bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating Force of Infection from Serologic Surveys with Imperfect Tests
Authors: Alexander Neal , Carabali Mabel , Lim Jacqueline K
Published: June 2020

The force of infection, or the rate at which susceptible individuals become infected, is an important public health measure for assessing the extent of outbreaks and the impact of control programs. Here we present methods for estimating force of infection from serological surveys of infections which produce lasting immunity, taking into account imperfections in the test used, and uncertainty in such imperfections. The methods cover both single serological surveys, in which age is a proxy for time at risk, and repeat surveys in the same people, in which the force of infection is estimated more directly. Fixed values can be used for the sensitivity and specificity of the tests, or existing methods for belief elicitation can be used to include uncertainty in these values. The latter may be applicable, for example, when the specificity of a test depends on co-circulating pathogens, which may not have been well characterized in the setting of interest. We illustrate the methods using data from two published serological studies of dengue.
Prevalence of anticipatory nausea and vomiting in children undergoing cytotoxic chemotherapy for malignant disease - the SiCK2 (Sickness prior to Chemotherapy in Kids) study
Authors: Phillips Bob , ffrench-Devitt Patric , Wellings Lucy
Published: June 2020

Introduction

Anticipatory nausea and vomiting (ANV) is thought to be a conditioned response to nausea and vomiting experienced in previous chemotherapy cycles, and has a significant negative impact on quality of life for children having treatment for cancer. The prevalence of this aversive experience with current antiemetics remains uncertain.

Methods

Self-report questionnaires completed by patients and parents across seven sites in the UK. Nausea and vomiting symptoms 24 hours prior to commencing chemotherapy were assessed with the Pediatric Nausea Assessment Tool (PeNAT). Data were also collected on the patients’ age, sex, oncological diagnosis, and previous experience of chemotherapy induced nausea and vomiting. Correlation between demographic data, chemotherapy information and prior reported experience of chemotherapy related nausea and vomiting was under-taken using multiple ordinal regression.

Results

191 episodes of anticipatory nausea and vomiting status were returned. 34% of patients described severe or very severe anticipatory nausea and/or vomiting. The severity of anticipatory nausea and vomiting was predicted two factors related to prior chemotherapy: control of anticipatory (OR 0.23 95%CI 0.09 to 0.53) and acute/delayed (OR 0.37, 95% CI 0.16 to 0.83) nausea and vomiting, and one current factor, the administration of antiemetic medication prior to arrival at the hospital (OR 3.0, 95%CI 1.3 to 6.8).

Conclusions

This study re-enforces, disappointingly, the continued high prevalence of anticipatory nau-sea and vomiting in children about to receive chemotherapy. There is clearly a need to improve interventions for this rarely discussed aversive experience of childhood cancer. Its high prevalence suggests trials of interventions should be possible to power effectively, and develop interventions that are both acceptable and deliverable.
Modeling the Transmission of Respiratory Infectious Diseases in Mass Transportation Systems
Authors: Buhat Christian Alvin H. , Lutero Destiny SM. , Olave Yancee H. , Torres Monica C. , Rabajante Jomar F.
Published: June 2020

Mass transportation is one of the areas that are badly hit by respiratory infectious disease outbreaks due to moderate to high exposure risk to pathogens brought about by the interaction among commuters. Here, we formulate agent-based models that simulate the spread of a respiratory infectious disease in a train wagon in the Manila Light Rail Transit System, and in a 49-seater public utility bus. We consider preventive measures such as implementation of social distancing, and limitation of interaction or movement among the commuters to investigate how these measures will inhibit disease transmission. We also consider the effect of protective gears and practices, crowd density, and prevalence of disease in the community on the possible number of newly-infected individuals. Our simulations show that (i) individuals must have protection with more than 90% effectiveness to inhibit transmission of the disease; (ii) social or physical distancing by more than 1m distance reduces the risk of being infected; (iii) minimizing movement or interaction with other passengers reduces the risk of transmission by 50%; (iv) passenger capacity should be less than 10-50% of the maximum seating capacity to reduce the number of infections depending on the level of imposed social distancing and passenger interaction; (v) vehicles with greater number of occupied seating capacity generate higher number of infections but vehicles with smaller dimensions have faster disease transmissions; and (vi) ideal set-up for a 24-seater train wagon (49-seater bus) is to allow a maximum of 12 (24) passengers, with little to no interaction among passengers, with social distancing of more than 1m distance apart, and each person has a protection with 90% effectiveness as much as possible. These results can aid policy makers in determining optimal strategies to minimize infections while maintaining transportation services during pandemics or disease outbreaks.
WELCOME-GP: A randomised controlled trial of the effectiveness of a targeted postal cancer awareness intervention for increasing attendance at general practice
Authors: Laake Jean-Pierre , Vulkan Daniel , Quaife Samantha L , Hamilton William T , Martins Tanimola , Waller Jo , Parmar Dharmishta , Sasieni Peter , Duffy Stephen W
Published: June 2020

Objective

To assess the effectiveness of a targeted postal promotion for improving cancer symptom awareness and increasing help-seeking in general practice, on subsequent general practitioner (GP) consultation rates in a population which has made infrequent use of consultations at their local practice.

Setting

23 general practices in England.

Design

Randomised controlled trial comparing a mailed leaflet providing information on six key cancer symptoms plus a covering letter signed by their general practitioner designed to reduce barriers to primary care help-seeking (intervention arm), with usual care (control arm).

Participants

1,513 adults aged 50-84 years (783 individually randomised to the intervention arm and 730 individually randomised to the control arm) who had not consulted their GP in the last 12 months and had at least two other risk factors for late presentation with cancer, identified by practice staff between November 2016 and May 2017. 749 individuals in the intervention arm and 705 in the control arm were included in the intention to treat analyses.

Outcome measure

The primary outcome was number of GP consultations in the six months subsequent to mailing of the intervention.

Results

There was a significantly higher rate of consultation in the intervention arm: 436 consultations compared to 335 in the control arm (RR = 1.40, 95% CI 1.11-1.77, p=0.004). However, there was no difference in the numbers of persons consulting their GP, with 165 in each group.

Conclusions

Targeted interventions of this nature can change behaviour. This intervention stimulated a greater number of consultations but not a greater number of patients consulting. There is a need to develop interventions which can be more effective on the broader less engaged population.

Trial registration

The trial was registered prospectively on the International Standard Randomised Controlled Trial Number (ISRCTN) registry (ISRCTN95610478).

Funding

This research is funded by the National Institute for Health Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis, 106/0001. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Additional support, including NHS service support costs, were provided by the National Institute for Health Research Clinical Research Network (NIHR CRN) (UKCRN ID 31163).
Initial Whole Genome Sequencing and Analysis of the Host Genetic Contribution to COVID-19 Severity and Susceptibility
Authors: Wang Fang , Huang Shujia , Gao Rongsui , Zhou Yuwen , Lai Changxiang , Li Zhichao , Xian Wenjie , Qian Xiaobo , Li Zhiyu , Huang Yushan , Tang Qiyuan , Liu Panhong , Chen Ruikun , Liu Rong , Li Xuan , Tong Xin , Zhou Xuan , Bai Yong , Duan Gang , Zhang Tao , Xu Xun , Wang Jian , Yang Huanming , Liu Siyang , He Qing , Jin Xin , Liu Lei
Published: June 2020

The COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene locus associated with severity is located in TMEM189-UBE2V1 involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We also identified that the HLA-A*11:01, B*51:01 and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial study of Chinese patients provides a comprehensive view of the genetic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.
An Ensembled Deep Learning Model Outperforms Human Experts in Diagnosing Biliary Atresia from Sonographic Gallbladder Images
Authors: Zhou Wenying , Yang Yang , Yu Cheng , Liu Juxian , Duan Xingxing , Weng Zongjie , Chen Dan , Liang Qianhong , Qing Fang , Zhou Jiaojiao , Ju Hao , Luo Zhenhua , Guo Weihao , Ma Xiaoyan , Xie Xiaoyan , Wang Ruixuan , Zhou Luyao
Published: June 2020

It is still difficult to make accurate diagnosis of biliary atresia (BA) by sonographic gallbladder images particularly in rural area lacking relevant expertise. To provide an artificial intelligence solution to help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model was developed based on a small set of sonographic images. The model yielded a patient-level sensitivity 93.1% and specificity 93.9% (with AUROC 0.956) on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performance of human experts with various levels would be improved further. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yielded expert-level performance. Our study provides a deep learning solution to help radiologists improve BA diagnosis in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise.
TMPRSS2 variants and their susceptibility to COVID-19: focus in East Asian and European populations
Authors: dos Santos Ney Pereira Carneiro , Khayat André Salim , Gomes Rodrigues Juliana Carla , Pinto Pablo , de Araújo Gilderlanio Santana , Pastana Lucas Favacho , Medeiros Jéssyca Amanda Gomes , Fernandes Marianne Rodrigues , Ribeiro-dos-Santos Arthur , Meireles Khayat Bruna Claudia , Moreira Fabiano Cordeiro , Ribeiro-dos-Santos André Maurício , de Assumpção Paula Baraúna , Ribeiro-dos-Santos Ândrea , Assumpção Paulo Pimentel de , Santos Sidney
Published: June 2020

The manifestation of the COVID-19 varies from absence of symptoms to Severe Acute Respiratory Syndrome. The epidemiological data indicate that infection and mortality rates are greater in European populations in comparison with eastern Asians. To test if epidemiological patterns may be partly determined by human genetic variation, we investigated, by exomic and databank analyses, the variability found in the TMPRSS2 gene in populations from different continents, since this gene is fundamental to virus access into human cells. The functional variants revealed low diversity. The analyses of the variation in the modifiers of gene expression indicate that the European populations may have much higher levels of pulmonary expression of the TMPRSS2 gene and would be more vulnerable to infection by SARS-CoV-2. By contrast, the pulmonary expression of the TMPRSS2 may be reduced in the populations from East Asia, which implies that they are less susceptible to the virus infection and, these genetic features might also favor their better outcomes. The presented data, if confirmed, indicates a potential genetic contribution of TMPRSS2 to individual susceptibility to viral infection, and might also influence COVID-19 outcome.
Work-related and Personal Factors Associated with Mental Well-being during COVID-19 Response: A Survey of Health Care and Other Workers
Authors: Evanoff Bradley A. , Strickland Jaime R. , Dale Ann Marie , Hayibor Lisa , Page Emily , Duncan Jennifer G. , Kannampallil Thomas , Gray Diana L.
Published: June 2020

Objective

Measure the prevalence of stress, anxiety, depression, work-exhaustion, burnout, and decreased well-being among faculty and staff at a university and academic medical center during the SARS-CoV-2 pandemic, and describe work-related and personal factors associated with mental health and well-being.

Design

Observational cohort study conducted between April 17 and May 1, 2020 using a web-based questionnaire.

Setting

Medical and main campuses of a university.

Participants

All faculty, staff, and post-doctoral fellows.

Exposures

Work factors including supervisor support and exposure to high-risk clinical settings; personal factors including demographics and family/home stressors.

Main Outcomes and Measures

Stress, anxiety, depression, work exhaustion, burnout, and decreased well-being.

Results

There were 5550 respondents (overall response rate of 34.3%). 38% of faculty and 14% of staff (n=915) were providing clinical care, while 57% of faculty and 77% of staff were working from home. The prevalence of anxiety, depression, and work exhaustion were somewhat higher among clinicians than non-clinicians. Among all workers, anxiety, depression, and high work exhaustion were independently associated with community or clinical exposure to COVID-19 [Prevalence Ratios and 95% confidence intervals 1.37(1.09- 1.73), 1.28(1.03 - 1.59), and 1.24(1.13 - 1.36) respectively]. Poor family supportive behaviors by supervisors were also associated with these outcomes [1.40 (1.21 - 1.62), 1.69 (1.48 - 1.92), 1.54 (1.44 - 1.64)]. Age below 40 and a greater number of family/home stressors were also associated with poorer outcomes. Among the subset of clinicians, caring for patients with COVID-19 and work in high-risk clinical settings were additional risk factors.

Conclusions and Implications

Our findings suggest that the pandemic has had negative effects on mental health and well-being among both clinical and non-clinical employees. Prevention of exposure to COVID-19 and increased supervisor support are modifiable risk factors that may protect mental health and well-being.
What does and does not correlate with COVID-19 death rates
Authors: Knittel Christopher R. , Ozaltun Bora
Published: June 2020

We correlate county-level COVID-19 death rates with key variables using both linear regression and negative binomial mixed models, although we focus on linear regression models. We include four sets of variables: socio-economic variables, county-level health variables, modes of commuting, and climate and pollution patterns. Our analysis studies daily death rates from April 4, 2020 to May 27, 2020. We estimate correlation patterns both across states, as well as within states. For both models, we find higher shares of African American residents in the county are correlated with higher death rates. However, when we restrict ourselves to correlation patterns within a given state, the statistical significance of the correlation of death rates with the share of African Americans, while remaining positive, wanes. We find similar results for the share of elderly in the county. We find that higher amounts of commuting via public transportation, relative to telecommuting, is correlated with higher death rates. The correlation between driving into work, relative to telecommuting, and death rates is also positive across both models, but statistically significant only when we look across states and counties. We also find that a higher share of people not working, and thus not commuting either because they are elderly, children or unemployed, is correlated with higher death rates. Counties with higher home values, higher summer temperatures, and lower winter temperatures have higher death rates. Contrary to past work, we do not find a correlation between pollution and death rates. Also importantly, we do not find that death rates are correlated with obesity rates, ICU beds per capita, or poverty rates. Finally, our model that looks within states yields estimates of how a given state’s death rate compares to other states after controlling for the variables included in our model; this may be interpreted as a measure of how states are doing relative to others. We find that death rates in the Northeast are substantially higher compared to other states, even when we control for the four sets of variables above. Death rates are also statistically significantly higher in Michigan, Louisiana, Iowa, Indiana, and Colorado. California’s death rate is the lowest across all states.

It is important to understand that this research, and other observational analyses like it, only identify correlations: these relationships are not necessarily causal. However, these correlations may help policy makers identify variables that may potentially be causally related to COVID-19 death rates and adopt appropriate policies after understanding the causal relationship.
Association between use of aspirin use before hospital admission and sepsis outcomes: a population-based cohort study
Authors: Hsu Wan-Ting , Porta Lorenzo , Hsu Tzu-Chun , Chen Shyr-Chyr , Lee Chien-Chang
Published: June 2020

Objectives

Antiplatelet agents have been shown to reduce serum levels of inflammatory markers and may reduce sepsis mortality. A previous randomized clinical trial did not find that aspirin use after hospitalization, compared with placebo, improve acute respiratory distress syndrome within 7 days. We aimed to examine the association between preadmission use of aspirin and sepsis outcome.

Methods

We conducted a population-based cohort study based on the National Health Insurance Research Database of Taiwan. The association between aspirin use and 90-day mortality in sepsis patients was determined by Cox proportional hazard models, adjusting for either individual covariates or a propensity score. Restricted mean survival time (RMST) analysis was performed as a sensitivity analysis.

Results

Of 52,982 patients with sepsis, 12,776 received preadmission use of aspirin, while 39,081 did not receive any antiplatelets. Use of aspirin before sepsis admission was associated with a decreased risk of 90-day mortality (PS-adjusted HR: 0.89, 95% CI: 0.84-0.93). RMST analysis confirmed the beneficial effect of aspirin which was associated with a 2% increase in survival time (RMST ratio 1.02, 95% CI: 1.01-1.03), when compared to nonuse. On PS adjusted analysis, the odds ratios (OR) of respiratory failure with the preadmission use of aspirin was 0.98 (95% CI: 0.93-1.03), but we did not find any significant association between prior aspirin use and respiratory failure.

Conclusions

Our study confirms that prehospital aspirin use was associated with a reduced 90-day mortality rate among sepsis patients, but we did not find any substantial association with respiratory or acute renal failure.
Child wasting and concurrent stunting in low- and middle-income countries
Authors: Mertens Andrew , Benjamin-Chung Jade , Colford John M , Hubbard Alan E , van der Laan Mark J , Coyle Jeremy , Sofrygin Oleg , Cai Wilson , Jilek Wendy , Rosete Sonali , Nguyen Anna , Pokpongkiat Nolan N , Djajadi Stephanie , Seth Anmol , Jung Esther , Chung Esther O , Malenica Ivana , Hejazi Nima , Li Haodong , Hafen Ryan , Subramoney Vishak , Häggström Jonas , Norman Thea , Christian Parul , Brown Kenneth H , Arnold Benjamin F. ,   members of the ki Child Growth Consortium
Published: June 2020

Sustainable Development Goal 2.2, to end malnutrition by 2030, includes elimination of child wasting, defined as weight-for-length more than 2 standard deviations below international standards. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery, and persistence — key features that inform preventive interventions and disease burden estimates. We analyzed 21 longitudinal cohorts to show wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. By age 24 months 29.2% of children had experienced at least one wasting episode, more than 5-fold higher than point prevalence (5.6%), demonstrating that wasting affects far more children than can be inferred through cross-sectional surveys. Children wasted before 6 months had faster recovery and shorter episodes than children wasted at older ages, but early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low height-for-age), increasing their risk of mortality. In diverse populations with high seasonal rainfall, population average weight-for-length varied substantially (>0.5 z in some cohorts), with the lowest mean Z-scores during the rainiest months, creating potential for seasonally targeted interventions. Our results elevate the importance of establishing interventions to prevent wasting from birth to age 6 months, likely through improved maternal nutrition, to complement current programs that focus on children ages 6-59 months.
Impact of COVID-19 pandemic on lung cancer treatment scheduling
Authors: Fujita Kohei , Ito Takanori , Saito Zentaro , Kanai Osamu , Nakatani Koichi , Mio Tadashi
Published: June 2020

Objective

Current pandemic of coronavirus disease 2019 (COVID-19) is associated with a heavy burden on the mental and physical health of patients, regional healthcare resources, and global economic activity. Many patients with lung cancer are thought to be affected by this situation. Therefore, we aimed to evaluate the impact of COVID-19 pandemic on lung cancer treatment scheduling.

Study design

We retrospectively reviewed the medical records of lung cancer patients who were undergoing anti-cancer treatment at the National Hospital Organization Kyoto Medical Center (600 beds) in Kyoto, Japan, between March 1, 2020 and May 31, 2020.

Methods

After the medical records were reviewed, the patients were assigned to one of two groups, depending on whether their lung cancer treatment schedule was delayed. We assessed the characteristics, types of histopathology and treatment, and the reason for the delay.

Results

A total 15 (9.1%) patients experienced the delay of lung cancer treatment during COVID-19 pandemic. Patients with treatment delay received significantly more ICIs monotherapy than patients without treatment delay (p=0.0057). On the contrary, no patients receiving molecular target agents experienced treatment delay during COVID-19 pandemic period (p=0.0027). The treatments of most of the patients were delayed per their request.

Conclusion

We revealed 9.1% lung cancer patients suffered anxiety and requested treatment delay during COVID-19 pandemic. Oncologists should keep in mind that patient with cancer have more anxiety than we expected under special occasions such as COVID-19 pandemic.
Causes and consequences of child growth faltering in low- and middle-income countries
Authors: Mertens Andrew , Benjamin-Chung Jade , Colford John M , Coyle Jeremy , van der Laan Mark J , Hubbard Alan E , Rosete Sonali , Malenica Ivana , Hejazi Nima , Sofrygin Oleg , Cai Wilson , Li Haodong , Nguyen Anna , Pokpongkiat Nolan N , Djajadi Stephanie , Seth Anmol , Jung Esther , Chung Esther O , Jilek Wendy , Subramoney Vishak , Hafen Ryan , Häggström Jonas , Norman Thea , Brown Kenneth H , Christian Parul , Arnold Benjamin F. ,   members of the ki Child Growth Consortium
Published: June 2020

Growth faltering (low length-for-age or weight-for-length) in the first 1000 days — from conception to two years of age — influences short and long-term health and survival. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Future preventive efforts will benefit from understanding age-windows and population subgroups in which to focus. Here, we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age Z of up to 0.40 and weight-for-length Z of up to 0.15 by age 24 months. Boys had consistently higher risk of all forms of growth faltering than girls. Early post-natal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits had higher mortality rates from birth to two years than those without deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes, and severe consequences for children who experienced early growth faltering, support a focus on pre-conception and pregnancy as key opportunities for new preventive interventions.
Identification of compounds producing non-visual photosensation via TRPA1 in zebrafish
Authors: Cheng Darya , McCarroll Matthew N , Taylor Jack C , Wu Taia , Kokel David
Published: June 2020

TRPA1 receptors sense chemical irritants, but they do not normally respond to light. Previous studies have identified compounds that confer photosensitivity onto vertebrate TRPA1. However, the pharmacology of TRPA1-mediated non-visual photosensation remains poorly understood. To identify novel compounds that affect this process, we screened a large chemical library for compounds that increased light-elicited motor activity in larval zebrafish. We found structurally diverse hit compounds that were photoreactive and produced specific behavioral phenotypes. A subset of these compounds required functional TRPA1 to produce behavioral phenotypes in vivo. These findings provide novel prototype compounds for controlling TRPA1 with light and improve our understanding of non-visual TRPA1-mediated photosensation.
Functional Analysis of Distinct Populations of Subthalamic Nucleus Neurons on Parkinson’s Disease and OCD-like Behaviors in Mice
Authors: Parolari Luca , Schneeberger Marc , Heintz Nathaniel , Friedman Jeffrey M.
Published: June 2020

The Subthalamic Nucleus (STN) is a component of the basal ganglia and plays a key role to control movement and limbic-associative functions. STN modulation with Deep Brain Stimulation (DBS) improves the symptoms of Parkinson’s Disease (PD) and Obsessive-Compulsive Disorder (OCD) patients. However, DBS does not allow for cell-type specific modulation of the STN. While extensive work has focused on understanding STN functionality, the understanding of its cellular components is limited.

Here, we first performed an anatomical characterization of molecular markers for specific STN neurons. These studies revealed that most STN neurons expressPitx2, and that different overlapping subsets expressGabrr3,NdnforNos1. Next, we used neuronal modulatory tools to demonstrate their roles in regulating locomotor and limbic functions in mice. Specifically, we showed that optogenetic photoactivation of STN neurons in Pitx2-Cre mice or of the Gabrr3-expressing subpopulation induces locomotor changes, and improves locomotion in a PD mouse model. Additionally, photoactivation of Pitx2 and Gabrr3 cells induced repetitive grooming, a phenotype associated with OCD. Repeated stimulation prompted a persistent increase in grooming that could be reversed by fluoxetine treatment, a first-line drug therapy for OCD. Conversely, repeated inhibition of STNGabrr3neurons suppressed grooming in Sapap3-KO mice, a model for OCD. Finally, circuit and functional mapping of STNGabrr3neurons showed that these effects are mediated via projections to the globus pallidus/entopeduncular nucleus and substantia nigra reticulata. Altogether, these data identify Gabrr3 neurons as a key population in mediating the beneficial effects of STN modulation thus providing a new molecular handle for PD and OCD drug discovery.
AP2rx7passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice
Authors: Er-Lukowiak Marco , Duan Yinghui , Rassendren Francois , Ulmann Lauriane , Nicke Annette , Ufer Friederike , Friese Manuel A. , Koch-Nolte Friedrich , Magnus Tim , Rissiek Björn
Published: June 2020

Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 (B6) background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several 129-originating transgenic mice in whichP2rx7-neighboring genes were targeted carry aP2rx7passenger mutation that affects the vitality and function of T cells. By the example ofP2rx4tm1Rasswe demonstrate that CD4+and CD8+T cells derived from these mice express higher levels of P2X7 when compared to corresponding cell populations in B6-WT mice. The increased T cell sensitivity towards the P2X7 activators adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) rendered these cells more vulnerable towards NAD-induced cell death (NICD) compared to their B6-WT counterparts. The enhanced NICD sensitivity significantly affected the outcome of functional assays e.g. cytokine production and cell migration. For P2rx4tm1Rass, we demonstrate that the expression of P2X7 is diminished in several innate immune cell populations, possibly as a side effect ofP2rx4targeting, and independent of theP2rx7passenger mutation. These results need to be considered when working with P2rx4tm1Rassmice or other 129-based transgenic strains that targetP2rx7neighboring genes and might have implications for other mouse models.
Beyond sharing unpleasant affect – evidence for pain-specific opioidergic modulation of empathy for pain
Authors: Rütgen Markus , Wirth Eva-Maria , Riečanský Igor , Hummer Allan , Windischberger Christian , Petrovic Predrag , Silani Giorgia , Lamm Claus
Published: June 2020

The neural mechanisms underpinning empathy for pain are still a matter of debate. One of the major questions is whether empathy-related pain responses indicate domain-general vs. pain-specific affective responses. Using fMRI and psychopharmacological experiments, we investigated if placebo analgesia reduces first-hand and empathic experiences of affective touch, and compared them to the effects on pain. Placebo analgesia also affected the first-hand and empathic experience of unpleasant touch, implicating domain-general effects. However, and in contrast to pain and pain empathy, administering an opioid antagonist did not block these effects. Moreover, placebo analgesia reduced neural activity related to both modalities in the bilateral insular cortex, while it specifically modulated activity in the anterior midcingulate cortex for pain and pain empathy. These findings provide causal evidence that one of the major neurochemical systems for pain regulation is involved in pain empathy, and crucially substantiate the role of shared representations in empathy.
Visualizing ATP Dynamics in Live Mice
Authors: Koitabashi Norimichi , Ogasawara Riki , Yasui Ryuto , Sugiura Yuki , Matsuda Hinako , Nonaka Shigenori , Izumi Takashi , Kurabayashi Masahiko , Suematsu Makoto , Yanagita Motoko , Imamura Hiromi , Yamamoto Masamichi
Published: June 2020

Analysis of the dynamics of adenosine triphosphate (ATP) is vital to quantitatively define the actual roles of ATP in biological activities. Here, we applied a genetically encoded Förster resonance energy transfer biosensor “GO-ATeam” and created a transgenic mouse model that allows systemic ATP levels to be quantitatively, sensitively, noninvasively, and spatiotemporally measured under physiological and pathological conditions. We used this model to readily conduct intravital imaging of ATP dynamics under three different conditions: during exercise, in all organs and cells; during myocardial infarction progression; and in response to the application of cardiotoxic drugs. These findings provide compelling evidence that the GO-ATeam mouse model is a powerful tool to investigate the multifarious functions of cellular ATPin vivowith unprecedented spatiotemporal resolution in real-time. This will inform predictions of molecular and morphological responses to perturbations of ATP levels, as well as the elucidation of physiological mechanisms that control ATP homeostasis.

One Sentence Summary

Intravital real-time imaging of ATP dynamics in multiple organs using GO-ATeam mice, can be used to quantitatively, sensitively, noninvasively, and spatiotemporally measure systemic ATP levels and provide a platform for preclinical pharmacological studies.
Phylogenetic Analysis of St. Louis Encephalitis Virus within Two Southwestern United State Counties: a case for a bulk introduction event into the southwest United States
Authors: Ridenour Chase , Cocking Jill , Poidmore Samuel , Erickson Daryn , Brock Breezy , Valentine Michael , Young Steven J , Henke Jennifer A , Hung Kim Y , Wittie Jeremy , O’Neill Heidie M Hornstra , Sheridan Krystal , Centner Heather , Lemmer Darrin , Fofanov Viacheslav , Smith Kirk , Will James , Townsend John , Keim Paul S. , Engelthaler David M. , Hepp Crystal M
Published: June 2020

St. Louis Encephalitis Virus (SLEV) has been seasonally detected within theCulex spp. populations within Maricopa County, Arizona and Coachella Valley, California since an outbreak in Maricopa County in 2015. Previous work revealed that the outbreak was caused by an importation of SLEV genotype III, which had only been detected within Argentina in prior years. However, little is known about when the importation occurred or the population dynamics since its arrival into the southwestern United States. In this study, we wanted to determine if the annual detection of SLEV in Maricopa and Riverside counties is due to enzootic cycling or new importations. To address this question, we analyzed 143 SLEV genomes (138 sequenced as part of this study) using the Bayesian phylogenetic analysis software, BEAST, to estimate the date of arrival into the American Southwest and characterize the underlying population structure of SLEV. Phylogenetic clustering showed that SLEV variants circulating in Arizona and California form two distinct populations with little evidence of transmission among the two populations since the onset of the outbreak. Interestingly, the SLEV variants in Coachella Valley appear to be annually imported from a nearby source, whereas the Arizona population is locally sourced each year. Finally, the earliest representatives of SLEV genotype III in the southwestern US formed a polytomy that includes both California and Arizona samples. We propose that the initial outbreak could have resulted from an introductory population of SLEV, perhaps in one or more bird flocks migrating north in 2013, rather than a single variant introduced by one bird.
Syndecan-4-/-mice have smaller muscle fibers, increased Akt/mTOR/S6K1 and Notch/HES-1 pathways, and alterations in extracellular matrix components
Authors: Rønning Sissel Beate , Carlson Cathrine Rein , Aronsen Jan Magnus , Pisconti Addolorata , Høst Vibeke , Lunde Marianne , Liland Kristian Hovde , Sjaastad Ivar , Kolset Svein Olav , Christensen Geir , Pedersen Mona Elisabeth
Published: June 2020

Background

Extracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4-/-mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation. A reduced myofiber basal lamina has also been reported in syndecan-4-/-muscle, indicating possible defects in ECM production. To get a better understanding of the underlying molecular mechanisms, we have here investigated the effects of syndecan-4 genetic ablation on molecules involved in ECM remodeling and muscle growth, both under steady state conditions and in response to exercise.

Methods

Tibialis anterior (TA) muscles from sedentary and exercised syndecan-4-/-and WT mice were analyzed by immunohistochemistry, real-time PCR and western blotting.

Results

Compared to WT, we found that syndecan-4-/-mice had reduced body weight, reduced muscle weight, muscle fibers with a smaller cross-sectional area, and reduced expression of myogenic regulatory transcription factors. Sedentary syndecan-4-/-had also increased mRNA levels of syndecan-2, decorin, collagens, fibromodulin, biglycan, and LOX. Some of these latter ECM components were reduced at protein level, suggesting them to be more susceptible to degradation or less efficiently translated when syndecan-4 is absent. At the protein level, TRPC7 was reduced, whereas activation of the Akt/mTOR/S6K1 and Notch/HES-1 pathways were increased. Finally, although exercise induced upregulation of several of these components in WT, a further upregulation of these molecules was not observed in exercised syndecan-4-/-mice.

Conclusions

Altogether our data suggest an important role of syndecan-4 in muscle development.
Forecasting virus diffusion with simple Bayesian forecast combination
Authors: Franses Philip Hans
Published: June 2020

There are various diffusion models for S shaped processes like virus diffusion and these models are typically not nested. In this note it is proposed to combine the forecasts using a simple Bayesian forecast combination algorithm. An illustration to daily data on cumulative Covid-19 cases in the Netherlands shows the ease of use of the algorithm and the accuracy of the thus combined forecasts.
The influence of Schizotypy on Event-Related Oscillations in Sensory Gating during early Infant Development
Authors: Smith Eleanor S. , Crawford Trevor J. , Reid Vincent M.
Published: June 2020

Maternal schizotypic personality is thought to influence childhood risk for mental health and is a personality dimension elevated among schizophrenia-spectrum patients and their first-degree relatives, in whom neuro-oscillatory deficits have been observed. The current study investigated whether 6-month-old infants (n=46), and a subset of their biological mothers (n=34), who identified as either schizotypic (n=14) non-schizotypic (n=14), or an intermediate group (n=6), displayed reduced evoked-oscillatory activity. All mothers completed the Oxford-Liverpool Inventory of Feelings and Experiences as an index of schizotypy dimensionality. An auditory paired-tone paradigm was used to probe oscillatory activity, revealing that although the infants’ evoked-oscillations displayed differences betweenStimulus 1and2, there were no group differences between infants of schizotypic and control mothers. Their mothers, however, displayed differences, with reduced amplitudes towardStimulus 1in schizotypic mothers; consistent with literature on early sensory processes, showing sensory gating is impaired in schizophrenia-spectrum disorders.
RNA-seq analyses: Benchmarking differential expression analyses tools reveals the effect of higher number of replicates on performance
Authors: Salifu Samson Pandam , Nyarko Hannah Nyarkoah , Doughan Albert , Msatsi Haward Keteyo , Mensah Isabel , Bukari Abdul-Rahman Adamu
Published: June 2020

The introduction of several differential gene expression analysis tools has made it difficult for researchers to settle on a particular tool for RNA-seq analysis. This coupled with the appropriate determination of biological replicates to give an optimum representation of the study population and make biological sense. To address these challenges, we performed a survey of 8 tools used for differential expression in RNA-seq analysis. We simulated 39 different datasets (from 10 to 200 replicates, at an interval of 5) using compcodeR with a maximum of 100 replicates. Our goal was to determine the effect of varying the number of replicates on the performance (F1-score, recall and precision) of the tools. EBSeq and edgeR-glmRT recorded the highest (0.9385) and lowest (0.6505) average F1-score across all replicates, respectively. We also performed a pairwise comparison of all the tools to determine their concordance with each other in identifying differentially expressed genes. We found the greatest concordance to be betweenlimma voom treatandlimma voom ebayes. Finally, we recommend employing edgeR-glmRT for RNA-seq experiments involving 10-50 replicates and edgeR-glmQLF for studies with 55 to 200 replicates.

Author summary

Downstream analysis of RNA-seq data in R often poses several challenges to researchers as it is a daunting task to choose a specific differential expression analysis tool over another. Researchers also find it challenging to determine the number (replicates) of samples to use in order to give comparable and accurate results. In this paper, we surveyed eight differential expression analysis tools using different number of replicates of simulated RNA-seq count data. We measured the performance of each tool and based on the recorded F1-scores, recall and precision, we made the following recommendations; consider edgeR-glmRT and edgeR-glmQLF for replicates of 10-50 and 55-200 respectively.
Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia Preconditioning in Zebrafish
Authors: Das Tapatee , Soren Kalyani , Yerasi Mounica , Kamle Avijeet , Kumar Arvind , Chakravarty Sumana
Published: June 2020

Hypoxia, the major cause of ischemia, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed ‘Hypoxic Preconditioning’ occurs when prior exposures to hypoxia eventually results in robust hypoxia resistance. Accordingly, we have developed a novel model of sex-specific hypoxic preconditioning in adult zebrafish to mimic the tolerance of mini stroke(s) in human, which appears to protect against the severe damage inflicted by a major stroke event. Remarkable difference in the progression pattern of neuroprotection between preconditioning hypoxia followed by acute hypoxia (PH) group, and acute hypoxia (AH) group were observed with noticeable sex difference. Since gender difference has been reported in stroke, it was pertinent to investigate whether any such sex difference also exists in PH’s protective mechanism against acute ischemic stroke. In order to elucidate the neural molecular mechanisms behind sex difference in neuroprotection induced by PH, a high throughput proteomics approach utilizing iTRAQ was performed, followed by protein enrichment analysis using Ingenuity Pathway Analysis. Out of thousands of altered proteins in zebrafish brain, the ones having critical role either in neuroglial proliferation/differentiation or neurotrophic functions, were validated by analyzing their expression levels in PH, AH and normoxia groups. Results indicate that female zebrafish brains are more protected against the severity of AH. The study also sheds light on the involvement of many signaling pathways underlying sex difference in pre-conditioning induced neuroprotective mechanism, which can be further validated for the therapeutic approach.
Slippery flowers as a mechanism of defence against nectar-thieving ants
Authors: Takeda Kazuya , Kadokawa Tomoki , Kawakita Atsushi
Published: June 2020

Background and Aims

The great diversity of floral characters among animal-pollinated plants is commonly understood as the result of coevolutionary interactions between plants and pollinators. Floral antagonists, such as nectar thieves, also have the potential to exert selection on floral characters, but adaptation against floral antagonists has attracted comparatively little attention. We found that the corollas of hornet-pollinatedCodonopsis lanceolata(Campanulaceae) and the tepals of bee-pollinatedFritillaria koidzumiana(Liliaceae) are slippery to nectar-thieving ants living in the plant’s habitat; because the flowers of both species have exposed nectaries, slippery perianths may function as a defence against nectar-thieving ants.

Methods

We conducted a behavioural experiment and observed perianth surface microstructure by scanning electron microscopy to investigate the mechanism of slipperiness. Field experiments were conducted to test whether slippery perianths prevent floral entry by ants, and whether ant presence inside flowers affects pollination.

Key Results

Scanning electron microscopy observations indicated that the slippery surfaces were coated with epicuticular wax crystals. The perianths lost their slipperiness when wiped with hexane. Artificial bridging of the slippery surfaces using non-slippery materials allowed ants to enter flowers more frequently. Experimental introduction of live ants to theCodonopsisflowers evicted hornet pollinators and shortened the duration of pollinator visits. However, no differences were found in the fruit or seed sets of flowers with and without ants.

Conclusions

Slippery perianths, most likely based on epicuticular wax crystals, prevent floral entry by ants that negatively affect pollinator behaviour. Experimental evidence of floral defence based on slippery surfaces is rare, but such a mode of defence may be widespread amongst flowering plants.
Evaluating the efficacy of RT-qPCR SARS-CoV-2 direct approaches in comparison to RNA extraction
Authors: Israeli Ofir , Beth-Din Adi , Paran Nir , Stein Dana , Lazar Shirley , Weiss Shay , Milrot Elad , Atiya-Nasagi Yafit , Yitzhaki Shmuel , Laskar Orly , Schuster Ofir
Published: June 2020

SARS-CoV-2 genetic identification is based on viral RNA extraction prior to RT-qPCR assay, however recent studies support the elimination of the extraction step. Herein, we assessed the RNA extraction necessity, by comparing RT-qPCR efficacy in several direct approaches vs. the gold standard RNA extraction, in detection of SARS-CoV-2 from laboratory samples as well as clinical Oro-nasopharyngeal SARS-CoV-2 swabs. Our findings show advantage for the extraction procedure, however a direct no-buffer approach might be an alternative, since it identified up to 70% of positive clinical specimens.