bluuebunny/crossref_metadata_2025 huggingface dataset:
What Do Mutual Fund Investors Really Care About?
Authors: Ben-David Itzhak , Li Jiacui , Rossi Andrea , Song Yang
Published: July 2021

We show that mutual fund investors rely on simple signals and likely do not engage in sophisticated learning about managers’ alpha as widely believed. Simplistic performance chasing best explains aggregate flows to the mutual fund space and flows across funds. These results hold for both actively managed and passive index funds. Empirical patterns commonly interpreted as reflecting learning about managerial skill also appear in falsification tests and are mechanical. Our results are consistent with the view that, on average, households are homo sapiens with limited financial sophistication rather than hyperrational alpha-maximizing agents, as often assumed in the literature.
First use of acoustic calls to distinguish cryptic members of a fish species complex
Authors: Parmentier Eric , Scalbert Robin , Raick Xavier , Gache Camille , Frédérich Bruno , Bertucci Frédéric , Lecchini David
Published: July 2021

Although molecular methods and bioacoustical analysis have been used to uncover cryptic species, the combination of both methodologies is still rare. The humbug damselfish complex, Dascyllus aruanus, is composed of at least two species with Dascyllus aruanus in the Pacific Ocean and Dascyllus abudafur in the Indian Ocean. However, genetic data suggest that additional species could be found. Therefore, we aimed to determine whether the sounds produced by different populations of fish could help to distinguish cryptic species. Recordings of chase and courtship sounds were made on humbug damselfish populations from Madagascar, Taiwan and French Polynesia. Chase sound features are more variable than courtship sounds, suggesting more constraints on courtship sounds, since they would contribute to premating isolation. Comparison between courtship sounds show the variation in acoustic features between Taiwan and Madagascar align with genetic differences, supporting that sounds could discriminate cryptic species in Teleosts. Moreover, differences in both acoustic features and genetic data are also found between Taiwan and French Polynesia, suggesting two clearly distinct populations. Consequently, the name D. emamo can be resurrected for the Polynesian humbug damselfish. External phenotype traits do not allow the distinction between populations, illustrating that only behaviour has been modified.
Characteristics Associated With Treatment Failure 1 Year After Midurethral Sling in Women With Mixed Urinary Incontinence
Authors: Sung Vivian W. , Richter Holly E. , Moalli Pamela , Weidner Alison C. , Nguyen John N. , Smith Ariana L. , Dunivan Gena , Ridgeway Beri , Borello-France Diane , Newman Diane K. , Mazloomdoost Donna , Carper Benjamin , Gantz Marie G. ,   for the NICHD Pelvic Floor Disorders Network
Published: July 2021

OBJECTIVE:

To evaluate characteristics associated with treatment failure 1 year after midurethral sling in women with mixed urinary incontinence.

METHODS:

Four-hundred three women who participated in a randomized trial that compared midurethral sling and behavioral and pelvic floor muscle therapy (combined group) compared with midurethral sling alone for mixed incontinence with 1-year follow-up data were eligible for this planned secondary analysis. Overall treatment failure was defined as meeting criteria for subjective or objective failure or both. Subjective failure was defined as not meeting the minimal clinical important difference for improvement on the UDI (Urogenital Distress Inventory) total score (26.1 points). Objective failure was defined as not achieving 70% improvement on mean incontinence episodes of any type per day or having undergone any additional treatment for persistent urinary symptoms at 12 months postoperative. Logistic regression models for treatment failure were constructed. Independent variables included site and treatment group, and clinical and demographic variables based on bivariate comparisons (P<.2). Treatment group interaction effects were evaluated.

RESULTS:

One hundred twelve of 379 (29.6%) women had overall treatment failure, with 56 of 379 (14.7%) undergoing additional treatment but only two needing intervention for stress incontinence. Previous overactive bladder (OAB) medication (unadjusted odds ratio [OR] 2.19, adjusted odds ratio [aOR] 1.96, 95% CI 1.17–3.31); detrusor overactivity on cystometrogram (OR 2.25, aOR 2.82, 95% CI 1.60–4.97); and higher volume at first urge (OR 1.03, aOR 1.04, 95% CI 1.01–1.07) were associated with overall failure. Worse UDI-urgency scores were associated with failure, with an added interaction effect in the midurethral sling–alone group.

CONCLUSIONS:

Certain clinical and urodynamic variables are associated with treatment failure after midurethral sling in women with mixed urinary incontinence. Women with more severe urgency symptoms at baseline may benefit from perioperative behavioral and pelvic floor muscle therapy combined with midurethral sling. Overall, the need for additional urinary treatment was low and primarily for OAB.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT01959347.
Intraoperative Rupture of the Ovarian Capsule in Early-Stage Ovarian Cancer
Authors: Dioun Shayan , Wu Jenny , Chen Ling , Kaplan Samantha , Huang Yongmei , Melamed Alexander , Gockley Allison , St. Clair Caryn M. , Hou June Y. , Tergas Ana I , Khoury-Collado Fady , Machida Hiroko , Mikami Mikio , Matsuo Koji , Hershman Dawn L. , Wright Jason D.
Published: July 2021

OBJECTIVE:

To examine the effects of intraoperative ovarian capsule rupture on progression-free survival and overall survival in women who are undergoing surgery for early-stage ovarian cancer.

DATA SOURCES:

MEDLINE using PubMed, EMBASE (Elsevier), ClinicalTrials.gov, and Scopus (Elsevier) were searched from inception until August 11, 2020.

METHODS OF STUDY SELECTION:

High-quality studies reporting survival outcomes comparing ovarian capsule rupture to no capsule rupture among patients with early-stage epithelial ovarian cancer who underwent surgical management were abstracted. Study quality was assessed with the Newcastle-Ottawa Scale, and studies with scores of at least 7 points were included.

TABULATION, INTEGRATION, AND RESULTS:

The data were extracted independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between ovarian capsule rupture and oncologic outcomes. Seventeen studies met all the criteria for inclusion in the meta-analysis. Twelve thousand seven hundred fifty-six (62.6%) patients did not have capsule rupture and had disease confined to the ovary on final pathology; 5,532 (33.7%) patients had intraoperative capsule rupture of an otherwise early-stage ovarian cancer. Patients with intraoperative capsule rupture had worse progression-free survival (hazard ratio [HR] 1.92, 95% CI 1.34–2.76, P<.001), with moderate heterogeneity (I2=41%, P=.07) when compared with those without capsule rupture. Pooled results from these studies showed a worse overall survival (HR 1.48, 95% CI 1.15–1.91, P=.003), with moderate heterogeneity (I2=53%, P=.02) when compared with patients without intraoperative capsule rupture. This remained significant in a series of sensitivity analyses.

CONCLUSION:

This systematic review and meta-analysis of high-quality observational studies shows that intraoperative ovarian capsule rupture results in decreased progression-free survival and overall survival in women with early-stage ovarian cancer who are undergoing initial surgical management.

SYSTEMATIC REVIEW REGISTRATION:

PROSPERO, CRD42021216561.
Educational Video on Pain Management and Subsequent Opioid Use After Cesarean Delivery
Authors: Mokhtari Neggin B. , Saeed Haleema , Kawakita Tetsuya , Huang Jim C. , Iqbal Sara N.
Published: July 2021

OBJECTIVE:

To evaluate whether viewing an educational video on pain management reduces opioid use after cesarean delivery.

METHODS:

We conducted a randomized, controlled trial of women aged 18 years or older who underwent cesarean delivery at a tertiary care center. Eligible women were randomized in a 1:1 ratio to usual discharge pain medication instructions plus an educational video on pain management or to usual discharge pain medication instructions alone. All women received the same opioid prescription at discharge: Twenty 5-mg oxycodone tablets. Participants were contacted at 7 days and at 14 days after delivery to assess the number of oxycodone tablets used, adjunct medication (acetaminophen and ibuprofen) use, pain scores, and overall satisfaction of pain control. The primary outcome was the number of oxycodone tablets used from discharge through postpartum day 14. A sample size of 23 per group (n=46) was planned to detect a 25% difference in mean number of oxycodone tablets used between groups, as from 20 to 15.

RESULTS:

From July 2019 through December 2019, 61 women were screened and 48 were enrolled—24 in each group. Women who viewed the educational video used significantly fewer opioid tablets from discharge through postpartum day 14 compared with women who received usual pain medication instructions (median 1.5, range 0–20 vs median 10, range 0–24, P<.001). Adjunct medication use, pain scores, and satisfaction with pain control did not differ significantly between groups.

CONCLUSION:

Among women who underwent cesarean delivery, viewing an educational video on pain management reduced postdischarge opioid use.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT03959969.
Wrong-Patient Orders in Obstetrics
Authors: Kern-Goldberger Adina R. , Kneifati-Hayek Jerard , Fernandes Yelstin , Applebaum Jo R. , Schechter Clyde B. , Adelman Jason S. , Goffman Dena
Published: July 2021

OBJECTIVE:

To compare rates of wrong-patient orders among patients on obstetric units compared with reproductive-aged women admitted to medical–surgical units.

METHODS:

This was an observational study conducted in a large health system in New York between January 1, 2016, and December 31, 2018. The primary outcome was near-miss wrong-patient orders identified using the National Quality Forum–endorsed Wrong-Patient Retract-and-Reorder measure. All electronic orders placed for eligible patients during the study period were extracted retrospectively from the health system data warehouse, and the unit of analysis was the order session (consecutive orders placed by a single clinician for a patient within 60 minutes). Multilevel logistic regression models were used to estimate odds ratios (ORs) and 95% CIs comparing the probability of retract-and-reorder events in obstetric and medical–surgical units, overall, and in subgroups defined by clinician type and order timing.

RESULTS:

Overall, 1,329,463 order sessions were placed during the study period, including 676,643 obstetric order sessions (from 45,436 patients) and 652,820 medical–surgical order sessions (from 12,915 patients). The rate of 79.5 retract-and-reorder events per 100,000 order sessions in obstetric units was significantly higher than the rate in the general medical–surgical population of 42.3 per 100,000 order sessions (OR 1.98, 95% CI 1.64–2.39). The obstetric retract-and-reorder event rate was significantly higher for attending physicians and house staff compared with advanced practice clinicians. There were no significant differences in error rates between day and night shifts.

CONCLUSION:

Order errors occurred more frequently on obstetric units compared with medical–surgical units. Systems strategies shown to decrease these events in other high-risk specialties should be explored in obstetrics to render safer maternity care.
The value of repeat patient testing for SARS-CoV-2: real-world experience during the first wave
Authors: Zhu Alex , Creagh Margaret , Qi Chao , Galvin Shannon , Bolon Maureen , Zembower Teresa
Published: July 2021

Introduction. Reports of false-negative quantitative reverse transcription PCR (RT-qPCR) results from patients with high clinical suspension for coronavirus disease 2019 (COVID-19), suggested that a negative result produced by a nucleic acid amplification assays (NAAs) did not always exclude the possibility of COVID-19 infection. Repeat testing has been used by clinicians as a strategy in an to attempt to improve laboratory diagnosis of COVID-19 and overcome false-negative results in particular.

Aim. To investigate whether repeat testing is helpful for overcoming false-negative results.

Methods. We retrospectively reviewed our experience with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, focusing on the yield of repeat patient testing for improving SARS-CoV-2 detection by NAA.

Results. We found that the yield from using repeat testing to identify false-negative patients was low. When the first test produced a negative result, only 6 % of patients tested positive by the second test. The yield decreased to 1.7 and then 0 % after the third and fourth tests, respectively. When comparing the results produced by three assays, the Centers for Disease Control and Prevention (CDC) SARS CoV-2 RT-qPCR panel, Xpert Xpress CoV-2 and ID NOW COVID-19, the ID NOW assay was associated with the highest number of patients who tested negative initially but positive on repeat testing. The CDC SARS CoV-2 RT-qPCR panel produced the highest number of indeterminate results. Repeat testing resolved more than 90 % of indeterminate/invalid results.

Conclusions. The yield from using repeat testing to identify false-negative patients was low. Repeat testing was best used for resolving indeterminate/invalid results.
An unusual case of infective spondylodiscitis caused by Campylobacter fetus subsp. fetus: molecular characterization by whole-genome sequencing
Authors: MS Dhiviya Prabaa , SS Jaya Lakshmi , Prakash John Antony Jude , David Kenny S. , Alagar Vijay , Veeraraghavan Balaji
Published: July 2021

Spondylodiscitis is an infectious inflammation that affects the intervertebral disc and adjacent structures. Treating infective spondylodiscitis is often challenging due to the lack of specific symptoms. Here we present an unusual case of infective spondylodiscitis caused by

Campylobacter fetus

subsp.

fetus

.
A stop–gain mutation in sigma factor SigH (MAB_3543c) may be associated with tigecycline resistance in Mycobacteroides abscessus
Authors: Lee Col Lin , Ng Hien Fuh , Ngeow Yun Fong , Thaw Zin
Published: July 2021

Introduction. Tigecycline is currently acknowledged to be one of the most effective antibiotics against infections caused by

Mycobacteroides abscessus

.

Gap statement. The genetic determinants of tigecycline resistance in

M. abscessus

are not well understood.

Aim. In this study, we characterized a tigecycline-resistant

M. abscessus

mutant, designated CL7, to identify the potential resistance mechanism.

Methodology. CL7 was characterized using antimicrobial susceptibility testing, whole-genome sequencing, PCR and RT-qPCR. For biological verification, gene overexpression assays were carried out.

Results. Whole-genome sequencing and the subsequent gene overexpression assays showed that CL7 harboured a stop–gain mutation in MAB_3543 c, which may be responsible for the tigecycline resistance phenotype. This gene encodes an orthologue of SigH, which is involved in the positive regulation of physiological stress response and is negatively regulated by the RshA anti-sigma factor in

Mycobacterium tuberculosis

. We hypothesized that the MAB_3543 c mutation may disrupt the interaction between SigH and RshA (MAB_3542 c). RT-qPCR analyses revealed the upregulation of MAB_3543 c and other key stress response genes, which has previously been shown to be a hallmark of SigH–RshA bond disruption and tigecycline resistance.

Conclusion. The MAB_3543c mutation may represent a novel determinant of tigecycline resistance in

M. abscessus

. The findings of this study will hopefully contribute to our knowledge of potential tigecycline resistance mechanisms in

M. abscessus

, which may lead to better diagnostics and treatment modalities in the future.
SARS-CoV-2 Infections in mRNA Vaccinated Individuals are Biased for Viruses Encoding Spike E484K and Associated with Reduced Infectious Virus Loads that Correlate with Respiratory Antiviral IgG levels
Authors: Mostafa Heba H. , Luo Chun Huai , Morris C. Paul , Li Maggie , Swanson Nicholas J. , Amadi Adannaya , Gallagher Nicholas , Pekosz Andrew
Published: July 2021

Introduction

COVID-19 large scale immunization in the US has been associated with infrequent breakthrough positive molecular testing. Whether a positive test is associated with a high viral RNA load, specific viral variant, recovery of infectious virus, or symptomatic infection is largely not known.

Methods

In this study, we identified 133 SARS-CoV-2 positive patients who had received two doses of either Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccines, the 2nd of which was received between January and April of 2021. The positive samples were collected between January and May of 2021 with a time that extended from 2 to 100 days after the second dose. Samples were sequenced to characterize the whole genome and Spike protein changes and cycle thresholds that reflect viral loads were determined using a single molecular assay. Local SARS-CoV-2 IgG antibodies were examined using ELISA and specimens were grown on cell culture to assess the recovery of infectious virus as compared to a control unvaccinated cohort from a matched time frame.

Results

Of 133 specimens, 24 failed sequencing and yielded a negative or very low viral load on the repeat PCR. Of 109 specimens that were used for further genome analysis, 68 (62.4%) were from symptomatic infections, 11 (10.1%) were admitted for COVID-19, and 2 (1.8%) required ICU admission with no associated mortality. The predominant virus variant was the alpha (B.1.1.7), however a significant association between lineage B.1.526 and amino acid change S: E484K with positives after vaccination was noted when genomes were compared to a large control cohort from a matched time frame. A significant reduction of the recovery of infectious virus on cell culture as well as delayed time to the first appearance of cytopathic effect was accompanied by an increase in local IgG levels in respiratory samples of vaccinated individuals but upper respiratory tract IgG levels were not different between symptomatic or asymptomatic infections.

Conclusions

Vaccination reduces the recovery of infectious virus in breakthrough infections accompanied by an increase in upper respiratory tract local immune responses.

Funding

National Institute of Health (The Johns Hopkins Center of Excellence in Influenza Research and Surveillance, HHSN272201400007C), Johns Hopkins University, Maryland Department of Health, Centers for Disease Control and Prevention.
Utilization, satisfaction and barriers to access of health services for Arabic-speaking refugees resettled in Connecticut, USA after completion of Refugee Medical Assistance (RMA)
Authors: Elreichouni Ali , Aly Sarah , Maciejewski Kaitlin , Salem Islam , Ghossein Noah , Mankash M. Salah , Dziura James , Mowafi Hani
Published: July 2021

Background

Arabic-speaking refugees are the largest group of resettled persons in the United States since 2008, yet little is known about their rates of healthcare access, utilization and satisfaction.

Methods

From January to December 2019, a household survey was conducted of Arabic-speaking refugees resettled in CT. Data collected included demographics, prevalence of chronic conditions, patterns of health seeking behavior, insurance status and patient satisfaction using the Patient Satisfaction Questionnaire (PSQ-18).

Results

Sixty-five households responded to the survey representing 295 Arabic-speaking refugees – of which 141 (48%) were children. Forty-seven households (72%) reported members with chronic conditions, 62 persons (21%) needed daily medication, 285 (97%) persons were insured. Respondents reported high median patient satisfaction with wide variation.

Conclusion

Arabic-speaking refugees resettled in CT are young but have similar adult rates of chronic medical conditions as the host community. They majority remained insured after RMA lapsed. They expressed median high satisfaction with health services but with wide variation. Inaccessibility of health services in Arabic and difficulty obtaining medications remain areas in need of improvement.
Derivation of anthropometric-based equations to predict lean body mass composition of cancer patients
Authors: Carey Autumn B. , Felix Ashley S. , Huling Jared D. , Odei James B. , Coss Christopher C. , Ning Xia , Donneyong Macarius M.
Published: July 2021

Background

Lean body mass (LBM) composition of cancer patients is a predictor of chemotherapy-related adverse events and overall cancer survival. However, clinicians lack validated algorithms that can be applied to measure the LBM of cancer patients to facilitate accurate chemotherapy dosing. Our goal was to develop LBM predictive equations using routinely measured anthropometric measures among cancer patients.

Methods

We leveraged the 1999-2006 National Health and Nutrition Examination Survey (NHANES) data cycles containing information on self-reported cancer diagnosis, LBM measures based on dual-energy x-ray absorptiometry (DXA) and several anthropometric and demographic factors. We restricted our analysis to participants who had been diagnosed with cancer at the time of surveys. The data was randomly split to 75%:25% to train and test predictive models. Least absolute shrinkage and selection operator (LASSO) models were used to predict LBM based on anthropometric and demographic factors, overall and separately among sex and sex-by-race/ethnic subgroups. LBM measured directly with DXA served as the gold standard for assessing the predictive abilities (correlations [R2] and the Root Mean Square Error [RMSE]) of the derived LBM-algorithms. We further compared the correlations between both DXA-based LBM and predicted LBM and urine creatinine levels, a known biomarker of muscle mass.

Results

We identified 1,777 cancer patients with a median age of 71 (interquartile range [IQR]: 60-80) years. The most parsimonious model comprised of height and weight, which accurately predicted LBM overall (R2=0.86, RMSE =2.26). The predictive abilities of these models varied across sex-by-race/ethnic groups. The magnitude of correlations between derived LBM-algorithm and urine creatinine levels were larger compared to those measured between DXA-based LBM and urine creatinine levels (R2=0.30 vs. R2=0.17)

Conclusions

We successfully developed a simple sex-specific and sex-by-race/ethnicity-specific models to accurately predict the LBM of cancer patients by using only height and weight. The simplicity and high accuracy of these models make them inexpensive alternatives to measuring the LBM of cancer patients. Data on the LBM of cancer patients could help guide optimal chemotherapy dose selection among cancer patients.
Predicting age from hearing test results with machine learning reveals the genetic and environmental factors underlying accelerated auditory aging
Authors: Goallec Alan Le , Diai Samuel , Vincent Théo , Patel Chirag J.
Published: July 2021

With the aging of the world population, age-related hearing loss (presbycusis) and other hearing disorders such as tinnitus become more prevalent, leading to reduced quality of life and social isolation. Unveiling the genetic and environmental factors leading to age-related auditory disorders could suggest lifestyle and therapeutic interventions to slow auditory aging. In the following, we built the first machine learning-based hearing age predictor by training models to predict chronological age from hearing test results (root mean squared error=7.10±0.07 years; R-Squared=31.4±0.8%). We defined hearing age as the prediction outputted by the model on unseen samples, and accelerated auditory aging as the difference between a participant’s hearing age and age. We then performed a genome wide association study [GWAS] and found that accelerated hearing aging is 14.1±0.4% GWAS-heritable. Specifically, accelerated auditory aging is associated with 662 single nucleotide polymorphisms in 243 genes (e.gOR2B4P, involved in smell perception). Similarly, it is associated with biomarkers (e.g cognitive tests), clinical phenotypes (e.g chest pain), diseases (e.g depression), environmental (e.g smoking, sleep) and socioeconomic (e.g income, education, social support) variables. The hearing age predictor could be used to evaluate the efficiency of emerging rejuvenation therapies on hearing.
Untargeted saliva metabolomics reveals COVID-19 severity
Authors: Frampas Cecile F. , Longman Katie , Spick Matt P. , Lewis Holly M. , Costa Catia D. S. , Stewart Alex , Dunn-Walters Deborah , Greener Danni , Evetts George E. , Skene Debra , Trivedi Drupad , Pitt Andrew R. , Hollywood Katherine , Barran Perdita , Bailey Melanie J.
Published: July 2021

Background

The COVID-19 pandemic is likely to represent an ongoing global health issue given the potential for vaccine escape and the low likelihood of eliminating all reservoirs of the disease. Whilst diagnostic testing has progressed at pace, there is an unmet clinical need to develop tests that are prognostic, to triage the high volumes of patients arriving in hospital settings. Recent research has shown that serum metabolomics has potential for prognosis of disease progression.1In a hospital setting, collection of saliva samples is more convenient for both staff and patients, and therefore offers an alternative sampling matrix to serum. We demonstrate here for the first time that saliva metabolomics can reveal COVID-19 severity.

Methods

88 saliva samples were collected from hospitalised patients with clinical suspicion of COVID-19, alongside clinical metadata. COVID-19 diagnosis was confirmed using RT-PCR testing. COVID severity was classified using clinical descriptors first proposed by SR Knight et al. Metabolites were extracted from saliva samples and analysed using liquid chromatography mass spectrometry.

Results

In this work, positive percent agreement of 1.00 between a PLS-DA metabolomics model and the clinical diagnosis of COVID severity was achieved. The negative percent agreement with the clinical severity diagnosis was also 1.00, for overall percent agreement of 1.00.

Conclusions

This research demonstrates that liquid chromatography-mass spectrometry can identify salivary biomarkers capable of separating high severity COVID-19 patients from low severity COVID-19 patients in a small cohort study.
Evaluation of Clinical Job Demands, Job Resources, and a Novel Intervention on Measures of Health Care Worker Stress at a Community Hospital Pre and Post COVID-19
Authors: Sels Jessica , Carroll Dylan , Duffee Doug
Published: July 2021

Objective

To explore the relationship and identity of Health Care Worker stressors to a measure of perceived burnout and to a novel intervention tool.

Participants and Methods

From July 2019 to June 2020, we surveyed Health Care Workers (HCW) pre and post COVID19 in an independent local community hospital for burnout with the Health Care Provider Wellness Assessment tool. Linear regression and means comparison were used to identify overall job demand and resource perception with burnout, unique stressor portraits by provider subtype and mean survey scores between those who did or did not voluntarily complete at least 14 days of a 28 day novel self-help intervention tool.

Results

Regarding the pre COVID-19 data, of 73 respondents, there was statistically significant (p<.01) correlation between overall job demands (directly) and resources (inversely) with burnout intensity. With respect to the HCW stressor characteristic analyses there was statistical significance (p<.05) between the mean frequency occurrence of the top 5 stressors identified by respondent subtype when compared to the mean occurrence of overall individual responses within the corresponding subtype. Finally, although limited by a low number of respondents, the intervention tool analysis suggested a therapeutic trend toward disruption of the stress-burnout relationship. Regarding the post COVID-19 data, 18 respondents did not show statistically significant characterizable stressor portraits (ie stressors were present but not patternable).

Conclusion

Unique stressor portraits were identified by HCW subtype which correlated with more intense burnout self-perception. Additionally, there was a trend toward self-help tool efficacy in mitigating burnout.
Yuel: Compound-Protein Interaction Prediction with High Generalizability
Authors: Wang Jian , Dokholyan Nikolay V.
Published: July 2021

Virtual drug screening has the potential to revolutionize the stagnant drug discovery field due to its low cost and fast speed. Predicting binding affinities between small molecules and the protein target is at the core of computational drug screening. Deep learning-based approaches have recently been adapted to predict binding affinities and claim to achieve high prediction accuracy in their tests, however, we show that current approaches are not reliable for virtual drug screening due to the lack of generalizability, i.e. the ability to predict interactions between unknown proteins and unknown small molecules. To address this shortcoming, we develop a compound-protein interaction predictor, Yuel. Upon comprehensive tests on various datasets, we find that out of all the deep-learning approaches surveyed, only Yuel can predict interactions between unknown compounds and unknown proteins. Additionally, Yuel can also be utilized to identify compound atoms and proteins residues that are involved in the binding.
Stimulus-induced narrowband gamma oscillations are test-retest reliable in healthy elderly in human EEG
Authors: Kumar Wupadrasta Santosh , Manikandan Keerthana , Murty Dinavahi V.P.S. , Ramesh Ranjini Garani , Purokayastha Simran , Javali Mahendra , Rao Naren Prahalada , Ray Supratim
Published: July 2021

Visual stimulus-induced narrowband gamma oscillations in electroencephalogram (EEG) recordings have been recently shown to be compromised in subjects with Mild Cognitive Impairment or Alzheimer’s Disease (AD), suggesting that gamma could be an inexpensive and easily accessible biomarker for early diagnosis of AD. However, to use gamma as a biomarker, its characteristics should remain consistent across multiple recordings, even when separated over long intervals. Previous magnetoencephalography studies in young subjects have reported that gamma power remains consistent over recordings separated by a few weeks to months. Here, we assessed the consistency of slow (20-35 Hz) and fast gamma (36-66 Hz) oscillations induced by static full-field gratings in male (N=20) and female (N=20) elderly subjects (>49 years) in EEG recordings separated by more than a year, and tested the consistency in the magnitude of gamma power, its temporal evolution and spectral profile. Gamma oscillations had distinct spectral and temporal characteristics across subjects, which remained consistent across recordings (average intraclass correlation, ICC of ∼0.7). Alpha oscillations (8-12 Hz) and steady-state-visually-evoked-potentials (SSVEPs) were also found to be reliable. We further tested how EEG features can be used to identify two recordings as belonging to the same versus different subjects and found high classifier performance (area under ROC curve of ∼0.89), with the temporal evolution of slow gamma and spectral profile emerging as the most informative features. These results suggest that EEG gamma oscillations are reliable across recordings and can be used as a clinical biomarker as well as a potential tool for subject identification.

Significance statement

We demonstrate the reliability of stimulus-induced gamma oscillations in elderly humans for the first time in EEG. Since gamma has recently been shown to be compromised in patients with Mild Cognitive Impairment or early Alzheimer’s Disease (AD), together these results mark the first steps towards an EEG based clinical biomarker for early diagnosis of AD. We observed high reliability in the power spectrum, gamma power and its temporal characteristics, within the test-retest period of one year. Alpha and steady-state-visually-evoked potential power were also found to be reliable. These spectral and temporal features could also be used to identify EEG recordings as belonging to the same versus different subjects with high performance, suggesting a potentially key role in subject identification also.
Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors
Authors: Fang Quan , Wang Zilong , Suttle Abbie , Chen Yong
Published: July 2021

Itch, particularly chronic itch, negatively impacts patients’ physical, social, and psychological well-being, leading to deterioration in their quality of life. Limited understanding of itch mechanisms hinders the development of effective antipruritic treatments.TRPV4, a multimodally activated nonselective cation channel, has been detected in sensory neurons of dorsal root and trigeminal ganglion (DRG, TG) and skin cells (e.g. keratinocytes, mast cells, and macrophages). Recent evidence from experimental and clinical relevant studies has implicated that TRPV4 in skin cells plays an important role in both acute and chronic itch. In contrast, little is known whether TRPV4 in sensory neurons directly contributes to scratching behaviors. Here we used sensory neuron-Trpv4 conditional knockout (cKO) mice to address this question. Our results showed that TRPV4 in sensory neurons contributes to scratching behavior evoked by histaminergic (histamine and 48/80) and partial histaminergic (5-HT), but not non-histaminergic (SLIGRL and CQ) pruritogens. Moreover, we observed that TRPV4 in sensory neurons is required for dry skin, but not allergic contact dermatitis, -associated chronic itch. These findings suggest that neuronal-TRPV4 might be specific for some forms of acute and chronic itch.
Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors
Authors: Foster Jessica B. , Griffin Crystal , Rokita Jo Lynne , Stern Allison , Brimley Cameron , Rathi Komal , Lane Maria V. , Buongervino Samantha N. , Smith Tiffany , Madsen Peter J. , Martinez Daniel , Wechsler-Reya Robert J. , Karikó Katalin , Storm Phillip B. , Barrett David M. , Resnick Adam C. , Maris John M. , Bosse Kristopher R.
Published: July 2021

Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Here we show that the cell surface oncoprotein glypican 2 (GPC2) is highly expressed on multiple lethal pediatric brain tumors, including medulloblastomas, embryonal tumors with multi-layered rosettes, other CNS embryonal tumors, as well as definable subsets of highly malignant gliomas. To target GPC2 on these pediatric brain tumors with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we developed four mRNA chimeric antigen receptor (CAR) T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment. First, we validated and prioritized these CARs using in vitro cytotoxicity and T cell degranulation assays with GPC2-expressing neuroblastoma cells. Next, we expanded the testing of the two most potent GPC2-directed CAR constructs prioritized from these studies to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, locoregional delivery bi-weekly of two to four million GPC2-directed mRNA CAR T cells induced significant and sustained tumor regression in two orthotopic medulloblastoma models, and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells.

One Sentence Summary

Glypican 2 is expressed on the surface of multiple pediatric brain tumors and can be successfully targeted with mRNA chimeric antigen receptor T cells.
Microchromosomes are building blocks of bird, reptile and mammal chromosomes
Authors: Waters Paul D. , Patel Hardip R. , Ruiz-Herrera Aurora , Álvarez-González Lucía , Lister Nicholas C. , Simakov Oleg , Ezaz Tariq , Kaur Parwinder , Frere Celine , Grützner Frank , Georges Arthur , Graves Jennifer A. Marshall
Published: July 2021

Microchromosomes, once considered unimportant shreds of the chicken genome, are gene rich elements with a high GC content and few transposable elements. Their origin has been debated for decades. We used cytological and whole genome sequence comparisons, and chromosome conformation capture, to trace their origin and fate in genomes of reptiles, birds and mammals. We find that microchromosomes as well as macrochromosomes are highly conserved across birds, and share synteny with single small chromosomes of the chordate amphioxus, attesting to their origin as elements of an ancient animal genome. Turtles and squamates (snakes and lizards) share different subsets of ancestral microchromosomes, having independently lost microchromosomes by fusion with other microchromosomes or macrochromosomes. Patterns of fusions were quite different in different lineages.

Cytological observations show that microchromosomes in all lineages are spatially separated into a central compartment at interphase and during mitosis and meiosis. This reflects higher interaction between microchromosomes than with macrochromosomes, as observed by chromosome conformation capture, and suggests some functional coherence. In highly rearranged genomes fused microchromosomes retain most ancestral characteristics, but these may erode over evolutionary time; surprisingly de novo microchromosomes have rapidly adopted high interaction.

Some chromosomes of early branching monotreme mammals align to several bird microchromosomes, suggesting multiple microchromosome fusions in a mammalian ancestor. Subsequently multiple rearrangements fueled the extraordinary karyotypic diversity of therian mammals.

Thus microchromosomes, far from being aberrant genetic elements, represent fundamental building blocks of amniote chromosomes, and it is mammals, rather than reptiles, that are atypical.

Significance Statement

Genomes of birds and reptiles, but not mammals, consist of a few large chromosomes and many tiny microchromosomes. Once considered unimportant shreds of the genome, microchromosomes are gene rich and highly conserved among bird and reptiles, and share homology with one or more of the tiny chromosomes of an invertebrate that diverged from the vertebrate lineage 684 million years ago. Microchromosomes interact strongly and crowd together at the centre of cells, suggesting functional coherence. Many microchromosomes have been lost independently in turtles, snakes and lizards as they have fused with each other, or with larger chromosomes. In mammals they have completely disappeared, yet some chromosomes of the basal platypus line up with several microchromosomes, suggesting that they are the building blocks of the atypically variable chromosomes of mammals.
Genome-wide association study reveals putative bacterial risk factors for cavitary Mycobacterium avium complex lung disease
Authors: Yano Hirokazu , Nishiuchi Yukiko , Arikawa Kentaro , Ota Atsushi , Miki Mari , Maruyama Fumito , Kida Hiroshi , Kitada Seigo , Iwamoto Tomotada
Published: July 2021

Mycobacterium avium complex (MAC) lung disease is a slowly progressive disease, and its increasing incidence has garnered increased research interests. Cavitary MAC lung disease is associated with a higher mortality rate. Though genetic studies have unraveled the human risk factors, the role of microbial factors on pathogenesis behind the disease remains elusive. In this study, M. avium isolates were collected from sputum specimens of 109 distinct Japanese patients with or without a cavity (60 with a cavity and 49 without cavity) in a hospital located in Osaka prefecture. M. avium genomes were sequenced and searched for DNA motifs associated with cavity formation using a bacterial GWAS. Excluding known macrolide resistance mutations; cavity formation was found to be primarily associated with variants of cytochrome P450 of the CYP139 family, type I polyketide synthase Pks13, and the promoter region of an operon encoding membrane-anchored protease FtsH and folate synthesis pathway enzymes. Cavity risk variants at these three loci were frequent in the MahEastAsia2 lineage among the six lineages detected in M. avium global populations. Furthermore, the study demonstrated a correlation between the cavity risk promoter variant and increased sulfamethoxazole/trimethoprim resistance. Together, these findings suggest that natural variation in the biosynthesis and maintenance processes of M. avium membrane components influences the disease type of MAC lung disease. Although further validation is needed, the bacterial genetic markers listed in the present study could contribute to prognosis prediction based on bacterial genotyping and help develop treatment strategies in the future.

IMPORTANCE

Nontuberculous mycobacterial lung disease is of great concern in countries with an increasingly aging population. The disease types can largely be classified into non-cavitary nodular bronchiectasis and cavitary diseases (fibrocavitary, nodular bronchiectasis with cavity) that require different treatment strategies depending on the causal agents. Several studies have reported human risk factors for the disease; however, little efforts were made to investigate the risk factors in nontuberculous mycobacteria. Moreover, molecular genetics experiments have been difficult to search for virulence factors in M. avium, which the population genomics approaches could overcome. Here, the GWAS results suggested variants in three chromosomal loci associated with mycobacterial membrane components as risk factors for cavitary MAC lung disease. These findings could help develop treatment strategies for MAC lung disease in the future.
Topology and habitat assortativity drive neutral and adaptive diversification in spatial graphs
Authors: Boussange Victor , Pellissier Loïc
Published: July 2021

Biodiversity results from differentiation mechanisms developing within biological populations. Such mechanisms are influenced by the properties of the landscape over which individuals interact, disperse and evolve. Notably, landscape connectivity and habitat heterogeneity constrain the movement and survival of individuals, thereby promoting differentiation through drift and local adaptation. Nevertheless, the complexity of landscape features can blur our understanding of how they drive differentiation. Here, we formulate a stochastic, eco-evolutionary model where individuals are structured over a graph that captures complex connectivity patterns and accounts for habitat heterogeneity. Individuals possess neutral and adaptive traits, whose divergence results in differentiation at the population level. The modelling framework enables an analytical underpinning of emerging macroscopic properties, which we complement with numerical simulations to investigate how the graph topology and the spatial habitat distribution affect differentiation. We show that in the absence of selection, graphs with high characteristic length and high heterogeneity in degree promote neutral differentiation. Habitat assortativity, a metric that captures habitat spatial autocorrelation in graphs, additionally drives differentiation patterns under habitat-dependent selection. While assortativity systematically amplifies adaptive differentiation, it can foster or depress neutral differentiation depending on the migration regime. By formalising the eco-evolutionary and spatial dynamics of biological populations in complex landscapes, our study establishes the link between landscape features and the emergence of diversification, contributing to a fundamental understanding of the origin of biodiversity gradients.

Significance statement

It is not clear how landscape connectivity and habitat heterogeneity influence differentiation in biological populations. To obtain a mechanistic understanding of underlying processes, we construct an individualbased model that accounts for eco-evolutionary and spatial dynamics over graphs. Individuals possess both neutral and adaptive traits, whose co-evolution results in differentiation at the population level. In agreement with empirical studies, we show that characteristic length, heterogeneity in degree and habitat assortativity drive differentiation. By using analytical tools that permit a macroscopic description of the dynamics, we further link differentiation patterns to the mechanisms that generate them. Our study provides support for a mechanistic understanding of how landscape features affect diversification.
Phloem transport limitation in Huanglongbing affected sweet orange is dependent on phloem-limited bacteria and callose
Authors: Welker Stacy , Pierre Myrtho , Santiago James P. , Dutt Manjul , Vincent Christopher , Levy Amit
Published: July 2021

Huanglongbing (HLB), caused by Candidatus Liberibacter asiaticus (CLas), is a phloem-limited disease which disrupts citrus production in affected areas. In HLB-affected plants, phloem sieve plate pores accumulate callose, and leaf carbohydrate export is reduced. However, whether HLB causes a reduction in carbohydrate phloem translocation speed, and the quantitative relationships among callose, CLas population, and phloem translocation are still unknown. In this work, a procedure was developed to concurrently measure sugar transport, callose deposition, and relative pathogen population at different locations throughout the stem. Increasing quantities of CLas genetic material were positively correlated with quantity and density of callose deposits, and negatively correlated with phloem translocation speed. Callose deposit quantity was site- and rootstock dependent, and were negatively correlated with phloem translocation speed, suggesting a localized relationship. Remarkably, callose accumulation and phloem translocation disruption in the scion was dependent on rootstock genotype. Regression results suggested that the interaction of Ct values and number of phloem callose depositions, but not their size or density, explained the effects on translocation speed. Sucrose, starch, and sink 14C label allocation data support the interpretation of a transport pathway limitation by CLas infection. This work shows that the interaction of local accumulation of callose and CLas affect phloem transport. Further, the extent of this accumulation is attenuated by the rootstock and provides important information about the disease mechanism of phloem-inhabiting bacteria. Together, these results constitute the first example of a demonstrated transport limitation of phloem function by a microbial infection.