heart transplantation at Stanford University Medical Center.

Methods.

This is a single-center retrospective review that includes 279 consecutive adult heart transplantation recipients from January 2008 to September 2017. Baseline demographic, clinical, serological, and outcomes information were collected. Kaplan-Meier estimator was used to assess survival stratified by IEp occurrence within the first year.

Results.

A total of 600 IEps occurred in 279 patients (2.15 IEps per patient) during a median follow-up period of 3 years. Overall survival was 83.3% (95% confidence interval [CI], 76.2-88.4) at 1 year posttransplantation for those with any IEp compared with 93.0% (95% CI, 87.2-96.4) in those without IEp (P = 0.07). Bacterial IEps were the most common (n = 375; 62.5%), followed by viral (n = 180; 30.0%), fungal (n = 40; 6.7%), and parasitic (n = 5; 0.8%). IEps by Gram-negative bacteria (n = 210) outnumbered those by Gram-positive bacteria (n = 142). Compared with prior studies from our center, there was a decreased proportion of viral (including cytomegalovirus), fungal (including Aspergillus spp. and non-Aspergillus spp. molds), and Nocardia infections. There were no IEps due to Mycobacterium tuberculosis, Pneumocystis jirovecii, or Toxoplasma gondii.

Conclusions.

A significant reduction in viral, fungal, and Nocardia IEps after heart transplantation was observed, most likely due to advancements in immunosuppression and preventive strategies, including pretransplant infectious diseases screening and antimicrobial prophylaxis.
Streptomyces aquilus sp. nov., a novel actinomycete isolated from a Chinese medicinal plant
Authors: Li Kaiqin , Guo Yihui , Wang Junzhen , Wang Zhiyong , Zhao Jiarong , Gao Jian
Published: May 2020

The taxonomic position of a novel actinomycete isolate, designated strain GGCR-6T, isolated from the healthy leaves of Xanthium sibiricum collected from the botanic garden of Hunan University of Science and Technology in Hunan province, PR China, was determined by a polyphasic approach. GGCR-6T grew well on ISP series media and formed well-developed, branched substrate hyphae and aerial mycelium that differentiated into straight spore chains consisting of cylindrical spores with smooth surfaces. The diagnostic diamino acid was ll-diaminopimelic acid. The major menaquinones were MK-9(H8), MK-9(H2), MK-9 and MK-9(H6). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphotidylinositol and phosphatidylinositol mannosides. The predominant fatty acids were C16 : 1ω9﻿c, iso-C16 : 0 and C16 : 0. The phenotypic characteristics of GGCR-6T indicated that it represented a member of the genus

Streptomyces

. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that GGCR-6T was most closely related to

Streptomyces cyaneus

NRRL B2296T and

Streptomyces griseoruber

NRRL B1818T. However, the digital DNA–DNA hybridization, the average nucleotide identity and the multi locus sequence analysis evolutionary distance clearly separate GGCR-6T from the phylogenetically closely related species. Furthermore, the novel isolate was distinctly differentiated from

S. cyaneus

NRRL B2296T and

S. griseoruber

NRRL B1818T by morphological, physiological and biochemical characteristics. Based on these data, strain GGCR-6T should be designated as a representative of a novel species of the genus

Streptomyces

, for which the name Streptomyces aquilus sp. nov. is proposed. The type strain is strain GGCR-6T (=CICC 11055T=JCM 33584T).
Estimation of the incubation period of SARS-CoV-2 in Vietnam
Authors: Bui Long Viet , Nguyen Ha Thu , Levine Hagai , Nguyen Ha , Nguyen Thu Anh , Nguyen Thuy Phuong , Nguyen Truong , Do Toan Thi Thanh , Tuan Ngoc Pham , Bui Hanh My
Published: May 2020

Objective: To estimate the incubation period of Vietnamese confirmed COVID−19 cases.
Methods: Only confirmed COVID−19 cases who are Vietnamese and locally infected with available data on date of symptom onset and clearly defined window of possible SARS−CoV−2 exposure were included. We used three parametric forms with Hamiltonian Monte Carlo method for Bayesian Inference to estimate incubation period for Vietnamese COVID−19 cases. Leave-one-out Information Criterion was used to assess the performance of three models.
Results: A total of 19 cases identified from 23 Jan 2020 to 13 April 2020 was included in our analysis. Average incubation periods estimated using different distribution model ranged from 6.0 days to 6.4 days with the Weibull distribution demonstrated the best fit to the data. The estimated mean of incubation period using Weibull distribution model was 6.4 days (95% credible interval (CI): 4.89 − 8.5), standard deviation (SD) was 3.05 (95%CI 3.05 − 5.30), median was 5.6, ranges from 1.35 to 13.04 days (2.5th to 97.5th percentiles). Extreme estimation of incubation periods is within 14 days from possible infection.
Conclusion: This analysis provides evidence for an average incubation period for COVID−19 of approximately 6.4 days. Our findings support existing guidelines for 14 days of quarantine of persons potentially exposed to SARS−CoV−2. Although for extreme cases, the quarantine period should be extended up to three weeks.
Triage tool for suspected COVID-19 patients in the emergency room: AIFELL score
Authors: Levenfus Ian , Ullmann Enrico , Battegay Edouard , Schuurmans Macé M.
Published: May 2020

Clinical prediction scores support the assessment of patients in the emergency setting to determine the need for further diagnostic and therapeutic steps. During the current COVID-19 pandemic, physicians in emergency rooms (ER) of many hospitals have a considerably higher patient load and need to decide within a short time frame whom to hospitalize. Based on our clinical experiences in dealing with COVID-19 patients at the University Hospital Zurich, we created a triage score with the acronym AIFELL consisting of clinical, radiological and laboratory findings.

The score was then evaluated in a retrospective analysis of 122 consecutive patients with suspected COVID-19 from March until mid-April 2020. Descriptive statistics, Student’s t-test, ANOVA and Scheffe’s post hoc analysis confirmed the diagnostic power of the score. The results suggest that the AIFELL score has potential as a triage tool in the ER setting intended to select probable COVID-19 cases for hospitalization in spontaneously presenting or referred patients with acute respiratory symptoms.
Sensitivity of UK Covid-19 deaths to the timing of suppression measures and their relaxation
Authors: Dagpunar John S
Published: May 2020

In this paper I examine the sensitivity of total UK Covid-19 deaths and the demand for intensive care and ward beds, to the timing and duration of suppression periods during a 500 day period. This is achieved via a SEIR model. Using an expected latent period of 4.5 days and infectious period of 3.8 days, R_0 was first estimated as 3.18 using observed death rates under unmitigated spread and then under the effects of the total lockdown (R_0=0.60) of 23 March. The case fatality rate given infection is taken as 1%. Parameter values for mean length of stay and conditional probability of death for ICU and non-ICU hospital admissions are guided by Ferguson et al.(2020). Under unmitigated spread the model predicts around 600,000 deaths in the UK. Starting with one exposed person at time zero and a suppression consistent with an R_0 of 0.60 on day 72, the model predicts around 39,000 deaths for a first wave, but this reduces to around 11,000 if the intervention takes place one week earlier. If the initial suppression were in place until day 200 and then relaxed to an R_0 of 1.5 between days 200 and 300, to be followed by a return to an R_0 of 0.60, the model predicts around 43,000 deaths. This would increase to around 64,000 if the release from the first suppression takes place 20 days earlier. The results indicate the extreme sensitivity to timing and the consequences of even small delays to suppression and premature relaxation of such measures.
The impact of isolation measures due to COVID-19 on energy intake and physical activity levels in Australian university students
Authors: Gallo Linda A. , Gallo Tania F. , Young Sophia L. , Moritz Karen M. , Akison Lisa K.
Published: May 2020

Background

The pandemic inflicted by coronavirus disease 2019 (COVID-19) resulted in physical isolation measures in many parts of the world. In Australia, nationwide restrictions included staying at home, unless seeking medical care, providing care, purchasing food, undertaking exercise, or attending work in an essential service. All undergraduate university classes transitioned to online, mostly home-based learning. This disruption to daily life may have consequences for eating and physical activity patterns.

Methods

In this observational study, we examined the effect of isolation measures, during the early phase of the COVID-19 pandemic in Australia (March/April), on diet (24-hour diet recall, ASA-24) and physical activity (Active Australia Survey) patterns among third-year biomedical students in Brisbane, Australia. Findings were compared to students enrolled in the same course in the previous two years.

Results

In females, energy intake was ~20% greater in 2020 compared with 2018 and 2019, and the frequency of snacking and energy density of consumed snacks were also increased. In males, there was no difference in energy intake or snacking behaviour. Physical activity was impacted for both sexes, whereby fewer students undertook any walking activity and, of those that did, time spent doing so was less compared with 2018 and 2019. The proportion of students reporting any vigorous activity was not different for males or females but, among males who participated in this level of activity, the duration was less in 2020 compared with previous years. The proportion of male and female students achieving ‘sufficient’ levels of activity, defined by at least 150 mins over at least 5 sessions, was ~30% less in 2020. Indeed, the majority of students reported as having undertaken less physical activity than usual.

Conclusions

Increased energy intake for females and reduced physical activity for males and females demonstrate impacts of isolation measures that may have deleterious consequences for physical and mental wellbeing, with the potential to affect long-term nutrition and activity patterns.
Modeling COVID 19 in the Basque Country: from introduction to control measure response
Authors: Aguiar Maíra , Millán Ortuondo Eduardo , Van-Dierdonck Joseba Bidaurrazaga , Mar Javier , Stollenwerk Nico
Published: May 2020

In March 2020, a multidisciplinary task force (so-called Basque Modelling Task Force, BMTF) was created to assist the Basque Health managers and the Basque Government during the COVID-19 responses. BMTF is a modeling team, working on different approaches, including stochastic processes, statistical methods and artificial intelligence. In this paper we describe and present the results obtained by a new stochastic SHARUCD model framework which was able to describe the disease incidence data provided by the Basque Health Services. Our models differentiate mild and asymptomatic from severe infections prone to be hospitalized and were able to predict the course of the epidemic, from introduction to control measure response, providing important projections on the national health system necessities during the increased population demand on hospital ad-missions. Short and longer-term predictions were tested with good results adjusted to the current epidemiological data, showing that the partial lockdown measures were effective and enough to slow down disease transmission in the Basque Country. The growth rate λ Is calculated from the model and from the data and the implications for the reproduction ratio r are shown. At the moment, the reproduction ratio r is estimated to be below the threshold behavior of r = 1, but still close to 1, meaning that although the number of new cases are decelerating, a careful monitoring of the development of the outbreak is required. This framework is now being used to monitor disease transmission while the country lock-down is gradually lifted, with insights to specific programs for a general policy of “social distancing” and home quarantining. These are the first publicly available modeling results for the Basque Country and the efforts will be continued taking into consideration the updated data and new information that are generated over time.
Covasim: an agent-based model of COVID-19 dynamics and interventions
Authors: Kerr Cliff C. , Stuart Robyn M. , Mistry Dina , Abeysuriya Romesh G. , Rosenfeld Katherine , Hart Gregory R. , Núñez Rafael C. , Cohen Jamie A. , Selvaraj Prashanth , Hagedorn Brittany , George Lauren , Jastrzębski Michał , Izzo Amanda , Fowler Greer , Palmer Anna , Delport Dominic , Scott Nick , Kelly Sherrie , Bennette Caroline S. , Wagner Bradley , Chang Stewart , Oron Assaf P. , Wenger Edward , Panovska-Griffiths Jasmina , Famulare Michael , Klein Daniel J.
Published: May 2020

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.
Modulation of motor cortical excitability by continuous theta-burst stimulation in adults with autism spectrum disorder: The roles of BDNF and APOE polymorphisms
Authors: Jannati Ali , Ryan Mary A , Block Gabrielle , Kayarian Fae B. , Oberman Lindsay M. , Rotenberg Alexander , Pascual-Leone Alvaro
Published: May 2020

Objective. To assess the utility of the modulation of motor cortex (M1) excitability by continuous theta-burst stimulation (cTBS) as a physiologic biomarker for adults with autism spectrum disorder (ASD), and to evaluate the influences of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) polymorphisms on cTBS aftereffects.
Methods. 44 neurotypical individuals (NT; age 21-65, 34 males) and 19 age-matched adults with high-functioning ASD (age 21-58, 17 males) underwent M1 cTBS. Cortico-motor reactivity was assessed before cTBS and thereafter every 5-10 minutes for 60 minutes (T5-T60).
Results. Logistic regressions found cTBS-induced change in amplitude of motor evoked potentials (ΔMEP) at T15 was a significant predictor of ASD diagnosis (p=0.04). ΔMEP at T15 remained a significant predictor of diagnosis among BDNF Met+ subjects and APOEε4- subjects (p-values < 0.05) but not BDNF Met- subjects. ΔMEP at T30 was the best predictor of diagnosis among APOEε4+ subjects (p = 0.08).
Conclusions. We confirm previous findings on the utility of cTBS measures of plasticity for adults with ASD, and we find the diagnostic utility of cTBS is modulated by BDNF and APOE SNPs.
Significance. It is important to control for BDNF and APOE polymorphisms when comparing TBS aftereffects in ASD and NT individuals.
De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
Authors: Klöckner Chiara , Sticht Heinrich , Zacher Pia , Popp Bernt , Bakker Dewi P. , Barwick Katy , Bonfert Michaela V. , Brilstra Eva H. ,   Care4Rare Canada Consortium, Chung Wendy K. , Clarke Angus J. , Devine Patrick , Friedman Jennifer , Gates Alyssa , Horvath Gabriella , Keller-Ramey Jennifer , Keren Boris , Kurian Manju A. , Lee Virgina , Leppig Kathleen A. , Lundgren Johan , McDonald Marie T. , McTague Amy , Mefford Heather C. , Mignot Cyril , Mikati Mohamad A. , Nava Caroline , Raymond F. Lucy , Sampson Julian R. , Sanchis-Juan Alba , Shashi Vandana , Shieh Joseph T.C. , Shinawi Marwan , Slavotinek Anne , Stödberg Tommy , Stong Nicholas , Sullivan Jennifer A. , Taylor Ashley C. , Toler Tomi L. , van den Bogaard Marie-José , van der Crabben Saskia N. , van Gassen Koen , van Jaarsveld Richard H. , Van Ziffle Jessica , Wadley Alexandrea F. , Wagner Matias , Wortmann Saskia B. , Møller Rikke S. , Lemke Johannes R. , Platzer Konrad
Published: May 2020

Purpose

This study aims to provide the first comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25- DEE) by reviewing newly identified and previously reported individuals.

Methods

Individuals harboring heterozygous missense or truncating variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms and literature review. For each individual, detailed phenotyping, classification and structural modeling of the identified variant was performed.

Results

The cohort comprises 20 individuals with (likely) pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cortical visual impairment and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion

We provide a first comprehensive description of SNAP25-DEE with intellectual disability and early onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1 or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies”.
Prevalence of Hospital PCR Confirmed COVID-19 Cases in Patients with Chronic Inflammatory and Autoimmune Rheumatic Diseases
Authors: Pablos José L. , Abasolo-Alcázar Lydia , Álvaro-Gracia José M. , Blanco Francisco J. , Blanco Ricardo , Castrejón Isabel , Fernández-Fernández David , Fernández-Gutierrez Benjamín , Galindo María , González-Gay Miguel A. , Manrique-Arija Sara , Mena-Vázquez Natalia , Mera-Varela Antonio , Retuerto Miriam , Seijas-Lopez Álvaro ,   RIER investigators group
Published: May 2020

Background

The susceptibility of patients with rheumatic diseases, and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown.

Methods

We performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with SARS-CoV-2 positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups.

Results

Patients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Systemic autoimmune or immune mediated diseases (AI/IMID) patients showed a significant increase, whereas inflammatory arthritis (IA) or systemic lupus erythematosus (SLE) patients did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. IA patients on targeted-synthetic or biological disease-modifying antirheumatic drugs (ts/bDMARD), but not those on conventional-synthetic (csDMARD), had a greater prevalence despite a similar age distribution.

Conclusion

Patients with AI/IMID show a variable risk of hospital diagnosed COVID-19. Interplay of aging, therapies, and disease specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyze the specific factors involved in COVID-19 susceptibility.
COVID-19 Pandemic in Pakistan: Stages and Recommendations
Authors: Saif Farhan
Published: May 2020

We present a real-time forecast of COVID-19 in Pakistan that is important for decision-making to control the spread of the pandemic in the country. The study helps to develop an accurate plan to eradicate the COVID-19 by taking calculated steps at the appropriate time, that are crucial in the absence of a tested medicine. We use four phenomenological mathematical models, namely Discrete Exponential Growth model, the Discrete Generalized Growth model, the Discrete Generalized Logistic Growth, and Discrete Generalize Richards Growth model. Our analysis explains the important characteristics quantitatively. The study leads to understand COVID-19 pandemic in Pakistan in three evolutionary stages, and provides understanding to control its spread in the short time domain and in the long term domain. For the reason the study is helpful in devising the measures to handle the emerging threat of similar outbreaks in other countries.
Monitoring and Tracking the Evolution of a Viral Epidemic Through Nonlinear Kalman Filtering: Application to the Covid-19 Case
Authors: Gomez-Exposito Antonio , Rosendo-Macias Jose A. , Gonzalez-Cagigal Miguel A.
Published: May 2020

This work presents a novel methodology for systematically processing the time series that report the number of positive, recovered and deceased cases from a viral epidemic, such as Covid-19. The main objective is to unveil the evolution of the number of real infected people, and consequently to predict the peak of the epidemic and subsequent evolution. For this purpose, an original nonlinear model relating the raw data with the time-varying geometric ratio of infected people is elaborated, and a Kalman Filter is used to estimate the involved state variables. A hypothetical simulated case is used to show the adequacy and limitations of the proposed method. Then, several countries, including China, South Korea, Italy, Spain, UK and the USA, are tested to illustrate its behavior when real-life data are processed. The results obtained clearly show the beneficial effect of the social distancing measures adopted worldwide, confirming that the Covid-19 epidemic peak is left behind in those countries where the outbreak started earlier, and anticipating when the peak will take place in the remaining countries.
Density-Preserving Data Visualization Unveils Dynamic Patterns of Single-Cell Transcriptomic Variability
Authors: Narayan Ashwin , Berger Bonnie , Cho Hyunghoon
Published: May 2020

Nonlinear data-visualization methods, such as t-SNE and UMAP, have become staple tools for summarizing the complex transcriptomic landscape of single cells in 2D or 3D. However, existing approaches neglect the local density of data points in the original space, often resulting in misleading visualizations where densely populated subpopulations of cells are given more visual space even if they account for only a small fraction of transcriptional diversity within the dataset. We present den-SNE and densMAP, our density-preserving visualization tools based on t-SNE and UMAP, respectively, and demonstrate their ability to facilitate more accurate visual interpretation of single-cell RNA-seq data. On recently published datasets, our methods newly reveal significant changes in transcriptomic variability within a range of biological processes, including cancer, immune cell specialization in human, and the developmental trajectory ofC. elegans. Our methods are readily applicable to visualizing high-dimensional data in other scientific domains.
RTEL1 Influences the Abundance and Localization of TERRA RNA
Authors: Ghisays Fiorella , Garzia Aitor , Wang Hexiao , Canasto-Chibuque Claudia , Hohl Marcel , Savage Sharon A. , Tuschl Thomas , Petrini John H. J.
Published: May 2020

Telomere repeat containing RNAs (TERRAs) are a family of long non-coding RNAs transcribed from the sub-telomeric regions of eukaryotic chromosomes. TERRA transcripts can form R-loops at chromosome ends; however the importance of these structures or the regulation of TERRA expression and retention in telomeric R-loops remain unclear. Here, we show that the RTEL1 (Regulator of Telomere Length 1) helicase influences the abundance and localization of TERRA in human cells. Depletion of RTEL1 leads to increased levels of TERRA RNA while reducing TERRA-containing R loops at telomeres. In vitro, RTEL1 shows a strong preference for binding G-quadruplex structures which form in TERRA. This binding is mediated by the C-terminal region of RTEL1, and is independent of the RTEL1 helicase domain. RTEL1 binding to TERRA appears to be essential for cell viability, underscoring the importance of this function. Degradation of TERRA containing R-loops by overexpression of RNAse H1 partially recapitulates the increased TERRA levels and telomeric instability associated with RTEL1 deficiency. Collectively, these data suggest that regulation of TERRA at the telomeres is a key function of the RTEL1 helicase, and that loss of that function may contribute to the disease phenotypes of patients with RTEL1 mutations.
Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)
Authors: Jiang Honglin , Muir Ryan K. , Gonciarz Ryan L. , Olshen Adam B. , Yeh Iwei , Hann Byron C. , Zhao Ning , Wang Yung-hua , Behr Spencer C. , Korkola James E. , Evans Michael J. , Collisson Eric A. , Renslo Adam R.
Published: May 2020

KRASmutations cause a quarter of cancer mortality and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at dosages required to adequately extinguish RAS/RAF/MAPK signaling. We found that oncogenic KRAS signaling induces ferrous iron (Fe2+) accumulation early in and throughout KRAS-mediated transformation. We used an FDA-approved MEK inhibitor to produce a prototypical Ferrous Iron–Activatable Drug Conjugate (FeADC) which achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor bearing animals, with tumor-selective drug activation producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation and FeADCs hold promise for improving treatment of KRAS-driven solid tumors.
Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells andDrosophila melanogastermodel of Alzheimer’s disease
Authors: Tan Florence Hui Ping , Ting Andrew Chung Jie , Najimudin Nazalan , Watanabe Nobumoto , Azzam Ghows
Published: May 2020

Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder worldwide. Its pathogenesis involves the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 has been found to be the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. With the ability to utilize various genetic manipulations,Drosophila melanogasteris ideal in analysing not only cellular characteristics, but also physiological and behavioural traits of human neurodegenerative diseases. Danshen water extract (DWE), obtained from the root ofSalvia miltiorrhizaBunge, was found to have a vast array of beneficial properties. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to ameliorate Aβ42’s effects. DWE, SalA and SalB were confirmed to be able to reduce fibrillation of Aβ42. As Aβ42 causes neurodegeneration on neurons, DWE, SalA and SalB were tested on Aβ42-treated PC12 neuronal cells and were shown to increase cell viability. DWE and its components were then tested on theDrosophila melanogasterAD model and their rescue effects were further characterized. When human Aβ42 was expressed, theDrosophilaexhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of ADDrosophilaand improved most of the mobility of ADDrosophila. In conclusion, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.
Using local convolutional neural networks for genomic prediction
Authors: Pook Torsten , Freudenthal Jan , Korte Arthur , Simianer Henner
Published: May 2020

The prediction of breeding values and phenotypes is of central importance for both livestock and crop breeding. With increasing computational power and more and more data to potentially utilize, Machine Learning and especially Deep Learning have risen in popularity over the last few years. In this study, we are proposing the use of local convolutional neural networks for genomic prediction, as a region specific filter corresponds much better with our prior genetic knowledge of traits than traditional convolutional neural networks. Model performances are evaluated on a simulated maize data panel (n = 10,000) and real Arabidopsis data (n = 2,039) for a variety of traits with the local convolutional neural network outperforming both multi layer perceptrons and convolutional neural networks for basically all considered traits. Linear models like the genomic best linear unbiased prediction that are often used for genomic prediction are outperformed by up to 24%. Highest gains in predictive ability was obtained in cases of medium trait complexity with high heritability and large training populations. However, for small dataset with 100 or 250 individuals for the training of the models, the local convolutional neural network is performing slightly worse than the linear models. Nonetheless, this is still 15% better than a traditional convolutional neural network, indicating a better performance and robustness of our proposed model architecture for small training populations. In addition to the baseline model, various other architectures with different windows size and stride in the local convolutional layer, as well as different number of nodes in subsequent fully connected layers are compared against each other. Finally, the usefulness of Deep Learning and in particular local convolutional neural networks in practice is critically discussed, in regard to multi dimensional inputs and outputs, computing times and other potential hazards.
RosENet: Improving binding affinity prediction by leveraging molecular mechanics energies with a 3D Convolutional Neural Network
Authors: Hassan-Harrirou Hussein , Zhang Ce , Lemmin Thomas
Published: May 2020

The worldwide increase and proliferation of drug resistant microbes, coupled with the lag in new drug development represents a major threat to human health. In order to reduce the time and cost for exploring the chemical search space, drug discovery increasingly relies on computational biology approaches. One key step in these approaches is the need for the rapid and accurate prediction of the binding affinity for potential leads.

Here, we present RosENet (RosettaEnergy NeuralNetwork), a three-dimensional (3D) Convolutional Neural Network (CNN), which combines voxelized molecular mechanics energies and molecular descriptors for predicting the absolute binding affinity of protein – ligand complexes. By leveraging the physico-chemical properties captured by the molecular force field, our model achieved a Root Mean Square Error (RMSE) of 1.26 on the PDBBind v2016core set. We also explored some limitations and the robustness of the PDBBind dataset and our approach, on nearly 500 structures, including structures determined by Nuclear Magnetic Resonance and virtual screening experiments. Our study demonstrated that molecular mechanics energies can be voxelized and used to help improve the predictive power of the CNNs. In the future, our framework can be extended to features extracted from other biophysical and biochemical models, such as molecular dynamics simulations.

Availability

https://github.com/DS3Lab/RosENet
Probing the functions of microglial cyclin-dependent kinase 5 under physiological and pathological conditions
Authors: Peng Zhuyu , Huang Wen-Chin , Chen Maggie , Penney Jay , Cam Hugh , Abdurrob Fatema , Akay Leyla , Chen Xiao , Ralvenius William T. , Rubino Lorena Pantano , Tsai Li-Huei
Published: May 2020

Cyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimer’s disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses.
Integration of haptics and vision in human multisensory grasping
Authors: Camponogara Ivan , Volcic Robert
Published: May 2020

Grasping actions are directed not only toward objects we see but also toward objects we both see and touch (multisensory grasping). In this latter case, the integration of visual and haptic inputs improves movement performance compared to each sense alone. This performance advantage could be due to the integration of all the redundant positional and size cues or to the integration of only a subset of these cues. Here we selectively provided specific cues to tease apart how these different sensory sources contribute to visuo-haptic multisensory grasping. We demonstrate that the availability of the haptic positional cue together with the visual cues is sufficient to achieve the same grasping performance as when all cues are available. These findings provide strong evidence that the human sensorimotor system relies on non-visual sensory inputs and open new perspectives on their role in supporting vision during both development and adulthood.