bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking
Authors: Andersson Linda , Cinato Mathieu , Mardani Ismena , Miljanovic Azra , Arif Muhammad , Koh Ara , Lindbom Malin , Laudette Marion , Bollano Entela , Omerovic Elmir , Klevstig Martina , Henricsson Marcus , Fogelstrand Per , Swärd Karl , Ekstrand Matias , Levin Max , Wikström Johannes , Doran Stephen , Hyötyläinen Tuulia , Sinisalu Lisanna , Orešič Matej , Tivesten Åsa , Adiels Martin , Bergo Martin O , Proia Richard , Mardinoglu Adil , Jeppsson Anders , Borén Jan , Levin Malin C
Published: June 2021

Aims 

Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.

Methods and results 

Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg  –/– mice). In 9- to 10-week-old hUgcg  –/– mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg  –/– mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg  –/– mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.

Conclusions 

Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.
Effects of canagliflozin on human myocardial redox signalling: clinical implications
Authors: Kondo Hidekazu , Akoumianakis Ioannis , Badi Ileana , Akawi Nadia , Kotanidis Christos P , Polkinghorne Murray , Stadiotti Ilaria , Sommariva Elena , Antonopoulos Alexios S , Carena Maria C , Oikonomou Evangelos K , Reus Elsa Mauricio , Sayeed Rana , Krasopoulos George , Srivastava Vivek , Farid Shakil , Chuaiphichai Surawee , Shirodaria Cheerag , Channon Keith M , Casadei Barbara , Antoniades Charalambos
Published: June 2021

Aims

Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans.

Methods and results

Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.− production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM.

Conclusions

We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy
Authors: Lopes Luis R , Garcia-Hernández Soledad , Lorenzini Massimiliano , Futema Marta , Chumakova Olga , Zateyshchikov Dmitry , Isidoro-Garcia Maria , Villacorta Eduardo , Escobar-Lopez Luis , Garcia-Pavia Pablo , Bilbao Raquel , Dobarro David , Sandin-Fuentes Maria , Catalli Claudio , Gener Querol Blanca , Mezcua Ainhoa , Garcia Pinilla Jose , Bloch Rasmussen Torsten , Ferreira-Aguar Ana , Revilla-Martí Pablo , Basurte Elorz Maria Teresa , Bautista Paves Alicia , Ramon Gimeno Juan , Figueroa Ana Virginia , Franco-Gutierrez Raul , Fuentes-Cañamero Maria Eugenia , Martinez Moreno Marina , Ortiz-Genga Martin , Piqueras-Flores Jesus , Analia Ramos Karina , Rudzitis Ainars , Ruiz-Guerrero Luis , Stein Ricardo , Triguero-Bocharán Mayte , de la Higuera Luis , Ochoa Juan Pablo , Abu-Bonsrah Dad , Kwok Cecilia Y T , Smith Jacob B , Porrello Enzo R , Akhtar Mohammed M , Jager Joanna , Ashworth Michael , Syrris Petros , Elliott David A , Monserrat Lorenzo , Elliott Perry M
Published: June 2021

Aims

The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.

Methods and results 

In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.

Conclusions 

Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Evaluating the genetic basiss of anti-cancer property of Taxol in Saccharomyces cerevisiae model
Authors: Veerabhadrappa Bhavana , Subramanian Subasri , S. J. Sudharshan , Dyavaiah Madhu
Published: June 2021

Taxol has been regarded as one of the most successful anti-cancer drugs identified from natural sources to date. Although Taxol is known to sensitize cells by stabilizing microtubules, its ability to cause DNA damage in peripheral blood lymphocytes and to induce oxidative stress and apoptosis indicates that Taxol may have other modes of cytotoxic action. This study focuses on identifying the additional targets of Taxol that may contribute to its multifaceted cell killing property, using Saccharomyces cerevisiae. We show that yeast oxidative stress response mutants (sod1Δ, tsa1Δ and cta1Δ) and DNA damage response mutants (mre11∆, sgs1∆ and sub1∆) are highly sensitive to Taxol. Our results also show that Taxol increases the level of reactive oxygen species (ROS) in yeast oxidative stress response mutant strains. Further, 4ʹ,6-Diamidino-2ʹ-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) staining show that Taxol induces apoptotic features such as nuclear fragmentation and chromatin condensation in DNA repair mutants. On the whole, our results suggest that Taxol's cytotoxic property is attributed to its multifaceted mechanism of action. Yeast S. cerevisiae anti-oxidant and DNA repair gene mutants are sensitive to Taxol compared to wild-type, suggesting yeast model can be used to identify the genetic targets of anti-cancer drugs.
Maternal Piwi regulates primordial germ cell development to ensure the fertility of female progeny in Drosophila
Authors: Gonzalez Lauren E , Tang Xiongzhuo , Lin Haifan
Published: June 2021

In many animals, germline development is initiated by proteins and RNAs that are expressed maternally. PIWI proteins and their associated small noncoding PIWI-interacting RNAs (piRNAs), which guide PIWI to target RNAs by base-pairing, are among the maternal components deposited into the germline of the Drosophila early embryo. Piwi has been extensively studied in the adult ovary and testis, where it is required for transposon suppression, germline stem cell self-renewal, and fertility. Consequently, loss of Piwi in the adult ovary using piwi-null alleles or knockdown from early oogenesis results in complete sterility, limiting investigation into possible embryonic functions of maternal Piwi. In this study, we show that the maternal Piwi protein persists in the embryonic germline through gonad coalescence, suggesting that maternal Piwi can regulate germline development beyond early embryogenesis. Using a maternal knockdown strategy, we find that maternal Piwi is required for the fertility and normal gonad morphology of female, but not male, progeny. Following maternal piwi knockdown, transposons were mildly derepressed in the early embryo but were fully repressed in the ovaries of adult progeny. Furthermore, the maternal piRNA pool was diminished, reducing the capacity of the PIWI/piRNA complex to target zygotic genes during embryogenesis. Examination of embryonic germ cell proliferation and ovarian gene expression showed that the germline of female progeny was partially masculinized by maternal piwi knockdown. Our study reveals a novel role for maternal Piwi in the germline development of female progeny and suggests that the PIWI/piRNA pathway is involved in germline sex determination in Drosophila.
Sex differences in outcomes following coronary artery bypass grafting: a meta-analysis
Authors: Bryce Robinson N , Naik Ajita , Rahouma Mohamed , Morsi Mahmoud , Wright Drew , Hameed Irbaz , Di Franco Antonino , Girardi Leonard N , Gaudino Mario
Published: June 2021

OBJECTIVES

Previous reports have found females are a higher risk of morbidity and mortality following isolated coronary artery bypass grafting (CABG). Here, we describe the differences in outcomes following isolated CABG between males and females.

METHODS

Following a systematic literature search, studies reporting sex-related outcomes following isolated CABG were pooled in a meta-analysis performed using the generic inverse variance method. The primary outcome was operative mortality. Secondary outcomes included rates of stroke, repeat revascularization, myocardial infarction, major adverse cardiac events, and late mortality. Subgroup analyses were performed for studies published before and after the year 2000 and for the type of risk adjustment.

RESULTS

Eighty-four studies were included with a total of 903 346 patients. Females were at higher risk for operative mortality (odds ratio: 1.77, 95% confidence interval [CI]: 1.64–1.92, P < 0.001). At subgroup analysis, there was no difference in operative or late mortality between studies published prior and after 2000 or between studies using risk adjustment. Females were at a higher risk of late mortality (incidence rate ratio [IRR]: 1.16, 95% CI: 1.06–1.26, P < 0.001), major adverse cardiac events (IRR: 1.40, 95% CI: 1.19–1.66, P < 0.001), myocardial infarction (IRR: 1.28, 95% CI: 1.13–1.45, P < 0.001) and stroke (IRR: 1.31, 95% CI: 1.15–1.51, P > 0.001) but not repeat revascularization (IRR: 0.99, 95% CI: 0.76–1.29, P = 0.95). The use of the off-pump technique or multiple arterial grafts was not associated with the primary outcome.

CONCLUSIONS

Females undergoing CABG are at higher risk for operative and late mortality as well as postoperative events including major adverse cardiac events, myocardial infarction and stroke.

PROSPERO registration

CRD42020187556
A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders
Authors: Romero-Miguel Diego , Casquero-Veiga Marta , MacDowell Karina S , Torres-Sanchez Sonia , Garcia-Partida José Antonio , Lamanna-Rama Nicolás , Romero-Miranda Ana , Berrocoso Esther , Leza Juan C , Desco Manuel , Soto-Montenegro María Luisa
Published: June 2021

Background

Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.

Methods

On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35–49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.

Results

MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).

Conclusions

MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2–ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
Smoking Affects the Patterns of Metabolic Disorders and Metabolic Syndrome in Patients With First-Episode Drug-Naive Schizophrenia: A Large Sample Study Based on the Chinese Han Population
Authors: Li Zezhi , Wang Shuning , Chen Yuping , Wu Xi , Gu Yinjun , Lang Xiaoe , Wu Fengchun , Zhang Xiang Yang
Published: June 2021

Objective

Although metabolic disorders and smoking are common in schizophrenia, few studies have investigated the effects of smoking on metabolic disorders or metabolic syndrome (MetS) in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. We sought to investigate the differences in metabolic disorders and MetS between smoking and nonsmoking FEDN schizophrenia patients.

Methods

A total of 428 FEDN schizophrenia patients and 435 controls were recruited. Blood pressure, waist circumference, body mass index (BMI), lipid profiles, and glucose metabolism were measured. The psychopathology was evaluated by Positive and Negative Syndrome Scale.

Results

FEDN schizophrenia patients had a higher smoking rate than controls (23.8% vs 14.0%, P < .001). After adjusting for confounding variables, the prevalence of MetS, overweight, hypertension, hypertriglyceridemia, elevated insulin, and insulin resistance in smoking patients was higher than those in nonsmoking patients, while overweight and hypertension were higher in the smoking controls than in nonsmoking controls (all P < .05). In smoking patients, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS, while in nonsmoking patients, waist circumference, systolic blood pressure, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS. In smoking patients, BMI and homeostatic model assessment for insulin resistance were associated factors of MetS (both P < .05). In nonsmoking patients, sex, BMI, insulin, and homeostatic model assessment for insulin resistance were associated factors of MetS (all P < .05).

Conclusions

Our study indicates that smoking schizophrenia patients have a higher prevalence of MetS and metabolic disorders than nonsmoking patients. Moreover, smoking and nonsmoking patients have different contributing components and associated factors for MetS.
The Limits of Static Interests: Appreciating Asylum Seekers’ Contributions to a Country’s Economy in Article 8 ECHR Adjudication on Expulsion
Authors: Reyhani Adel-Naim , Golmohammadi Gloria
Published: June 2021

This article critiques the European Court of Human Rights’ approach towards assessing asylum seekers’ right to respect for private and family life under article 8 of the European Convention on Human Rights in the context of their expulsion. In balancing the right of the individual against the public interest, it is argued that the court’s case law follows a static perspective. The rigidly defined assumption that the public interest lies in enforcing migration control and that the societal contributions of asylum seekers cannot influence the strength of the public interest is prevalent in jurisprudence yet underexplored in scholarship. The article uses the case of asylum seekers who contribute to a country’s economy to demonstrate that the court currently fails to appreciate the interdependence between these interests. It then suggests a path by which the court’s approach might be adjusted towards more nuance, ultimately allowing the contributions of asylum seekers to European communities to be appropriately reflected in legal determinations.
Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages
Authors: Liu Kaiwen , Sato Ryota , Shibata Takuma , Hiranuma Ryosuke , Reuter Tatjana , Fukui Ryutaro , Zhang Yun , Ichinohe Takeshi , Ozawa Manabu , Yoshida Nobuaki , Latz Eicke , Miyake Kensuke
Published: June 2021

RNase T2, a ubiquitously expressed RNase, degrades RNAs in the endosomal compartments. RNA sensors, double-stranded RNA (dsRNA)-sensing Toll-like receptor 3 (TLR3) and single-stranded RNA (ssRNA)-sensing TLR7, are localized in the endosomal compartment in mouse macrophages. We here studied the role of RNase T2 in TLR3 and TLR7 responses in macrophages. Macrophages expressed RNase T2 and a member of the RNase A family RNase 4. RNase T2 was also expressed in plasmacytoid and conventional dendritic cells. Treatment with dsRNAs or type I interferon (IFN) up-regulated expression of RNase T2 but not RNase 4. RNase T2-deficiency in macrophages up-regulated TLR3 responses but impaired TLR7 responses. Mechanistically, RNase T2 degraded both dsRNAs and ssRNAs in vitro, and its mutants showed a positive correlation between RNA degradation and the rescue of altered TLR3 and TLR7 responses. H122A and C188R RNase T2 mutations, not H69A and E118V mutations, impaired both RNA degradation and the rescue of altered TLR3 and TLR7 responses. RNase T2 in bone marrow-derived macrophages was broadly distributed from early endosomes to lysosomes, and colocalized with the internalized TLR3 ligand poly(I:C). These results suggest that RNase T2-dependent RNA degradation in endosomes/lysosomes negatively and positively regulates TLR3 and TLR7 responses, respectively, in macrophages.
Description of the Etiologies, Clinical Characteristics, and Outcomes in Patients with Hyperferritinemia in a Colombian Tertiary Hospital
Authors: Ruiz-Ordoñez Ingrid , Puerta-Sarmiento Germán , Muñoz-Patiño Valentina , Giraldo-Fernández Valentina , Nieto-Aristizábal Ivana , Vivas Álvaro J , Tobón Gabriel J
Published: June 2021

Background

This study analyzes the clinical characteristics, outcomes, and conditions associated with hyperferritinemia (≥5000 ng/mL) in a high-complexity center in Colombia.

Methods

This retrospective and descriptive study was performed between 2011 and 2020, at the Fundación Valle del Lili, Cali, Colombia, by reviewing medical charts from patients who had serum ferritin measurements equal to or greater than 5000 ng/mL.

Results

We found 350 reports of ferritin values ≥5000 ng/mL, corresponding to 317 patients, with a median ferritin value of 8789 (6001–15 373)  ng/mL. The most frequent etiologies were infection (n = 198, 56.57%), hematologic disorders (n = 104, 29.71%), and blood transfusion (n = 98, 28.00%). These last 2 etiologies cooccurred in 37 (10.57%) cases. The main clinical signs accompanying hyperferritinemia were fever in 199 (56.86%) cases, multiorgan involvement in 125 (35.71%), and hepatomegaly in 95 (27.14%) cases. Ninety-four (29.65%) patients died in the hospital, and 11 (3.47%) died within 30 days after medical discharge, mainly due to infection (n = 51, 48.57%). Intrahospital mortality was associated with significantly higher ferritin levels (10 846, IQR: 6425–23 459) than survival (8452, IQR: 5980–13 932) (P = 0.018).

Conclusions

Hyperferritinemia is related to many underlying causes, with infection being the principal cause in our cohort, followed by hematologic disorders. Additionally, in-hospital mortality was related to higher ferritin levels.
Smart about medications (SAM): a digital solution to enhance medication management following hospital discharge
Authors: Márquez Fosser Santiago , Mahmoud Nadar , Habib Bettina , Weir Daniala L , Chan Fiona , El Halabieh Rola , Vachon Jeanne , Thakur Manish , Tran Thai , Bustillo Melissa , Beauchamp Caroline , Bonnici André , Buckeridge David L , Tamblyn Robyn
Published: June 2021

Objective

To outline the development of a software solution to improve medication management after hospital discharge, including its design, data sources, intrinsic features, and to evaluate the usability and the perception of use by end-users.

Materials and Methods

Patients were directly involved in the development using a User Center Design (UCD) approach. We conducted usability interviews prior to hospital discharge, before a user started using the application. A technology acceptance questionnaire was administered to evaluate user self-perception after 2 weeks of use.

Results

The following features were developed; pill identification, patient-friendly drug information leaflet, side effect checker, and interaction checker, adherence monitoring and alerts, weekly medication schedule, daily pill reminders, messaging service, and patient medication reviews. The usability interviews show a 98.3% total success rate for all features, severity (on a scale of 1–4) 1.4 (SD 0.79). Regarding the self-perception of use (1–7 agreement scale) the 3 highest-rated domains were: (1) perceived ease of use 5.65 (SD 2.02), (2) output quality 5.44 (SD 1.65), and (3) perceived usefulness 5.29 (SD 2.11).

Discussion

Many medication management apps solutions have been created and most of them have not been properly evaluated. SAM (Smart About Medications) includes the user perspective, integration between a province drug database and the pharmacist workflow in real time. Its features are not limited to maintaining a medication list through manual entry.

Conclusion

We can conclude after evaluation that the application is usable and has been self-perceived as easy to use by end-users. Future studies are required to assess the health benefits associated with its use.
Buprenorphine-Related Deaths in North Carolina from 2010 to 2018
Authors: Bishop-Freeman Sandra C , Friederich Laura W , Feaster Marc S , Hudson Jason S
Published: June 2021

Buprenorphine (BUP) is a commonly prescribed medication for the treatment of opioid use disorder (OUD). As prescriptions increase in North Carolina, BUP is more frequently encountered statewide in routine postmortem casework. Between 2010 and 2018, there were 131 select cases investigated by the Office of the Chief Medical Examiner where BUP was detected in peripheral blood and considered a primary cause of death (COD), with no other opioids present and no other non-opioid substances found in the lethal range. The decedents ranged in age from 14 to 64 years, with 67% male. The mean/median peripheral blood concentrations were 4.1/2.1 ng/mL for BUP and 7.8/3.4 ng/mL for its metabolite, norbuprenorphine. These postmortem blood concentrations overlap antemortem therapeutic concentrations in plasma reported in the literature for opioid-dependent subjects receiving sublingual maintenance therapy. The pathologist considered scene findings, prescription history, autopsy findings, toxicological analysis and decedent behavior prior to death to conclude a drug-related COD. Many of the deaths were complicated by the presence of other central nervous system depressants along with contributory underlying cardiovascular and respiratory disease. The three most prevalent additive substances were alprazolam, ethanol and gabapentin, found in 67, 36 and 32 cases out of 131, respectively. Interpreting BUP involvement in a death is complex, and instances may be underestimated in epidemiological data because of the lack of a defined toxic or lethal range in postmortem blood along with its good safety profile. As expansion of access to OUD treatment becomes a priority, awareness of the challenges of postmortem interpretation is needed as increased use and diversion of BUP are inevitable.
Spectral relaxation computation of electroconductive nanofluid convection flow from a moving surface with radiative flux and magnetic induction
Authors: Akter Shahina , Ferdows M , Bég Tasveer A , Bég O Anwar , Kadir A , Sun Shuyu
Published: June 2021

A theoretical model is developed for steady magnetohydrodynamic viscous flow resulting from a moving semi-infinite flat plate in an electrically conducting nanofluid. Thermal radiation and magnetic induction effects are included in addition to thermal convective boundary conditions. Buongiorno’s two-component nanoscale model is deployed, which features Brownian motion and thermophoresis effects. The governing nonlinear boundary layer equations are converted to nonlinear ordinary differential equations by using suitable similarity transformations. The transformed system of differential equations is solved numerically, employing the spectral relaxation method (SRM) via the MATLAB R2018a software. SRM is a simple iteration scheme that does not require any evaluation of derivatives, perturbation, and linearization for solving a nonlinear system of equations. Effects of embedded parameters such as sheet velocity parameter$\lambda$, magnetic field parameter$\beta$, Prandtl number$Pr$, magnetic Prandtl number$Prm$, thermal radiation parameter$Rd$, Lewis number$Le$, Brownian motion parameter$Nb$, and thermophoresis parameter$Nt$ on velocity, induced magnetic field, temperature, and nanoparticle concentration profiles are investigated. The skin-friction results, local Nusselt number, and Sherwood number are also discussed for various values of governing physical parameters. To show the convergence rate against iteration, residual error analysis has also been performed. The flow is strongly decelerated, and magnetic induction is suppressed with greater magnetic body force parameter, whereas temperature is elevated due to extra work expended as heat in dragging the magnetic nanofluid. Temperatures are also boosted with increment in nanoscale thermophoresis parameter and radiative parameter, whereas they are reduced with higher wall velocity, Brownian motion, and Prandtl numbers. Both hydrodynamic and magnetic boundary layer thicknesses are reduced with greater reciprocal values of the magnetic Prandtl number Prm. Nanoparticle (concentration) boundary layer thickness is boosted with higher values of thermophoresis and Prandtl number, whereas it is diminished with increasing wall velocity, nanoscale Brownian motion parameter, radiative parameter, and Lewis number. The simulations are relevant to electroconductive nanomaterial processing.
DESIGN is Everywhere: Elements of Design and MoMA’s Evolving Design Pedagogy
Authors: Rasmussen Briley
Published: June 2021

This essay examines Elements of Design, a circulating exhibition poster set produced by MoMA in 1945 and distributed worldwide. Through an examination of archived drafts, this exhibition set is discussed as an example of how the museum refined its educational approach through an evolving understanding of modern art and design. In particular, Elements of Design reflects MoMA’s expanding notion of audiences for modern art and design. This essay is the first scholarly examination of Elements of Design, including its archival drafts and documentation. Elements of Design was created by Robert Jay Wolff, former professor at the New Bauhaus, in collaboration with members of MoMA’s staff. Wolff merged Bauhaus–style foundations exercises with his experience developing visual instruction materials during the Second World War to create this visually engaging and instructive exhibition. This essay establishes important components of MoMA’s presentation of modern art and the pedagogy that would guide their educational activities for the next two decades: a focus on formal design and teaching aesthetic appreciation, a dedication to presenting modern art to the widest possible audiences, and an emphasis on the universality and unifying nature of modern art.
Jumping a Moving Train: SARS-CoV-2 Evolution in Real Time
Authors: Moustafa Ahmed M , Planet Paul J
Published: June 2021

The field of molecular epidemiology responded to the SARS-CoV-2 pandemic with an unrivaled amount of whole viral genome sequencing. By the time this sentence is published we will have well surpassed 1.5 million whole genomes, more than 4 times the number of all microbial whole genomes deposited in GenBank and 35 times the total number of viral genomes. This extraordinary dataset that accrued in near real time has also given us an opportunity to chart the global and local evolution of a virus as it moves through the world population. The data itself presents challenges that have never been dealt with in molecular epidemiology, and tracking a virus that is changing so rapidly means that we are often running to catch up. Here we review what is known about the evolution of the virus, and the critical impact that whole genomes have had on our ability to trace back and track forward the spread of lineages of SARS-CoV-2. We then review what whole genomes have told us about basic biological properties of the virus such as transmissibility, virulence, and immune escape with a special emphasis on pediatric disease. We couch this discussion within the framework of systematic biology and phylogenetics, disciplines that have proven their worth again and again for identifying and deciphering the spread of epidemics, though they were largely developed in areas far removed from infectious disease and medicine.
ALMA discovery of a dual dense probably rotating outflow from a massive young stellar object G18.88MME
Authors: Zinchenko I I , Dewangan L K , Baug T , Ojha D K , Bhadari N K
Published: June 2021

We report the discovery of a very dense jet-like fast molecular outflow surrounded by a wide-angle wind in a massive young stellar object (MYSO) G18.88MME (stellar mass ∼8 M⊙) powering an extended green object G18.89−0.47. Four cores MM1–4 are identified in the Atacama Large Millimeter/submillimeter Array (ALMA) 1.3 mm continuum map (resolution ${\sim} 0.8\, \mathrm { arcsec}$) towards G18.88MME, and are seen at the centre of the emission structure (extent ∼0.3 pc × 0.2 pc) detected in the ALMA map. G18.88MME is embedded in the core MM1 (mass ∼13–18 M⊙), where no radio continuum emission is detected. The molecular outflow centred at MM1 is investigated in the SiO(5–4), HC3N(24–23) and 13CO(2–1) lines. The detection of HC3N in the outflow is rare in MYSOs and indicates its very high density. The position–velocity diagrams display a fast narrow outflow (extent ∼28 000 AU) and a slower wide-angle more extended outflow towards MM1, and both of these components show a transverse velocity gradient indicative of a possible rotation. All these observed features together make G18.88MME as a unique object for studying the unification of the jet-driven and wind-driven scenarios of molecular outflows in MYSOs.
Tunicates Illuminate the Enigmatic Evolution of Chordate Metallothioneins by Gene Gains and Losses, Independent Modular Expansions, and Functional Convergences
Authors: Calatayud Sara , Garcia-Risco Mario , Palacios Òscar , Capdevila Mercè , Cañestro Cristian , Albalat Ricard
Published: June 2021

To investigate novel patterns and processes of protein evolution, we have focused in the metallothioneins (MTs), a singular group of metal-binding, cysteine-rich proteins that, due to their high degree of sequence diversity, still represents a “black hole” in Evolutionary Biology. We have identified and analyzed more than 160 new MTs in nonvertebrate chordates (especially in 37 species of ascidians, 4 thaliaceans, and 3 appendicularians) showing that prototypic tunicate MTs are mono-modular proteins with a pervasive preference for cadmium ions, whereas vertebrate and cephalochordate MTs are bimodular proteins with diverse metal preferences. These structural and functional differences imply a complex evolutionary history of chordate MTs—including de novo emergence of genes and domains, processes of convergent evolution, events of gene gains and losses, and recurrent amplifications of functional domains—that would stand for an unprecedented case in the field of protein evolution.
A sensitive repeat identification framework based on short and long reads
Authors: Liao Xingyu , Li Min , Hu Kang , Wu Fang-Xiang , Gao Xin , Wang Jianxin
Published: June 2021

Numerous studies have shown that repetitive regions in genomes play indispensable roles in the evolution, inheritance and variation of living organisms. However, most existing methods cannot achieve satisfactory performance on identifying repeats in terms of both accuracy and size, since NGS reads are too short to identify long repeats whereas SMS (Single Molecule Sequencing) long reads are with high error rates. In this study, we present a novel identification framework, LongRepMarker, based on the global de novo assembly and k-mer based multiple sequence alignment for precisely marking long repeats in genomes. The major characteristics of LongRepMarker are as follows: (i) by introducing barcode linked reads and SMS long reads to assist the assembly of all short paired-end reads, it can identify the repeats to a greater extent; (ii) by finding the overlap sequences between assemblies or chomosomes, it locates the repeats faster and more accurately; (iii) by using the multi-alignment unique k-mers rather than the high frequency k-mers to identify repeats in overlap sequences, it can obtain the repeats more comprehensively and stably; (iv) by applying the parallel alignment model based on the multi-alignment unique k-mers, the efficiency of data processing can be greatly optimized and (v) by taking the corresponding identification strategies, structural variations that occur between repeats can be identified. Comprehensive experimental results show that LongRepMarker can achieve more satisfactory results than the existing de novo detection methods (https://github.com/BioinformaticsCSU/LongRepMarker).
Accurate assembly of minority viral haplotypes from next-generation sequencing through efficient noise reduction
Authors: Knyazev Sergey , Tsyvina Viachaslau , Shankar Anupama , Melnyk Andrew , Artyomenko Alexander , Malygina Tatiana , Porozov Yuri B , Campbell Ellsworth M , Switzer William M , Skums Pavel , Mangul Serghei , Zelikovsky Alex
Published: June 2021

Rapidly evolving RNA viruses continuously produce minority haplotypes that can become dominant if they are drug-resistant or can better evade the immune system. Therefore, early detection and identification of minority viral haplotypes may help to promptly adjust the patient’s treatment plan preventing potential disease complications. Minority haplotypes can be identified using next-generation sequencing, but sequencing noise hinders accurate identification. The elimination of sequencing noise is a non-trivial task that still remains open. Here we propose CliqueSNV based on extracting pairs of statistically linked mutations from noisy reads. This effectively reduces sequencing noise and enables identifying minority haplotypes with the frequency below the sequencing error rate. We comparatively assess the performance of CliqueSNV using an in vitro mixture of nine haplotypes that were derived from the mutation profile of an existing HIV patient. We show that CliqueSNV can accurately assemble viral haplotypes with frequencies as low as 0.1% and maintains consistent performance across short and long bases sequencing platforms.
A rare case of desmoid fibromatosis of the transverse colon mimicking a perforated malignancy
Authors: Shah Isran Ali , Toor Sheza Arif , Gerogiannis Ioannis
Published: June 2021

Desmoid tumour of the colon is a very rare and aggressive type of intra-abdominal desmoid fibromatosis. Patients can present with a range of symptoms from a mild chronic abdominal pain to those of an acute abdomen. We present a rare case of abdominal fibromatosis that presented as a rapidly growing mass with free intraperitoneal gas. Intraoperatively however, we found a large tumour arising from the wall of the transverse colon and local necrosis. No bowel perforation was noted. The tumour was removed with a wide resection of transverse colon’s wall instead of colectomy. The histopathology reported benign fibromatosis and excluded malignancy.
Intraocular foreign body in the anterior chamber angle of the eye—a 30-year-old ‘emergency’
Authors: Ali Nadir A M , Buscombe Charlotte P , Jones David H
Published: June 2021

We report an unusual case of a missed intraocular foreign body, which was incidentally discovered in the anterior chamber drainage angle of the left eye of a retired masonry worker, some 30 years after the inciting injury. The ocular penetration and intraocular foreign body were missed during initial emergency management, despite the high-velocity mechanism of chiselling granite, which was reported. This case effectively highlights the need for a careful history and examination in high-velocity injuries to the eye (such as those caused by hammering and grinding), a high index of suspicion for intraocular foreign bodies, and considers best practice in managing such presentations.
Sporadic and rapidly progressive arrhythmogenic right ventricular cardiomyopathy in a 12-year-old boy who was diagnosed with epilepsy
Authors: Al-Khleaf Alaa , Babi Amal , Jarjanazi Mulham , Haddad Walid
Published: June 2021

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the leading causes of sudden cardiac death amongst young people and athletes. In this genetic disease, arrhythmia and fibro-fatty changes in the right ventricular myocardium are the main characteristics of the disease.

Here, we report a case of ARVC in a 12-year-old boy who was previously diagnosed with epilepsy, the patient’s condition manifested sporadically and was complicated by rapid progression, and unfortunate fatal deterioration after admission into the pediatric emergency room due to fatigue, dizziness and palpitation.

A diagnosis of ARVC was established, even though a family history was absent. Due to possible rapid deterioration, as described in this case, we recommend immediate primary and secondary prevention of arrhythmias in these patients, and to take in consideration of the potential risks of using sodium valproate in these patients.
Introduction
Authors: Roth Daniel
Published: June 2021

This introductory chapter defines the key terms and methodology through which the book will be analyzed. It begins with defining “third-party peacemaking and Jewish “rabbinic literature.” Then lays out the flow and structure of the various chapters of the book. The chapter then defines the various types of case studies to be examined in the book, consisting of “legends,” “historical accounts,” and ‘stories.” Finally, the chapter concludes with defining the three-layered methodology through which each case study will be analyzed: “text,” “theory,” and ‘practice.”
Wild emmer introgression alters root-to-shoot growth dynamics in durum wheat in response to water stress
Authors: Bacher Harel , Zhu Feiyu , Gao Tian , Liu Kan , Dhatt Balpreet K , Awada Tala , Zhang Chi , Distelfeld Assaf , Yu Hongfeng , Peleg Zvi , Walia Harkamal
Published: June 2021

Water deficit during the early vegetative growth stages of wheat (Triticum) can limit shoot growth and ultimately impact grain productivity. Introducing diversity in wheat cultivars to enhance the range of phenotypic responses to water limitations during vegetative growth can provide potential avenues for mitigating subsequent yield losses. We tested this hypothesis in an elite durum wheat background by introducing a series of introgressions from a wild emmer (Triticum turgidum ssp. dicoccoides) wheat. Wild emmer populations harbor rich phenotypic diversity for drought-adaptive traits. To determine the effect of these introgressions on vegetative growth under water-limited conditions, we used image-based phenotyping to catalog divergent growth responses to water stress ranging from high plasticity to high stability. One of the introgression lines exhibited a significant shift in root-to-shoot ratio in response to water stress. We characterized this shift by combining genetic analysis and root transcriptome profiling to identify candidate genes (including a root-specific kinase) that may be linked to the root-to-shoot carbon reallocation under water stress. Our results highlight the potential of introducing functional diversity into elite durum wheat for enhancing the range of water stress adaptation.
Effectiveness of Exergame Intervention on Walking in Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Janhunen Maarit , Karner Vera , Katajapuu Niina , Niiranen Oona , Immonen Jaakko , Karvanen Juha , Heinonen Ari , Aartolahti Eeva
Published: June 2021

Objective

The objective of this review was to systematically evaluate the effectiveness of exergaming on walking in older adults. In addition, the aim was to investigate the relationship between the exergaming effect and age, baseline walking performance, exercise traits, technology used, and the risk of bias.

Methods

A literature search was carried out in the databases MEDLINE, CINAHL, CENTRAL, EMBASE, WoS, PsycInfo, and PEDro up to January 10, 2020. Studies with a randomized controlled trial design, people ≥60 years of age without neurological disorders, comparison group with other exercise or no exercise, and walking-related outcomes were included. Cochrane RoB2, meta-analysis, meta-regression, and Grading of Recommendations, Assessment, Development and Evaluation were used to estimate quality, treatment effect, covariates’ effect, and the certainty of evidence, respectively.

Results

In the studies included (n = 66), the overall risk of bias was low (n = 2), unclear (n = 48), or high (n = 16). Compared with comparison groups, exergaming interventions were more effective for walking improvements (standardized mean difference = −0.21; 95% CI = −0.36 to −0.06; 3102 participants, 58 studies; moderate-quality evidence) and more or equally effective (standardized mean difference = −0.32; 95% CI = −0.64 to 0.00; 1028 participants, 13 studies; low-quality evidence) after nonexergaming follow-up. The strongest effect for covariates was observed with the type of comparison group, explaining 18.6% of the variance.

Conclusion

For older adults without neurological disorders, exergame-based training improved walking, and improvements were maintained at follow-up. Greater benefits were observed when exergaming groups were compared with inactive comparison groups. To strengthen the evidence, further randomized controlled trials on the effectiveness of gamified exercise intervention are needed.

Impact

Exergaming has an effect equivalent to other types of exercising on improving walking in older adults. Physical therapists and other rehabilitation professionals may consider exergaming as a promising form of exercise in this age group.
Apparent Discordance Between the Epidemiology of COVID-19 and Recommended Outcomes and Treatments: A Scoping Review
Authors: Webber Sandra C , Tittlemier Brenda J , Loewen Hal J
Published: June 2021

Objective

Many survivors of COVID-19 experience ongoing signs and symptoms affecting multiple body systems that impair function and negatively affect participation and quality of life. The purpose of this review was to identify and synthesize outpatient rehabilitation assessment and treatment recommendations for adults in postacute COVID-19 stages.

Methods

MEDLINE (Ovid), EMBASE (Ovid), Central, CINAHL, and Scopus were searched from January 1, 2020, to December 7, 2020. Teams of 2 reviewers independently assessed study eligibility and extracted data. All study designs that included rehabilitation recommendations were included. Study design, country, study population, purpose, and rehabilitation recommendations were recorded. Select questions from the Appraisal of Guidelines for Research and Evaluation instrument were used to evaluate the quality of consensus guidelines.

Results

Forty-eight articles fit the inclusion and exclusion criteria (11 systematic reviews, 1 scoping review, 6 original research studies, 4 consensus guidelines, 26 narrative reviews, and editorials/commentaries). Recommended outcomes included exercise tolerance, respiratory function, muscle strength, and activities of daily living or functional independence. Recommended treatments included respiratory rehabilitation, exercise therapy, education, psychological support, activities of daily living and gait training, traditional Chinese medicine, and cognitive and vocational rehabilitation.

Conclusion

There were incongruities between what is known about postacute COVID-19 and what was recommended in the literature. Given the relatively large proportion of survivors who experience ongoing symptomatic COVID-19 or post–COVID-19 syndrome, it is important to quickly develop tools for self-management and access to rehabilitation specialists in multidisciplinary teams.

Impact

Physical therapists, occupational therapists, and respiratory therapists have an important role to play. Clinicians should focus on epidemiological evidence and emerging information on late sequelae of COVID-19 to inform rehabilitation programming and future research.