bluuebunny/crossref_metadata_2025 huggingface dataset:
Crucial role of the intracellular α-glucosidase MalT in the activation of the transcription factor AmyR essential for amylolytic gene expression in Aspergillus oryzae
Authors: Ichikawa Takanori , Tanaka Mizuki , Watanabe Takayasu , Zhan Sitong , Watanabe Akira , Shintani Takahiro , Gomi Katsuya
Published: July 2021

We examined the role of the intracellular α-glucosidase gene malT, which is part of the maltose-utilizing cluster (MAL cluster) together with malR and malP, in amylolytic gene expression in Aspergillus oryzae. malT disruption severely affected fungal growth on medium containing maltose or starch. Furthermore, the transcription level of the α-amylase gene was significantly reduced by malT disruption. Given that the transcription factor AmyR responsible for amylolytic gene expression is activated by isomaltose converted from maltose incorporated into the cells, MalT may have transglycosylation activity that converts maltose to isomaltose. Indeed, transglycosylated products such as isomaltose/maltotriose and panose were generated from the substrate maltose by MalT purified from a malT-overexpressing strain. The results of this study, taken together, suggests that MalT plays a pivotal role in AmyR activation via its transglycosylation activity that converts maltose to the physiological inducer isomaltose.
Exploratory prospective study of the influence of radical esophagectomy on perioperative physical activity in patients with thoracic esophageal cancer
Authors: Matsui Kazuaki , Kawakubo Hirofumi , Mayanagi Shuhei , Matsuda Satoru , Irino Tomoyuki , Fukuda Kazumasa , Nakamura Rieko , Wada Norihito , Kitagawa Yuko
Published: July 2021

Sarcopenia, which involves two important aspects, namely skeletal muscle loss and decreased physical function, was suggested as a poor prognostic factor in esophageal cancer surgery. The purpose of this study was to clarify the perioperative change in daily physical activity and propose effective preventive strategies. We prospectively enrolled patients with esophageal cancer who were scheduled to undergo radical esophagectomy. Their daily physical activities were recorded using an accelerometer before surgery, immediately after discharge, and 6 months after surgery. The relationships of physical activity level and the perioperative factors, especially skeletal muscle change, with the risk factors of low daily activity level were investigated. The data of 20/28 enrolled patients were analyzed. The mean activity level of the 20 patients decreased after discharge and subsequently recovered on postoperative month 6. The percentage of activity levels >1.5 metabolic equivalents/day after discharge significantly correlated to the change rate in total muscle cross-sectional area from baseline to POM 6 (r = 0.452, P = 0.045). In a stepwise multiple regression analysis, age, neoadjuvant chemotherapy, and anastomotic leakage were identified as negative associated factors of activity time at >1.5 metabolic equivalents at postoperative month 6. Activity level immediately after discharge was significantly associated with skeletal muscle loss at postoperative month 6 in patients with esophageal cancer who underwent esophagectomy. Elderly patients and patients who received neoadjuvant chemotherapy and had an anastomotic leakage might require intensive prevention. Prospective interventions aimed at increasing daily activity can prevent sarcopenia.
Anxiety and Depressive Symptoms Are Not Associated With Future Pediatric Crohn’s Disease Activity
Authors: Brenner Erica J , Long Millie D , Mann Courtney M , Lin Li , Chen Wenli , Reyes Camila , Bahnson Kirsten M , Reeve Bryce B , Kappelman Michael D
Published: July 2021

Background

Studies of adults with Crohn’s disease (CD) suggest that poor mental health precedes worsening disease activity. We evaluated whether depression and/or anxiety forecast worsening pediatric CD disease activity.

Methods

Through the Inflammatory Bowel Disease Partners Kids & Teens internet-based cohort, children with CD age 9 to 17 completed Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures and the short Crohn’s disease activity index (sCDAI). Using general linear models, we examined how baseline PROMIS Pediatric anxiety and depressive symptom scores independently associate with subsequent sCDAI scores (average survey interval 6.4 months). Models included baseline PROMIS Pediatric anxiety and depressive symptoms scores, baseline sCDAI, sex, age, parental education, race/ethnicity, and prior IBD-related surgery. We performed a post hoc subanalysis of children in baseline remission (sCDAI <150) with otherwise identical models.

Results

We analyzed 159 children with CD (mean age 14 years, 45% female, 84% in baseline remission). We found no association between baseline PROMIS Pediatric anxiety score and subsequent sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric −0.89; 95% CI −4.81 to 3.03). Baseline PROMIS Pediatric depressive symptoms score was not associated with future sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric <0.01; 95% CI −4.54 to 4.53). In a subanalysis of patients in remission at baseline, the lack of association remained.

Conclusion

We found that neither anxiety nor depressive symptoms associate with subsequent disease activity in pediatric CD. These findings contrast with adult IBD studies, thus underschoring the unique pathophysiology, natural history, and outcomes of pediatric CD.
Colorectal Cancer Prevention in Inflammatory Bowel Disease: A Systematic Analysis of the Overall Quality of Guideline Recommendations
Authors: Weissman Simcha , Systrom Hannah K , Aziz Muhammad , El-Dallal Mohammed , Lee-Smith Wade , Sciarra Michael , Feuerstein Joseph D
Published: July 2021

Background

Owing to the increased risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD), numerous societies developed preventative guidelines. We aimed to assess the overall quality of CRC prevention guidelines in IBD.

Methods

A systematic search was performed in multiple databases to identify all guidelines pertaining to CRC prevention in IBD in September 2020. All guidelines were reviewed for conflicts of interest (COIs)/funding, recommendation quality/strength, external guideline review, use of patient representation, and plans for update—as per Institute of Medicine standards. In addition, recommendations were compared amongst societies.

Results

One hundred forty-nine recommendations from 14 different guidelines/societies were included. Not all guidelines provided recommendations on key elements surrounding (1) screening initiation and surveillance, (2) screening modality, (3) pharmacological chemoprevention, (4) dysplasia management and follow-up, and (5) molecular marker use. Only 71% of guidelines disclosed COIs, 43% reported industry funding, 14% were externally reviewed, 7% included patient representation, and 36% had plans for update. Of the total recommendations, 7.4%, 23.5%, and 69.1% were based on high,- moderate-, and low-quality evidence, respectively. Additionally, 20.1% of recommendations were strong, 14.1%, were weak/conditional, and 65.8% did not provide a strength. The proportion of high-quality evidence (P = 0.34) and strong recommendations (P = 0.57) did not significantly differ across societies.

Conclusions

Many guidelines do not provide recommendations on key aspects of CRC prevention in IBD. Over 90% of recommendations are based on low- to moderate-quality evidence; therefore, further studies on CRC prevention in IBD are needed to improve the overall quality of evidence.
Identifying possible drivers of the abrupt and persistent delay in capelin spawning timing following the 1991 stock collapse in Newfoundland, Canada
Authors: Murphy Hannah M , Adamack Aaron T , Cyr Frédéric
Published: July 2021

Spawning timing in fish is generally cyclical in temperate regions in order to increase the probability of matching larval occurrence with ideal environmental conditions. The capelin stock in Northwest Atlantic Fisheries Organization Divisions 2J3KL collapsed in 1990–1991 and has not recovered. This collapse was concomitant with collapses in groundfish stocks and cold oceanographic conditions. Using citizen science data, newspaper archives, grey and primary literature, and monitoring data, a century of capelin beach spawning times were compiled. Capelin beach spawning has been persistently 3 weeks later since the stock collapse. To identify potential predictors of capelin spawning timing, an exploratory analysis was conducted using environmental and biological variables and a period factor that categorized a year as either pre-collapse (1990 and earlier) or post-collapse (post-1990) in a step-wise multiple regression model. Spawning timing was predicted to be delayed in the post-collapse period when there were negative anomalies in the Newfoundland and Labrador Climate Index and summer (June–August) North Atlantic Oscillation, and when there was a decrease in mean length of the spawning population. The production of weak year-classes is predicted when spawning is delayed, suggesting that late spawning is severely inhibiting the recovery of the stock.
Can surgical repair for pectus excavatum contribute to lung growth?
Authors: Ito Yuki , Suzuki Hidemi , Sasahara Yoshitaro , Mitsukawa Nobuyuki , Yoshino Ichiro
Published: July 2021

OBJECTIVES

This study investigates whether the surgical correction of chest deformity is associated with the growth of the lung parenchyma after surgery for pectus excavatum.

METHODS

Ten patients with pectus excavatum who were treated by the Nuss procedure were examined. The preoperative and postoperative computed tomography (2.5 ± 1.2 years after surgery) scans were performed, and the Haller index, lung volume and lung density were analyzed using a three-dimensional image analysis system (SYNAPSE VINCENT, Fujifilm, Japan). The radiological lung weight was calculated as follows: lung volume (ml) × lung density (g/ml).

RESULTS

The average age of the 10 patients (men 8; women 2) was 13.8 years (range: 6–26 years). The Haller index was significantly improved from the preoperative value of 5.18 ± 2.20 to the postoperative value of 3.68 ± 1.38 (P = 0.0025). Both the lung volume and weight had significantly increased by 107.1 ± 19.6% and 121.6 ± 11.3%, respectively, after surgery.

CONCLUSIONS

A significant increase in the weight of the lung after surgical correction suggests that the growth of the lung parenchyma is associated with the correction of chest deformity in younger patients with pectus excavatum.
Forty years of score-based soccer match outcome prediction: an experimental review
Authors: Hubáček Ondřej , Šourek Gustav , železný Filip
Published: July 2021

We investigate the state-of-the-art in score-based soccer match outcome modelling to identify the top-performing methods across diverse classes of existing approaches to the problem. Namely, we bring together various statistical methods based on Poisson and Weibull distributions and several general ranking algorithms (Elo, Steph ratings, Gaussian-OD ratings) as well as domain-specific rating systems (Berrar ratings, pi-ratings). We review, reimplement and experimentally compare these diverse competitors altogether on the largest database of soccer results available to identify true leaders. Our results reveal that the individual predictions, as well as the overall performances, are very similar across the top models tested, likely suggesting the limits of this generic approach to score-based match outcome modelling. No study of a similar scale has previously been done.
A survey of extant organizational and computational setups for deploying predictive models in health systems
Authors: Kashyap Sehj , Morse Keith E , Patel Birju , Shah Nigam H
Published: July 2021

Objective

Artificial intelligence (AI) and machine learning (ML) enabled healthcare is now feasible for many health systems, yet little is known about effective strategies of system architecture and governance mechanisms for implementation. Our objective was to identify the different computational and organizational setups that early-adopter health systems have utilized to integrate AI/ML clinical decision support (AI-CDS) and scrutinize their trade-offs.

Materials and Methods

We conducted structured interviews with health systems with AI deployment experience about their organizational and computational setups for deploying AI-CDS at point of care.

Results

We contacted 34 health systems and interviewed 20 healthcare sites (58% response rate). Twelve (60%) sites used the native electronic health record vendor configuration for model development and deployment, making it the most common shared infrastructure. Nine (45%) sites used alternative computational configurations which varied significantly. Organizational configurations for managing AI-CDS were distinguished by how they identified model needs, built and implemented models, and were separable into 3 major types: Decentralized translation (n = 10, 50%), IT Department led (n = 2, 10%), and AI in Healthcare (AIHC) Team (n = 8, 40%).

Discussion

No singular computational configuration enables all current use cases for AI-CDS. Health systems need to consider their desired applications for AI-CDS and whether investment in extending the off-the-shelf infrastructure is needed. Each organizational setup confers trade-offs for health systems planning strategies to implement AI-CDS.

Conclusion

Health systems will be able to use this framework to understand strengths and weaknesses of alternative organizational and computational setups when designing their strategy for artificial intelligence.
The Protective Effect of Natural Compounds on Doxorubicin-Induced Cardiotoxicity via Nicotinamide Adenine Dinucleotide Phosphate Oxidase Inhibition
Authors: Yousefian Mozhdeh , Hosseinzadeh Hossein , Hayes A Wallace , Hadizadeh Farzin , Karimi Gholamreza
Published: July 2021

Objectives

Doxorubicin (DOX) is widely prescribed for the treatment of several human cancers. Unfortunately, cumulative doses of DOX are the main cause of myocardial dysfunction. Although preclinical and pharmaceutical studies were performed to investigate the potential of natural compounds in minimizing DOX toxicity, a comprehensive review of them is not available. This review can help the researchers for an effective search strategy.

Key findings

Oxidative stress and p53 play an important role in DOX-associated cardiotoxicity. DOX activates nicotinamide adenine dinucleotide phosphate NADPH oxidase (NOX) in the heart, resulting in excessive reactive oxygen species that can induce cardiomyocyte apoptosis through phosphorylation of p53, DNA damage and/or mitogen-activated protein kinases-mediated cardiomyocyte apoptosis. Although a few chemical drugs with high efficacy are administered along with DOX to prevent or more likely to reduce cardiovascular toxicity, their use is often limited by additional side effects. Recently, attention has been drawn to natural compounds that prevent DOX cardiotoxicity. This review focuses on some of the natural bioactive compounds with potential therapeutic efficacy against DOX-induced cardiotoxicity (DIC).

Some natural compounds, especially flavonols, flavonoids and proanthocyanidins, have the most protective effects against DIC by forming stable radicals and preventing the assembly of the NOX subunits.
Behavioral Health Provider Attitudes Toward Behavioral Health Profiles in the U.S. Army
Authors: Curley Justin M , Clarke-Walper Kristina M , Nugent Katie L , Wilk Joshua E
Published: July 2021

Introduction

U.S. Army healthcare providers’ use of profiles to document and communicate behavioral health (BH) condition limitations to commanders is vital to understanding both the individual soldier’s BH readiness for missions and, as an aggregate, the unit’s overall BH readiness status. Quantitative work exploring the link between soldier attitudes toward BH profiles and treatment utilization found that profiles may actually promote increases in treatment-seeking behavior in those receiving conventional BH services. BH provider attitudes on the subject, however, have not been quantitatively explored. Using data from the recently described Behavioral Health Readiness and Decision-Making Instrument (B-REDI) study, the current inquiry addresses this by examining BH providers’ pre-/post-B-REDI attitudes toward BH profiles, including therapeutic alliance, to better understand how BH profiles may impact BH treatment.

Methods

This study was approved by the WRAIR Institutional Review Board and is part of the larger B-REDI study. BH providers (n = 307) across five installations supporting active duty U.S. Army Divisions completed surveys longitudinally across three time points from September 2018 to March 2019. The survey specific to this study included five items, developed by WRAIR, assessing BH provider attitudes toward BH profiles. Of the providers who completed the survey, 250 (81%) consented to participate in the study and 149 (60%) completed the 3-month follow-up survey.

Results

Over 80% of BH providers expressed agreement with each of three items assessing rationale for issuing BH profiles in both the pre- and post B-REDI period. Specifically, most providers agreed that profiles facilitate commander support to the soldier, afford soldiers resources for recovery, and give commanders increased understanding of soldier health for mission planning. Twenty-six percent of BH providers agreed, 46% were neutral, and 28% disagreed on whether profile impact on the soldier was positive or not in the pre-B-REDI period, but there was a significant positive trend relative to baseline in the post B-REDI period. The vast majority of providers (≥94%) did not endorse agreement that BH profiles negatively impact therapeutic alliance in either the pre- or post-B-REDI period.

Conclusions

Assuming that therapeutic alliance and perceptions of BH profile impact on soldiers are useful proxy measures of how treatment utilization may be affected by profiling, this inquiry fails to establish any meaningful negative association between them. This may provide some additional reassurance to BH providers and policymakers that efforts to improve readiness decision-making, such as B-REDI, and increased profiling in conventional military BH settings may not negatively impact treatment utilization rates.
Perinatal Symptoms and Treatment Engagement in Female Veterans
Authors: Anderson Elizabeth H , Morrow Carolyn , Mattocks Kristin M , Shivakumar Geetha
Published: July 2021

Introduction

Women veterans using Veterans Health Care Administration maternity benefits have a high prevalence of mental health disorders, including depression, PTSD, and anxiety. Additionally, women with psychiatric histories often experience a relapse or worsening of symptoms during pregnancy and postpartum. Adequate perinatal mental healthcare engagement is critical to optimizing outcomes for mother and child.

Materials and Methods

This study evaluated psychiatric symptom severity and predictors of women veteran’s mental health treatment engagement during pregnancy and postpartum at the VA North Texas Health Care System. Seventy women using Veterans Health Administration were assessed longitudinally via chart review and interviews (including the Edinburgh Postnatal Depression Scale) during pregnancy and postpartum. A Friedman test was used to evaluate the change in symptom severity during (1) the 6 months before pregnancy, (2) pregnancy, and (3) postpartum. Multivariate logistic regressions were used to determine predictors of attending outpatient mental health appointments. Potential predictors examined included sociodemographic factors, symptoms of depression, history of military sexual assault, presence of a pre-pregnancy psychiatric diagnosis, and attendance of mental health appointments before pregnancy.

Results

Approximately 40% of participants demonstrated at least mild psychiatric symptoms before pregnancy, and symptom severity did not significantly change across the perinatal period (pre-pregnancy, pregnancy, and postpartum) X2 (2, n = 70) = 3.56, P = .17. Depressive symptoms during the 2nd or 3rd trimester were a significant predictor for attendance of mental health appointments during both pregnancy (OR = 1.18, 95% CI, 1.04 to 1.34) and postpartum (OR = 1.18, 95% CI, 1.02 to 1.36). An active psychiatric diagnosis during the 6 months before pregnancy was also a significant predictor of attendance following delivery (OR = 14.63, 95% CI, 1.55 to 138.51).

Conclusion

Our results demonstrate that women with prior histories of mental health conditions will continue to be symptomatic, and this is a good predictor of mental health treatment engagement during the perinatal period.
Central dynamics of multimass rotating star clusters
Authors: Tiongco Maria , Collier Angela , Varri Anna Lisa
Published: July 2021

We investigate the evolutionary nexus between the morphology and internal kinematics of the central regions of collisional, rotating, multimass stellar systems, with special attention to the spatial characterization of the process of mass segregation. We report results from idealized, purely N-body simulations that show multimass, rotating, and spherical systems rapidly form an oblate, spheroidal massive core, unlike single-mass rotating, or multimass non-rotating configurations with otherwise identical initial properties, indicating that this evolution is a result of the interplay between the presence of a mass spectrum and angular momentum. This feature appears to be long-lasting, preserving itself for several relaxation times. The degree of flattening experienced by the systems is directly proportional to the initial degree of internal rotation. In addition, this morphological effect has a clear characterization in terms of orbital architecture, as it lowers the inclination of the orbits of massive stars. We offer an idealized dynamical interpretation that could explain the mechanism underpinning this effect and we highlight possible useful implications, from kinematic hysteresis to spatial distribution of dark remnants in dense stellar systems.
Pilot study of smartphone-based health outcome tracking (OurBrainBank) for glioblastoma patients
Authors: Ellen Jacob G , Boele Florien W , Hellman Bruce , Duprey Kelli , Nayak Lakshmi , Morris Jessica
Published: July 2021

Background

Patients with glioblastoma (GBM) typically have high symptom burden impacting on quality of life. Mobile apps may help patients track their condition and provide real-time data to clinicians and researchers. We developed a health outcome reporting app (OurBrainBank [OBB]) for GBM patients. Our primary aim was to explore the feasibility and take-up of OBB. Secondary aims were to examine the potential value of OBB app usage for patient well-being and clinical research.

Methods

Participants (or caregiver proxies) completed baseline surveys and tracked 10 health outcomes over time. We evaluated usage and engagement, and relationships between clinical/sociodemographic variables and OBB use. Participant satisfaction and feedback were described. To demonstrate usefulness for clinical research, health outcomes were compared with corresponding items on a validated measure (EQ-5D-5L).

Results

From March 2018 to February 2021, OBB was downloaded by 630 individuals, with 15 207 sets of 10 health outcomes submitted. Higher engagement was associated with being a patient rather than a caregiver (χ 2(2,568) = 28.6, P < .001), having higher self-rated health scores at baseline (F(2,460) = 4.8, P = .009) and more previous experience with mobile apps (χ 2(2,585) = 9.6, P = .008). Among the 66 participants who completed a feedback survey, most found health outcome tracking useful (average 7/10), and would recommend the app to others (average 8.4/10). The OBB health outcomes mapped onto corresponding EQ-5D-5L items, suggesting their validity.

Conclusions

OBB can efficiently collect GBM patients’ health outcomes. The long-term goal is to create a unique database of thousands of deidentified GBM patients, with open access to qualified researchers.
Virologic Outcomes Among People Living With Human Immunodeficiency Virus With High Pretherapy Viral Load Burden Initiating on Common Core Agents
Authors: Mills Anthony M , Schulman Kathy L , Fusco Jennifer S , Wohlfeiler Michael B , Priest Julie L , Oglesby Alan , Brunet Laurence , Lackey Philip C , Fusco Gregory P
Published: July 2021

Background

People living with human immunodeficiency virus (PLWH) initiating antiretroviral therapy (ART) with viral loads (VLs) ≥100 000 copies/mL are less likely to achieve virologic success, but few studies have characterized real-world treatment outcomes.

Methods

ART-naive PLWH with VLs ≥100 000 copies/mL initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) between 12 August 2013 and 31 July 2017 were identified from the OPERA database. Virologic failure was defined as (i) 2 consecutive VLs ≥200 copies/mL after 36 weeks of ART; (ii) 1 VL ≥200 copies/mL with core agent discontinuation after 36 weeks; (iii) 2 consecutive VLs ≥200 copies/mL after suppression (≤50 copies/mL) before 36 weeks; or (iv) 1 VL ≥200 copies/mL with discontinuation after suppression before 36 weeks. Cox modeling estimated the association between regimen and virologic failure.

Results

There were 2038 ART-naive patients with high VL who initiated DTG (36%), EVG (46%), DRV (16%), or RAL (2%). Median follow-up was 18.1 (interquartile range, 12.4–28.9) months. EVG and DTG initiators were similar at baseline, but RAL initiators were older and more likely to be female with low CD4 cell counts while DRV initiators differed notably on factors associated with treatment failure. Virologic failure was experienced by 9.2% DTG, 13.2% EVG, 18.4% RAL, and 18.8% DRV initiators. Compared to DTG, the adjusted hazard ratio (95% confidence interval) was 1.46 (1.05–2.03) for EVG, 2.24 (1.50–3.34) for DRV, and 4.13 (1.85–9.24) for RAL.

Conclusions

ART-naive PLWH with high VLs initiating on DTG were significantly less likely to experience virologic failure compared to EVG, RAL, and DRV initiators.

Antiretroviral therapy-naïve people living with HIV (PLWH) initiating therapy with viral loads ≥100,000 copies/mL varied markedly at baseline. In adjusted models, PLWH initiating dolutegravir-based regimens were less likely to experience virologic failure as compared to elvitegravir, raltegravir and darunavir initiators.
Oral Polio Vaccine to Protect Against COVID-19: Out of the Box Strategies?
Authors: Malave Sanchez Melanie , Saleeb Paul , Kottilil Shyam , Mathur Poonam
Published: July 2021

The global coronavirus disease 2019 pandemic has raised significant concerns of developing rapid, broad strategies to protect the vulnerable population and prevent morbidity and mortality. However, even with an aggressive approach, controlling the pandemic has been challenging, with concerns of emerging variants that likely escape vaccines, nonadherence of social distancing/preventive measures by the public, and challenges in rapid implementation of a global vaccination program that involves mass production, distribution, and execution. In this review, we revisit the utilization of attenuated vaccinations, such as the oral polio vaccine, which are safe, easy to administer, and likely provide cross-protection against respiratory pathogens. We discuss the rationale and data supporting its use and detail description of available vaccines that could be repurposed for curtailing the pandemic.
Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder
Authors: Reiner Benjamin C , Doyle Glenn A , Weller Andrew E , Levinson Rachel N , Rao Aditya M , Davila Perea Emilie , Namoglu Esin , Pigeon Alicia , Arauco-Shapiro Gabriella , Weickert Cyndi Shannon , Turecki Gustavo , Crist Richard C , Berrettini Wade H
Published: July 2021

Studies of the genetic heritability of schizophrenia and bipolar disorder examining single nucleotide polymorphisms (SNPs) and copy number variations have failed to explain a large portion of the genetic liability, resulting in substantial missing heritability. Long interspersed element 1 (L1) retrotransposons are a type of inherited polymorphic variant that may be associated with risk for schizophrenia and bipolar disorder. We performed REBELseq, a genome wide assay for L1 sequences, on DNA from male and female persons with schizophrenia and controls (n = 63 each) to identify inherited L1 insertions and validated priority insertions. L1 insertions of interest were genotyped in DNA from a replication cohort of persons with schizophrenia, bipolar disorder, and controls (n = 2268 each) to examine differences in carrier frequencies. We identified an inherited L1 insertion in ARHGAP24 and a quadallelic SNP (rs74169643) inside an L1 insertion in SNTG2 that are associated with risk for developing schizophrenia and bipolar disorder (all odds ratios ~1.2). Pathway analysis identified 15 gene ontologies that were differentially affected by L1 burden, including multiple ontologies related to glutamatergic signaling and immune function, which have been previously associated with schizophrenia. These findings provide further evidence supporting the role of inherited repetitive genetic elements in the heritability of psychiatric disorders.
Ketamine for refractory chronic pain: a 1-year follow-up study
Authors: Corriger Alexandrine , Voute Marion , Lambert Céline , Pereira Bruno , Pickering Gisèle
Published: July 2021

Ketamine is often used in pain clinics for refractory chronic pain, but its long-term efficacy is poorly reported. The main objective was to assess the long-term effect of ketamine on pain and health variables in patients with refractory chronic pain. A prospective, multicenter, 1-year follow-up observational study (NCT03319238) was conducted in 30 French pain clinics where ketamine is commonly prescribed. This study focused on patients with 1 ketamine delivery procedure (n = 256). The primary endpoint was pain intensity (0-10 numerical pain rating scale) before and after ketamine every month for 1 year. Secondary outcomes aimed to identify pain trajectories by semiparametric mixture models and to collect adverse events. The following data were obtained for 256 patients: Pain intensity decreased significantly (6.8 ± 1.8, n = 240 at baseline vs 5.7 ± 1.8, n = 93 at 12 months; P < 0.001). The effect size of the main endpoint was 0.61 (95% confidence interval: [0.40-0.80]; P < 0.001). Three pain trajectories were identified: 16.0% of patients in “mild pain” (mostly neuropathic pain), 35.3% in “moderate pain,” and 45.7% in “severe pain” (mostly fibromyalgia) trajectory. Neuropathic pain and fibromyalgia presented opposite outcomes, pain severity being associated with anxiety, depression, and a poorer quality of life. Adverse events occurred at 1 week in 108/218 [50%] patients, and this rate gradually decreased throughout the follow-up. This real-life study in chronic pain identified distinct pain trajectories and predictive variables of ketamine efficacy. It is now pivotal to further study and optimize the subtyping of patients to provide the most effective and safe ketamine treatment in this vulnerable population.
The replaceable master of sex determination: bottom-up hypothesis revisited
Authors: Adolfi Mateus Contar , Herpin Amaury , Schartl Manfred
Published: July 2021

Different group of vertebrates and invertebrates demonstrate an amazing diversity of gene regulations not only at the top but also at the bottom of the sex determination genetic network. As early as 1995, based on emerging findings in
Drosophila melanogaster
and
Caenorhabditis elegans
, Wilkins suggested that the evolution of the sex determination pathway evolved from the bottom to the top of the hierarchy. Based on our current knowledge, this review revisits the ‘bottom-up’ hypothesis and applies its logic to vertebrates. The basic operation of the determination network is through the dynamics of the opposing male and female pathways together with a persistent need to maintain the sexual identity of the cells of the gonad up to the reproductive stage in adults. The sex-determining trigger circumstantially acts from outside the genetic network, but the regulatory network is not built around it as a main node, thus maintaining the genetic structure of the network. New sex-promoting genes arise either through allelic diversification or gene duplication and act specially at the sex-determination period, without integration into the complete network. Due to this peripheral position the new regulator is not an indispensable component of the sex-determining network and can be easily replaced.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Sex determination without sex chromosomes
Authors: Weber Ceri , Capel Blanche
Published: July 2021

With or without sex chromosomes, sex determination is a synthesis of many molecular events that drives a community of cells towards a coordinated tissue fate. In this review, we will consider how a sex determination pathway can be engaged and stabilized without an inherited genetic determinant. In many reptilian species, no sex chromosomes have been identified, yet a conserved network of gene expression is initiated. Recent studies propose that epigenetic regulation mediates the effects of temperature on these genes through dynamic post-transcriptional, post-translational and metabolic pathways. It is likely that there is no singular regulator of sex determination, but rather an accumulation of molecular events that shift the scales towards one fate over another until a threshold is reached sufficient to maintain and stabilize one pathway and repress the alternative pathway. Investigations into the mechanism underlying sex determination without sex chromosomes should focus on cellular processes that are frequently activated by multiple stimuli or can synthesize multiple inputs and drive a coordinated response.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Effectiveness of Rosuvastatin plus Colchicine, Emtricitabine/Tenofovir and a combination of them in Hospitalized Patients with SARS Covid-19
Authors: Gaitán-Duarte Hernando Guillermo , Álvarez-Moreno Carlos , Rincón-Rodríguez Carlos Javier , Yomayusa-González Nancy , Cortés Jorge Alberto , Villar Juan Carlos , Bravo-Ojeda Juan Sebastián , García-Peña Ángel , Adarme-Jaimes Wilson , Rodríguez-Romero Viviana Alejandra , Villate-Soto Steffany Lorena , Buitrago Giancarlo , Chacón-Sarmiento Julio , Macías-Quintero Martín , Vaca Claudia Patricia , Gómez-Restrepo Carlos , Rodríguez-Malagón Nelcy
Published: July 2021

BACKGROUND

The effectiveness of rosuvastatin plus colchicine, emtricitabine/tenofovir, and of their combined use in hospitalized patients with coronavirus disease 2019 (Covid-19) pneumonia is unclear.

METHODS

In each hospital, hospitalized adults with Covid-19 pneumonia, were randomly assigned, in a 1:1 ratio, to receive: a) standard of care; or b) emtricitabine/tenofovir; or c) colchicine + rosuvastatin; or d) emtricitabine/tenofovir + colchicine + rosuvastatin. The primary outcome was all-cause mortality within the first 28 days after randomization. Severe adverse events (SAE) were those with a high probability of being treatment-related.

RESULTS

633 patients were randomized in 6 hospitals in Bogota, Colombia. Overall, 98% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death through day 28 was 10.7% in the emtricitabine/tenofovir + colchicine + rosuvastatin arm, 14.4% in the colchicine + rosuvastatin arm, 13.8% in the emtricitabine/tenofovir arm, and 17.4% in the standard of care arm, with adjusted risk differences (aRD) against the standard treatment of -0.07 (95% confidence interval [CI], -0.17 to 0.04), aRD -0.03 (95%CI: -0.11 to 0.05) and aRD: -0.05 (95%CI: -0.15 to 0.05), respectively. Need for invasive mechanical ventilation was lower in the emtricitabine/tenofovir + colchicine + rosuvastatin arm compared to the standard treatment arm, aRD: -0.06 (95%CI: -0.11 to -0,01), but no differences were found between the other comparisons. SAE occurred in 3 patients distributed in the 3 treatment arms.

CONCLUSIONS

Among patients hospitalized with moderate and severe SARS Covid-19, the use of the emtricitabine/tenofovir + colchicine + rosuvastatin combination emerges as a treatment alternative.

ClinicalTrials.gov number:NCT04359095
Aorta-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease
Authors: Abudupataer Mieradilijiang , Zhu Shichao , Yan Shiqiang , Xu Kehua , Zhang Jingjing , Luo Shaman , Ma Wenrui , Alam Md. Fazle , Tang Yuyi , Huang Hui , Chen Nan , Wang Li , Yan Guoquan , Li Jun , Lai Hao , Wang Chunsheng , Zhu Kai , Zhang Weijia
Published: July 2021

Background

Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

Methods

A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

Results

Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

Conclusions

The aorta-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

Funding

National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.
A case of autosomal dominant osteopetrosis type II with a severe bone phenotype but no amino acid converting mutation in the CLCN7 gene
Authors: Hofstaetter Jochen G. , Atkins Gerald J. , Kogawa Masakazu , Blouin Stéphane , Misof Barbara M. , Roschger Paul , Evdokiou Andreas , Solomon L. Bogdan , Findlay David M. , Ito Nobuaki
Published: July 2021

Autosomal Dominant Osteopetrosis type II (ADOII), also known as Albers-Schönberg disease, is caused by mutation of the CLCN7 chloride channel gene and is characterized by reduced bone resorption. Here we report on an individual with the classic features of ADOII, who had a history of fractures from childhood, displayed high bone mass and characteristic “sandwich vertebrae” on x-ray. Our genetic analyses showed no amino acid converting mutation in the patient’s DNA but we did find evidence of haploinsufficiency of CLCN7 mRNA. An iliac crest bone sample from the patient revealed bone tissue and material abnormalities relative to normal controls based on quantitative backscattered electron imaging and histomorphometric analyses. Additionally to lamellar bone, we observed significant amounts of woven bone and mineralised cartilage, as well as an increased frequency and thickness (up to 15 microns) of cement lines. Giant osteoclasts with numerous nuclei were present. The bone mineralisation density distribution (BMDD) of the entire bone area revealed markedly increased average mineral content of the dense bone (CaMean T-score +10.1) and frequency of bone with highest mineral content (CaHigh T-score +19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except the OLS shape which was unusually circular. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture.
Efficacy and safety of Andrographis paniculata extract in patients with mild COVID-19: A randomized controlled trial
Authors: Wanaratna Kulthanit , Leethong Pornvimol , Inchai Nitapha , Chueawiang Wararath , Sriraksa Pantitra , Tabmee Anutida , Sirinavin Sayomporn
Published: July 2021

Objectives

To assess the efficacy and safety of Andrographis paniculata extract (APE) in adults with mild COVID-19.

Methods

Sixty-three adults aged 18-60 years, without co-morbidity, with laboratory-confirmed mild COVID-19, were randomized 1:1 to receive APE (60 mg andrographolide, t.i.d, for 5 days) or placebo within 24 hours after admission, plus standard supportive care. The outcomes were clinical recovery rates by Day 5 using self-assessment scores, pneumonia by chest X-rays, nasopharyngeal SARS-CoV-2 detection by rRT-PCR on Day 5, changes of serum CRP levels, and adverse drug reactions. Chest X-rays and blood tests for CRP, liver and renal function, were performed on Days 1, 3, and 5.

Results

Baseline characteristics of patients in the APE-treatment (n=29) and placebo-control (n=28) groups were comparable. None had self-assessment scores showing complete clinical recovery by Day 5. Pneumonia occurred in 0/29 (0%) versus 3/28 (10.7%), (p=0.112). On Day 5, patients with SARS-CoV-2 detection were 10/29 (34.5%) versus 16/28 (57.1%), (p=0.086); patients with CRP >10 mg/L were 0/29 (0%) versus 5/28 (17.9%), (p=0.023), for APE-treatment and placebo-control groups, respectively. All three patients with pneumonia had substantially rising serum CRP; and high CRP levels on Day 5. None had evidence of hematologic, hepatic or renal impairment.

Conclusion

Even though the study was limited by small sample size, our findings suggested promising efficacy and safety of the APE-treatment regimen in adults with mild COVID-19. Further studies, with adequate power to assure these findings, are required.
Hepatoprotective effects of Aureobasidium pullulans derived Beta 1,3-1,6 biological response modifier glucans in a STAM- animal model of non-alcoholic steatohepatitis
Authors: Ikewaki Nobunao , Kurosawa Gene , Iwasaki Masaru , Preethy Senthilkumar , Dedeepiya Vidyasagar Devaprasad , Vaddi Suryaprakash , Senthilkumar Rajappa , Levy Gary A , Abraham Samuel JK
Published: July 2021

Background

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Lifestyle disorders such as obesity, diabetes and dyslipidaemia predispose to and are associated with the disease progression. Conventional modalities are mainly symptomatic, with no definite solution. Beta glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects.Aureobasidium pullulansstrains AFO-202 and N-163 beta glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study.

Methods

In the STAM™ murine model of NASH, five groups were studied for eight weeks— (1) vehicle (RO water), (2) AFO-202 beta glucan; (3) N-163 beta glucan, (4) AFO-202+N-163 beta glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed.

Results

AFO-202 beta glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta glucan decreased fibrosis and inflammation significantly (p value<0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups.

Conclusion

This preclinical study supports the potential of N-163 and AFO-202 beta glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.

Graphical abstract
Multi-environment QTL analysis delineates a major locus associated with homoeologous exchanges for water-use efficiency and seed yield in allopolyploidBrassica napus
Authors: Raman Harsh , Raman Rosy , Pirathiban Ramethaa , McVittie Brett , Sharma Niharika , Liu Shengyi , Qiu Yu , Zhu Anyu , Killian Andrzej , Cullis Brian , Farquhar Graham D. , Williams Hilary S. , White Rosemary , Tabah David , Easton Andrew , Zhang Yuanyuan
Published: July 2021

Canola varieties exhibit discernible variation in drought avoidance and drought escape traits, suggesting its adaptation to water-deficit environments. However, the underlying mechanisms are poorly understood.

A doubled haploid (DH) population was analysed to identify QTL associated with water use efficiency (WUE) related traits. Based on the resequenced parental genome data, we developed sequence-capture based markers for fine mapping. mRNA-Seq was performed to determine the expression of candidate genes underlying QTL for carbon isotope discrimination (Δ13C).

QTL contributing to main and QTL × Environment interaction effects for Δ13C and for agronomic WUE were identified. One multi-trait QTL for Δ13C, days to flower, plant height and seed yield was identified on chromosome A09, in the vicinity ofERECTA. Interestingly, this QTL region was overlapped with a homoeologous exchange event (HE), suggesting its association with the major QTL. Transcriptome analysis revealed several differentially expressed genes between parental lines, including in HE regions.

This study provides insights into the complexity of WUE related genes in the context of canola adaptation to water-deficit conditions. Our results suggest that alleles for high Δ13C contribute positively to canola yield. Genetic and genomic resources developed herein could be utilised to make genetic gains for improving canola WUE.
COVID-19 and Herpes Simplex Virus Infection: A Cross-Sectional Study
Authors: Shanshal Mohammed , Ahmed Hayder Saad
Published: July 2021

Background

Despite being variable and poorly characterized, the reported cutaneous manifestations of COVID-19 are of increasing concern.

Aim of the Study

This study aimed to assess the prevalence and possible association between COVID-19 and herpes simplex virus (HSV) infection.

Patients and methods

A 9-item questionnaire was sent to 120 PCR-confirmed COVID-19 patients with a response rate of 66.67%. This cross-sectional observational study included 80 patients with mild to moderate COVID-19 infection who did not require hospitalization or steroid therapy.

Results

One or more HSV infections were observed in 28 patients (35%) with COVID-19 infection, including 10 males (35.7%) and 18 females (64.29%). Of the 28 patients, fever was reported in 17 patients (75%) during COVID-19. Most of the respondents (78%) described a single HSV reactivation, 14.29% had 2 attacks, and 7.14% experienced 3 attacks. Compared to previous non-COVID-19 related HSV reactivation, the COVID-19 related attacks were more severe in 12 patients (42.85%), equally severe in 5 patients (17.85%) and less severe in 1 patient (3.57%). Interestingly, 10 patients (35.71%) developed an initial symptomatic HSV attack during COVID-19 infection.

Conclusions

This study demonstrated a possible association between COVID-19 infection and primary HSV infection and/or reactivation. The COVID-19 direct neuronal effect in addition to COVID-19 related psychological stress, fever and immunological dysregulation could play a potential role.