bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Genetics and Complex Inheritance of Congenital Heart Disease
Authors: Diab Nicholas S. , Barish Syndi , Dong Weilai , Zhao Shujuan , Allington Garrett , Yu Xiaobing , Kahle Kristopher T. , Brueckner Martina , Jin Sheng Chih
Published: June 2021

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
Long-Term Results of Joint Arthroplasty with Total Prosthesis for Trapeziometacarpal Osteoarthritis in Patients over 65 Years of Age
Authors: Martin-Ferrero Miguel Angel , Trigueros-Larrea Jose Maria , Martin-de la Cal Elsa , Coco-Martin Begoña , Simon-Perez Clarisa
Published: June 2021

Trapeziometacarpal osteoarthritis (TMCOA) is a highly prevalent disease in the older population. Many different types of surgical treatments are possible, depending on the degree of joint involvement, the personal and professional circumstances of the patient and the preferences of the orthopedic surgeon. This paper evaluated the clinical and radiological results of consecutive cohorts of patients over 65 years old treated with total joint arthroplasties (TJA) of the ball and socket type (B&S) for TMCOA, with a minimum of 10 years follow-up. The survival rate (Kaplan–Meier) of the functional prostheses at 10 years was 92.2% (95% CI (89.1%, 96.1%). These functional arthroplasty patients, after 10 years of follow-up, showed little or no pain, good function and good key pinch, without radiological alterations. TJAs of the B&S type are a long lasting, effective and reliable alternative to surgical treatment of TMCOA in patients over 65 years of age, when they are performed with the patient selection criteria and surgical technique described throughout this study.
Sharing Biomedical Data: Strengthening AI Development in Healthcare
Authors: Pereira Tania , Morgado Joana , Silva Francisco , Pelter Michele M. , Dias Vasco Rosa , Barros Rita , Freitas Cláudia , Negrão Eduardo , Flor de Lima Beatriz , Correia da Silva Miguel , Madureira António J. , Ramos Isabel , Hespanhol Venceslau , Costa José Luis , Cunha António , Oliveira Hélder P.
Published: June 2021

Artificial intelligence (AI)-based solutions have revolutionized our world, using extensive datasets and computational resources to create automatic tools for complex tasks that, until now, have been performed by humans. Massive data is a fundamental aspect of the most powerful AI-based algorithms. However, for AI-based healthcare solutions, there are several socioeconomic, technical/infrastructural, and most importantly, legal restrictions, which limit the large collection and access of biomedical data, especially medical imaging. To overcome this important limitation, several alternative solutions have been suggested, including transfer learning approaches, generation of artificial data, adoption of blockchain technology, and creation of an infrastructure composed of anonymous and abstract data. However, none of these strategies is currently able to completely solve this challenge. The need to build large datasets that can be used to develop healthcare solutions deserves special attention from the scientific community, clinicians, all the healthcare players, engineers, ethicists, legislators, and society in general. This paper offers an overview of the data limitation in medical predictive models; its impact on the development of healthcare solutions; benefits and barriers of sharing data; and finally, suggests future directions to overcome data limitations in the medical field and enable AI to enhance healthcare. This perspective is dedicated to the technical requirements of the learning models, and it explains the limitation that comes from poor and small datasets in the medical domain and the technical options that try or can solve the problem related to the lack of massive healthcare data.
Challenges in Maternal and Child Health Services Delivery and Access during Pandemics or Public Health Disasters in Low-and Middle-Income Countries: A Systematic Review
Authors: Sahoo Krushna Chandra , Negi Sapna , Patel Kripalini , Mishra Bijaya Kumar , Palo Subrata Kumar , Pati Sanghamitra
Published: June 2021

Maternal and child health (MCH) has been a global priority for many decades and is an essential public health service. Ensuring seamless delivery is vital for desirable MCH outcomes. This systematic review outlined the challenges in accessing and continuing MCH services during public health emergencies—pandemics and disasters. A comprehensive search approach was built based on keywords and MeSH terms relevant to ‘MCH services’ and ‘pandemics/disasters’. The online repositories Medline, CINAHL, Psyc INFO, and Epistemonikos were searched for studies. We included twenty studies—seven were on the Ebola outbreak, two on the Zika virus, five related to COVID-19, five on disasters, and one related to conflict situations. The findings indicate the potential impact of emergencies on MCH services. Low utilization and access to services have been described as common challenges. The unavailability of personal safety equipment and fear of infection were primary factors that affected service delivery. The available evidence, though limited, indicates the significant effect of disasters and pandemics on MCH. However, more primary in-depth studies are needed to understand better the overall impact of emergencies, especially the COVID-19 pandemic, on MCH. Our synthesis offers valuable insights to policymakers on ensuring the uninterrupted provision of MCH services during an emergency.
Implementation of Triage System and Shortening Patient Journey Time to Prevent COVID-19 Transmission in a University Hospital during a Pandemic
Authors: Kongkamol Chanon , Padungkul Laaong , Rattanajarn Nuttanicha , Srisara Supawich , Rangsinobpakhun Lalita , Apiwan Kanarit , Sompan Jittiwat , Prathipsawangwong Chatchanok , Buathong Pennapa , Chann Sinat , Sathirapanya Pornchai , Sathirapanya Chutarat
Published: June 2021

To explore the characteristics of the patient under investigation (PUI), and the routes and the patient journey time in our outpatient service, we examined the demographic data, presenting symptoms, risks of contact with COVID-19 cases, and the results of real-time polymerase chain reaction (PCR) tests in PUI cases from March to May 2020. The contact time, transfer time and total journey time of patient journey routes in our hospital were also explored. The results were shown in numbers, percentages and medians (interquartile range, IQR). A total of 334 PUI cases were identified from our triage system. The median (IQR) age was 35 (27, 47) years. Cough was the most common presenting symptom (56.2%), while fever (≥37.5 °C) was found in only 19.8% of the cases. The median (IQR) time of onset of the presenting symptoms was 3 (1, 5) days. The most common risk of contact with COVID-19 cases found during the triage was living in or returning from an outbreak area. Fifteen (4.5%) of the PUI cases had positive real-time PCR tests. The contact time and transfer time were longest in the PUI ward and from the Emergency Department (ED) to the PUI ward, respectively. Plans and actions to shorten the transfer time between the ED and the PUI ward and the total journey time should be developed.
What Does CLARITY-BPA Mean for Canadians?
Authors: Rogers Lindsay D.
Published: June 2021

Bisphenol A is an extremely high-volume chemical widely used in polycarbonate plastics, the linings of food and beverage tins, and shopping receipts. Canadians are ubiquitously exposed to bisphenol A and research shows that exposure at environmentally relevant doses causes endocrine disruption. Recent risk assessments and exposure estimates by the European Food Safety Authority have guided increased restrictions around the use of bisphenol A and established a lower tolerable daily intake, while the CLARITY-BPA program in the United States identified several adverse effects below this exposure level. Within the context of bisphenol toxicity and international regulation, this paper describes the need for revised bisphenol A risk assessments in Canada. Completed in 2008, the most recent bisphenol A risk assessment conducted by Health Canada does not include risks from alternative bisphenols or non-dietary exposure. It also does not account for the additive effects caused by simultaneous exposure to multiple endocrine-disrupting chemicals.
Analyses of Child and Youth Self-Poisoning Hospitalizations by Substance and Socioeconomic Status
Authors: Pawer Samantha , Rajabali Fahra , Zheng Alex , Smith Jennifer , Purssell Roy , Pike Ian
Published: June 2021

Child and youth self-poisoning is a growing public health issue in many regions of the world, including British Columbia (BC), Canada, where 15–19-year-olds have the highest rates of self-poisoning hospitalizations compared with those of all other ages. The purpose of this study was to identify what substances children and youth commonly used to poison themselves in BC and how socioeconomic status may impact self-poisoning risk. Self-poisoning hospitalization rates among 10–14 and 15–19-year-olds from 1 April 2012 to 31 March 2020 were calculated by substance using ICD-10-CA codes X60-X69 and T36-T65, as well as by socioeconomic status using the Institut National de Santé Publique du Québec’s Deprivation Index. Nonopioid analgesics, antipyretics, and antirheumatics were the most common substances involved, with rates of 27.6 and 74.3 per 100,000 population among 10–14 and 15–19-year-olds, respectively, followed by antiepileptic, sedative–hypnotic, antiparkinsonism, and psychotropic drugs, with rates of 20.2 and 68.1 per 100,000 population among 10–14 and 15–19-year-olds, respectively. In terms of socioeconomic status, rates were highest among 10–19-year-olds living in neighbourhoods with the fewest social connections (243.7 per 100,000 population). These findings can inform poisoning prevention strategies and relevant policies, thereby reducing the number of self-poisoning events among children and youth.
The Socioeconomic Characteristics of Childhood Injuries in Regional Victoria, Australia: What the Missing Data Tells Us
Authors: Peck Blake , Terry Daniel , Kloot Kate
Published: June 2021

Background: Injury is the leading cause of death among those between 1–16 years of age in Australia. Studies have found that injury rates increase with socioeconomic disadvantage. Rural Urgent Care Centres (UCC) represent a key point of entry into the Victorian healthcare system for people living in smaller rural communities, often categorised as lower socio-economic groups. Emergency presentation data from UCCs is not routinely collated in government datasets. This study seeks to compare socioeconomic characteristics of children aged 0–14 attending a UCC to those who attend a 24-h Emergency Departments with an injury-related emergency presentation. This will inform gaps in our current understanding of the links between socioeconomic status and childhood injury in regional Victoria. Methods: A network of rural hospitals in South West Victoria, Australia provide ongoing detailed de-identified emergency presentation data as part of the Rural Acute Hospital Data Register (RAHDaR). Data from nine of these facilities was extracted and analysed for children (aged 0–14 years) with any principal injury-related diagnosis presenting between 1 February 2017 and 31 January 2020. Results: There were 10,137 injury-related emergency presentations of children aged between 0–14 years to a participating hospital. The relationship between socioeconomic status and injury was confirmed, with overall higher rates of child injury presentations from those residing in areas of Disadvantage. A large proportion (74.3%) of the children attending rural UCCs were also Disadvantaged. Contrary to previous research, the rate of injury amongst children from urban areas was significantly higher than their more rural counterparts. Conclusions: Findings support the notion that injury in Victoria differs according to socioeconomic status and suggest that targeted interventions for the reduction of injury should consider socioeconomic as well as geographical differences in the design of their programs.
Association between GnRH Receptor Polymorphisms and Luteinizing Hormone Levels for Low Ovarian Reserve Infertile Women
Authors: Weng Shun-Long , Tzeng Shu-Ling , Lee Chun-I , Liu Chung-Hsien , Huang Chun-Chia , Yang Shun-Fa , Lee Maw-Sheng , Lee Tsung-Hsien
Published: June 2021

The choice of ovarian stimulation protocols in assisted reproduction technology (ART) cycles for low ovarian reserve patients is challenging. Our previous report indicated that the gonadotrophin-releasing (GnRH) agonist (GnRHa) protocol is better than the GnRH antagonist (GnRHant) protocol for young age poor responders. Here, we recruited 269 patients with anti-Müllerian hormone (AMH) < 1.2 ng/mL undergoing their first ART cycles for this nested case-control study. We investigated the genetic variants of the relevant genes, including follicular stimulating hormone receptor (FSHR; rs6166), AMH (rs10407022), GnRH (rs6185), and GnRH receptor (GnRHR; rs3756159) in patients <35 years (n = 86) and patients ≥35 years of age (n = 183). Only the genotype of GnRHR (rs3756159) is distributed differently in young (CC 39.5%, CT/TT 60.5%) versus advanced (CC 24.0%, CT/TT 76.0%) age groups (recessive model, p = 0.0091). Furthermore, the baseline luteinizing hormone (LH) levels (3.60 (2.45 to 5.40) vs. 4.40 (2.91 to 6.48)) are different between CC and CT/TT genotype of GnRHR (rs3756159). In conclusion, the genetic variants of GnRHR (rs3756159) could modulate the release of LH in the pituitary gland and might then affect the outcome of ovarian stimulation by GnRHant or GnRHa protocols for patients with low AMH levels.
Sustainability of Household Food Waste Reduction: A Fresh Insight on Youth’s Emotional and Cognitive Behaviors
Authors: Attiq Saman , Chau Ka Yin , Bashir Shahid , Habib Muhammad Danish , Azam Rauf I. , Wong Wing-Keung
Published: June 2021

The sustainability of food waste is one of the most important contemporary economic, social, and environmental issues that encompasses useful academic, practical, and policymaking implications. Under the domain of sustainability, food waste is a serious global challenge with a growing public, political, and corporate concern. Existing literature regarding the sensitization of consumers and the promotion of waste cautious behaviors still has much room for improvement in household waste. To bridge the gap in the literature, this study identifies and examines determinants of young consumers’ food waste reduction behavior in households. Using a sample size of 391 young consumers of household food products from Pakistan, a full-scaled administrative survey is conducted, and our hypotheses are empirically tested by using the PLS structural modeling equation. Our findings reveal significant impacts from both cognitive and emotional aspects on sustainable food waste reduction behavior. Our results have several important implications for policymakers and all the stakeholders, especially for marketers, including advertising strategies, policies to mitigate the impact of food waste, and the development of educational programs related to food waste.
Predictors of Depression and Anxiety Symptoms in Brazil during COVID-19
Authors: Zhang Stephen X. , Huang Hao , Li Jizhen , Antonelli-Ponti Mayra , Paiva Scheila Farias de , da Silva José Aparecido
Published: June 2021

The COVID-19 pandemic in Brazil is extremely severe, and Brazil has the third-highest number of cases in the world. The goal of the study is to identify the prevalence rates and several predictors of depression and anxiety in Brazil during the initial outbreak of COVID-19. We surveyed 482 adults in 23 Brazilian states online on 9–22 May 2020, and found that 70.3% of the adults (n = 339) had depressive symptoms and 67.2% (n = 320) had anxiety symptoms. The results of multi-class logistic regression models revealed that females, younger adults, and those with fewer children had a higher likelihood of depression and anxiety symptoms; adults who worked as employees were more likely to have anxiety symptoms than those who were self-employed or unemployed; adults who spent more time browsing COVID-19 information online were more likely to have depression and anxiety symptoms. Our results provide preliminary evidence and early warning for psychiatrists and healthcare organizations to better identify and focus on the more vulnerable sub-populations in Brazil during the ongoing COVID-19 pandemic.
Using Geographically Weighted Regression to Study the Seasonal Influence of Potential Risk Factors on the Incidence of HFMD on the Chinese Mainland
Authors: Sun Jingtao , Wu Sensen , Yan Zhen , Li Yadong , Yan Cheng , Zhang Feng , Liu Renyi , Du Zhenhong
Published: June 2021

Hand, foot, and mouth disease (HFMD) is an epidemic infectious disease in China. Its incidence is affected by a variety of natural environmental and socioeconomic factors, and its transmission has strong seasonal and spatial heterogeneity. To quantify the spatial relationship between the incidence of HFMD (I-HFMD) and eight potential risk factors (temperature, humidity, precipitation, wind speed, air pressure, altitude, child population density, and per capita GDP) on the Chinese mainland, we established a geographically weighted regression (GWR) model to analyze their impacts in different seasons and provinces. The GWR model successfully describes the spatial changes of the influence of potential risks, and shows greatly improved estimation performance compared with the ordinary linear regression (OLR) method. Our findings help to understand the seasonally and spatially relevant effects of natural environmental and socioeconomic factors on the I-HFMD, and can provide information to be used to develop effective prevention strategies against HFMD at different locations and in different seasons.
Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice
Authors: Negron Marcus , Kristensen Jeffrey , Nguyen Van Thuan , Gansereit Lauren E. , Raucci Frank J. , Chariker Julia L. , Heck Aaron , Brula Imamulhaq , Kitchen Gabrielle , Awgulewitsch Cassandra P. , Zhong Lin , Rouchka Eric C. , Banga Simran , Galindo Cristi L.
Published: June 2021

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.
The Glucosylceramide Synthase Inhibitor PDMP Causes Lysosomal Lipid Accumulation and mTOR Inactivation
Authors: Hartwig Pia , Höglinger Doris
Published: June 2021

For many years, the biology of glycosphingolipids was elucidated with the help of glucosylceramide synthase (GCS) inhibitors such as 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Additionally, PDMP gained interest because of its chemosensitizing effects. Several studies have successfully combined PDMP and anti-cancer drugs in the context of cancer therapy. However, the mechanism of action of PDMP is not fully understood and seems to go beyond glycolipid inhibition. Here, we used a functionalized sphingosine analogue (pacSph) to investigate the acute effects of PDMP on cellular sphingolipid distribution and found that PDMP, but not other GCS inhibitors, such as ND-DNJ (also called Miglustat), induced sphingolipid accumulation in lysosomes. This effect could be connected to defective export from lysosome, as monitored by the prolonged lysosomal staining of sphingolipids as well as by a delay in the metabolic conversion of the pacSph precursor. Additionally, other lipids such as lysobisphosphatidic acid (LBPA) and cholesterol were enriched in lysosomes upon PDMP treatment in a time-dependent manner. We could further correlate early LBPA enrichment with dissociation of the mechanistic target of rapamycin (mTOR) from lysosomes followed by nuclear translocation of its downtream target, transcription factor EB (TFEB). Altogether, we report here a timeline of lysosomal lipid accumulation events and mTOR inactivation arising from PDMP treatment.
Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1G93A Transgenic Mice
Authors: Post Julia , Schaffrath Anja , Gering Ian , Hartwig Sonja , Lehr Stefan , Shah N. Jon , Langen Karl-Josef , Willbold Dieter , Kutzsche Janine , Willuweit Antje
Published: June 2021

Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1G93A mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1G93A mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1G93A mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1G93A mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1G93A mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.
The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology
Authors: Hudák Anett , Jósvay Katalin , Domonkos Ildikó , Letoha Annamária , Szilák László , Letoha Tamás
Published: June 2021

Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aβ pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE–heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aβ uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aβ, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aβ aggregated: while ApoE2 reduced the uptake of Aβ aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4′s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aβ pathology.
Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19
Authors: Kaliamurthi Satyavani , Selvaraj Gurudeeban , Selvaraj Chandrabose , Singh Sanjeev Kumar , Wei Dong-Qing , Peslherbe Gilles H.
Published: June 2021

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton’s tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.
The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development
Authors: Wagstaff Ellie , Heredero Berzal Andrea , Boon Camiel , Quinn Peter , ten Asbroek Anneloor , Bergen Arthur
Published: June 2021

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.
Thirty-Year Lessons from the Newborn Screening for Congenital Adrenal Hyperplasia (CAH) in Japan
Authors: Tsuji-Hosokawa Atsumi , Kashimada Kenichi
Published: June 2021

Congenital adrenal hyperplasia (CAH) is an inherited disorder caused by the absence or severely impaired activity of steroidogenic enzymes involved in cortisol biosynthesis. More than 90% of cases result from 21-hydroxylase deficiency (21OHD). To prevent life-threatening adrenal crisis and to help perform appropriate sex assignments for affected female patients, newborn screening (NBS) programs for the classical form of CAH have been introduced in numerous countries. In Japan, the NBS for CAH was introduced in 1989, following the screenings for phenylketonuria and congenital hypothyroidism. In this review, we aim to summarize the experience of the past 30 years of the NBS for CAH in Japan, composed of four parts, 1: screening system in Japan, 2: the clinical outcomes for the patients with CAH, 3: various factors that would impact the NBS system, including timeline, false positive, and LC-MS/MS, 4: Database composition and improvement of the screening program.
A Pilot Feasibility Randomized Controlled Trial on the Ontario Brain Injury Association Peer Support Program
Authors: Levy Ben B. , Luong Dorothy , Bayley Mark T. , Sweet Shane N. , Voth Jennifer , Kastner Monika , Nelson Michelle L. A. , Jaglal Susan B. , Salbach Nancy M. , Wilcock Ruth , Thoms Carla , Shepherd John , Munce Sarah E. P.
Published: June 2021

Background: The long-term consequences of traumatic brain injury can create major barriers to community integration. Peer support represents a sustainable model of support across this transition. The objective of the current study was to determine the feasibility of conducting a randomized controlled trial on the Ontario Brain Injury Association Peer Support Program and the preliminary effectiveness of the program on community integration, mood, health-related quality of life, and self-efficacy; Methods: A pilot feasibility randomized controlled trial with an embedded qualitative component was conducted. Mentees with moderate-to-severe traumatic brain injury (n = 13) were randomized to a weekly intervention or waitlist control group. Interviews were conducted with a subset of mentees and peer mentors (n = 10). Integration of the quantitative and qualitative data was completed using a joint display approach; Results: No statistically significant results were found for community integration, mood, or self-efficacy; however, changes in these outcomes were accompanied by moderate-to-large effect sizes. Within health-related quality of life, the mean pain score of the intervention group was significantly lower than that of the control group at the two-month timepoint but not at completion. Interviews revealed proximal improvements in knowledge, skills, and goals, and identified two domains related to trial acceptability: (1) environmental context and resources, and (2) reinforcement; Conclusions: Given the conceivable importance of proximal improvements in domains such as knowledge, skills, and/or goals for the attainment of more distal outcomes, modifications to the existing Peer Support Program may be warranted. The introduction of program recommendations which promote discussion around particular domains may help facilitate long-term improvements in health outcomes.
Symptoms and Quality of Life Changes after Hysteroscopic Treatment in Patients with Symptomatic Isthmocele—Preliminary Results
Authors: Szafarowska Monika , Biela Magdalena , Wichowska Joanna , Sobociński Kamil , Segiet-Święcicka Agnieszka , Doniec Jacek , Kamiński Paweł
Published: June 2021

Due to an increasing number of cesarean section deliveries, the common consequences of that surgery are observed more often in the population. One of them is the uterine cesarean scar defect known as niche or isthmocele. Most patients with that aliment are asymptomatic, but some of them can report abnormal uterine bleeding, pelvic pain, subfertility which can be the reason for reduced quality of life (QoL) of the patients. In our study, we analyzed the subjective feelings of changes in the severity of symptoms and quality of life of women with niche after diagnostic and operative hysteroscopy. The patients n = 85 included in the study group completed a follow up questionnaire six months after the procedure. Patients after operative hysteroscopy in comparison to patients after diagnostic procedure reported statistically significant reduction in post-menstruation bleeding/spotting and improvement in the quality of sexual activity. We have also noticed a higher pregnancy rate in the operative group, however, the difference was not statistically significant. According to our study, most women reported a positive effect of hysteroscopy on their QoL in social, psychological, environmental, and health domains.
Anti-Inflammatory Effects of Low-Dose Glucocorticoids Compensate for Their Detrimental Effects on Bone Mineral Density in Patients with Rheumatoid Arthritis
Authors: Kim Ji-Won , Jung Ju-Yang , Kim Hyoun-Ah , Suh Chang-Hee
Published: June 2021

Objectives: This study aimed to provide reliable information on the impact of low-dose glucocorticoids (GCs) on the bone mineral density (BMD) of patients with rheumatoid arthritis (RA). Methods: This retrospective study enrolled 933 patients with RA who continued the consumption of GCs (GC group) and 100 patients who had discontinued consumption for >1 year (no-GC group). The BMD values were measured at baseline and follow-up, and the annual rate of change in BMD between the groups was compared using dual-energy X-ray absorptiometry. We used multiple linear regression analysis to identify the factors associated with changes in BMD. Results: The demographic characteristics and use of medical treatments affecting bone metabolism were similar between the two groups. Furthermore, there were no significant differences in the annual rate of changes in BMD and incidence of newly developed osteoporosis and incidental fractures between the two groups. Multiple linear regression analysis revealed that the disease activity score for 28 joints with erythrocyte sedimentation rate was the only factor affecting the annual rate of changes in BMD, and it was inversely proportional to changes in BMD. Conclusion: The benefits of GC therapy in attenuating inflammation compensate for the risk of osteoporosis if adequate measures to prevent bone loss are implemented in patients with RA.
Psychopharmacological Treatment, Intraocular Pressure and the Risk of Glaucoma: A Review of Literature
Authors: Ciobanu Adela Magdalena , Dionisie Vlad , Neagu Cristina , Bolog Otilia Maria , Riga Sorin , Popa-Velea Ovidiu
Published: June 2021

Through the years, the available psychopharmacological treatments have expanded with numerous new drugs. Besides weight gain, gastro-intestinal problems or Parkinson-like symptoms, ocular adverse effects of psychiatric drugs have been reported. These adverse effects are not common, but can be dangerous for the patient. This review summarises the current knowledge on the risk of raised intraocular pressure and glaucoma entailed by psychopharmacological treatment. Also, it provides updated data for clinicians involved in the treatment of patients with glaucoma or glaucoma risk factors. For this purpose, we performed an extensive literature search in the PubMed database using specific terms. Selective serotonin and noradrenaline reuptake inhibitors are the best evidenced as having no association with glaucoma. Antipsychotics, and especially first generation, seem to have no correlation with an increased intraocular pressure and therefore possibly with a risk of glaucoma, although a special attention should be paid when using ziprasidone. Tricyclic antidepressants, benzodiazepines and topiramate should be avoided in patients diagnosed with glaucoma or at risk. Clinicians should be aware of the possible psychotropic drug induced glaucoma and monitor at risk patients closely in order to prevent this condition. Irrespective of the psychopharmacological regimen taken into consideration, the glaucoma patient should be under the strict supervision of the ophthalmologist.
Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial
Authors: Tong Hoi , Borobia Alberto , Quintana-Díaz Manuel , Fabra Sara , González-Viñolis Manuel , Fernández-Capitán Carmen , Rodriguez-Dávila María , Lorenzo Alicia , López-Parra Ana , Ruiz-Giménez Nuria , Abad-Santos Francisco , Suarez Carmen , Madridano Olga , Gómez-Cerezo Jorge , Llamas Pilar , Baeza-Richer Carlos , Arroyo-Pardo Eduardo , Carcas Antonio ,   The PGX-ACE Spanish Investigators Group
Published: June 2021

Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.
In-Situ Seawater Gamma Spectrometry with LaBr3 Detector at a Nuclear Power Plant Outlet
Authors: Dou Daowei , Zeng Zhi , Yu Wen , Zeng Ming , Men Wu , Lin Feng , Ma Hao , Cheng Jianping , Li Junli
Published: June 2021

In a nuclear emergency, the application of in situ spectrometers for monitoring environmental radioactivity is significantly important, as information on the type and activity of radionuclides released from the accident can be obtained quickly. However, in emergency environmental radiological monitoring, a balance between energy resolution and detecting efficiency must be considered in selecting an appropriate detector. In this study, in situ gamma spectrometry was conducted with the LaBr3 detector to determine the radioactivity of seawater at the discharging outlet of a coastal nuclear power plant in southeast China. The results show that the LaBr3 scintillator has excellent energy resolution and detection efficiency, making it a promising detector for emergency monitoring.
Oxidative Stress Causes Vacuolar Fragmentation in the Human Fungal Pathogen Cryptococcus neoformans
Authors: Kim Donghyeun , Song Moonyong , Do Eunsoo , Choi Yoojeong , Kronstad James W. , Jung Won Hee
Published: June 2021

Vacuoles are dynamic cellular organelles, and their morphology is altered by various stimuli or stresses. Vacuoles play an important role in the physiology and virulence of many fungal pathogens. For example, a Cryptococcus neoformans mutant deficient in vacuolar functions showed significantly reduced expression of virulence factors such as capsule and melanin synthesis and was avirulent in a mouse model of cryptococcosis. In the current study, we found significantly increased vacuolar fragmentation in the C. neoformans mutants lacking SOD1 or SOD2, which respectively encode Zn, Cu-superoxide dismutase and Mn-superoxide dismutase. The sod2 mutant showed a greater level of vacuole fragmentation than the sod1 mutant. We also observed that the vacuoles were highly fragmented when wild-type cells were grown in a medium containing high concentrations of iron, copper, or zinc. Moreover, elevated temperature and treatment with the antifungal drug fluconazole caused increased vacuolar fragmentation. These conditions also commonly cause an increase in the levels of intracellular reactive oxygen species in the fungus, suggesting that vacuoles are fragmented in response to oxidative stress. Furthermore, we observed that Sod2 is not only localized in mitochondria but also in the cytoplasm within phagocytosed C. neoformans cells, possibly due to copper or iron limitation.
Fungal Infections in Liver Transplant Recipients
Authors: Scolarici Michael , Jorgenson Margaret , Saddler Christopher , Smith Jeannina
Published: June 2021

Invasive fungal infections (IFIs) are one of the most feared complications associated with liver transplantation, with high rates of morbidity and mortality. We discuss the most common invasive fungal infections in the setting of liver transplant, including Candida, Aspergillus, and Cryptococcal infections, and some less frequent but devastating mold infections. Further, we evaluate the use of prophylaxis to prevent invasive fungal infection in this population as a promising mechanism to reduce risks to patients after liver transplant.
Arbuscular Mycorrhizae Mitigate Aluminum Toxicity and Regulate Proline Metabolism in Plants Grown in Acidic Soil
Authors: Alotaibi Modhi O. , Saleh Ahmed M. , Sobrinho Renato L. , Sheteiwy Mohamed S. , El-Sawah Ahmed M. , Mohammed Afrah E. , Elgawad Hamada Abd
Published: June 2021

Arbuscular mycorrhizal fungi (AMF) can promote plant growth and induce stress tolerance. Proline is reported to accumulate in mycorrhizal plants under stressful conditions, such as aluminum (Al) stress. However, the detailed changes induced in proline metabolism under AMF–plant symbiosis has not been studied. Accordingly, this work aimed to study how Al-stressed grass (barley) and legume (lotus) species respond to AMF inoculation at growth and biochemical levels. The associated changes in Al uptake and accumulation, the rate of photosynthesis, and the key enzymes and metabolites involved in proline biosynthesis and degradation pathways were studied. Soil contamination with Al induced Al accumulation in tissues of both species and, consequently, reduced plant growth and the rate of photosynthesis, while more tolerance was noticed in lotus. Inoculation with AMF significantly reduced Al accumulation and mitigated the negative impacts of Al on growth and photosynthesis in both species; however, these positive effects were more pronounced in barley plants. The mitigating action of AMF was associated with upregulation of proline biosynthesis through glutamate and ornithine pathways, more in lotus than in barley, and repression of its catabolism. The increased proline level in lotus was consistent with improved N metabolism (N level and nitrate reductase). Overall, this study suggests the role of AMF in mitigating Al stress, where regulation of proline metabolism is a worthy mechanism underlying this mitigating action.
Robotic Colorectal Cancer Surgery. How to Reach Expertise? A Single Surgeon-Experience
Authors: Manigrasso Michele , Vertaldi Sara , Anoldo Pietro , D’Amore Anna , Marello Alessandra , Sorrentino Carmen , Chini Alessia , Aprea Salvatore , D’Angelo Salvatore , D’Alesio Nicola , Musella Mario , Vitiello Antonio , De Palma Giovanni Domenico , Milone Marco
Published: June 2021

The complexity associated with laparoscopic colorectal surgery requires several skills to overcome the technical difficulties related to this procedure. To overcome the technical challenges of laparoscopic surgery, a robotic approach has been introduced. Our study reports the surgical outcomes obtained by the transition from laparoscopic to robotic approach in colorectal cancer surgery to establish in which type of approach the proficiency is easier to reach. Data about the first consecutive 15 laparoscopic and the first 15 consecutive robotic cases are extracted, adopting as a comparator of proficiency the last 15 laparoscopic colorectal resections for cancer. The variables studied are operative time, number of harvested nodes, conversion rate, postoperative complications, recovery outcomes. Our analysis includes 15 patients per group. Our results show that operative time is significantly longer in the first 15 laparoscopic cases (p = 0.001). A significantly lower number of harvested nodes was retrieved in the first 15 laparoscopic cases (p = 0.003). Clavien Dindo I complication rate was higher in the first laparoscopic group, but without a significant difference among the three groups (p = 0.09). Our results show that the surgeon needed no apparent learning curve to reach their laparoscopic standards. However, further multicentric prospective studies are needed to confirm this conclusion.