bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical characterization of a novel RAB39B nonstop mutation in a family with ASD and severe ID causing RAB39B downregulation and study of a Rab39b knock down mouse model
Authors: Mignogna Maria Lidia , Ficarella Romina , Gelmini Susanna , Marzulli Lucia , Ponzi Emanuela , Gabellone Alessandra , Peschechera Antonia , Alessio Massino , Margari Lucia , Gentile Mattia , D’Adamo Patrizia
Published: November 2021

Autism spectrum disorder (ASD) and intellectual disability (ID) often exist together in patients. The RAB39B gene has been reported to be mutated in ID patients with additional clinical features ranging from ASD, macrocephaly, seizures and/or early-onset parkinsonism. Here, we describe a novel RAB39B nonstop mutation [Xq28; c.640 T > C; p.(*214Glnext*21)] in a family with ASD, severe ID and poor motor coordination, and we assessed the pathogenicity of the mutation. A heterologous cell system and a Rab39b knockdown (KD) murine model, which mimic the nonstop mutation, were used to validate the deleterious effect of the RAB39B mutation. The mutation led to RAB39B protein instability, resulting in its increased degradation and consequent downregulation. Using a Rab39b KD mouse model, we demonstrated that the downregulation of RAB39B led to increased GluA2 lacking Ca2+-permeable AMPAR composition at the hippocampal neuronal surface and increased dendritic spine density that remained in an immature filopodia-like state. These phenotypes affected behavioural performance in a disease-specific manner. Rab39b KD mice revealed impaired social behaviour but intact social recognition. They also showed normal anxiety-like, exploratory and motivational behaviours but impaired working and associative memories. In conclusion, we found a novel RAB39B nonstop variant that segregated in a family with a clinical phenotype including ID, ASD and poor motor coordination. The pathogenicity of mutations causing the downregulation of RAB39B proteins, impacting AMPAR trafficking and dendritic spine morphogenesis, reinforced the idea that AMPAR modulation and dendritic spine assets could be considered hallmarks of neurodevelopmental disorders.
Impact of aortic root repair or replacement in severe destructive aortic valve endocarditis with paravalvular abscesses on long-term survival
Authors: Gollmann-Tepeköylü Can , Abfalterer Hannes , Pölzl Leo , Müller Ludwig , Grimm Michael , Holfeld Johannes , Bonaros Nikolaos , Bates Katie , Ulmer Hanno , Ruttmann Elfriede
Published: November 2021

OBJECTIVES

Surgical treatment of destructive infective endocarditis consists of extensive debridement followed by root repair or replacement. However, it remains unknown whether 1 is superior to the other. We aimed to analyse whether long-term results were better after root repair or replacement in patients with root endocarditis.

METHODS

A total of 148 consecutive patients with root endocarditis treated with surgery from 1997 to 2020 at our department were included. Patients were divided into 2 groups: aortic root repair (n = 85) or root replacement using xenografts or homografts (n = 63).

RESULTS

Patients receiving aortic root repair showed significantly better long-term survival compared to patients receiving aortic root replacement (log-rank: P = 0.037). There was no difference in terms of freedom from valvular reoperations among both treatment groups (log-rank: P = 0.58). Patients with aortic root repair showed higher freedom from recurrent endocarditis compared to patients with aortic root replacement (log-rank: P = 0.022). Patients with aortic root repair exhibited higher event-free survival (defined as a combination end point of freedom from death, valvular reoperation or recurrent endocarditis) compared to patients receiving aortic root replacement (log-rank: P = 0.022). Age increased the risk of mortality with 1.7% per year. Multi-variable adjusted statistical analysis revealed improved long-term event-free survival after aortic root repair (hazards ratio: 0.57, 95% confidence interval: 0.39–0.95; P = 0.031).

CONCLUSIONS

Aortic root repair and replacement are feasible options for the surgical treatment of root endocarditis and are complementary methods, depending on the extent of infection. Patients with less advanced infection have a more favourable prognosis.

Clinical trial registration

UN4232 382/3.1 (retrospective study).
Longitudinal assessment of taurine and amino acid concentrations in dogs fed a green lentil diet
Authors: Reilly Lauren M , He Fei , Clark Lindsay , de Godoy Maria R C
Published: November 2021

A recent association between the inclusion of pulses in canine diets and taurine deficiency has become a prevalent issue in the pet food industry. Although dogs do not currently have a nutritional requirement for taurine, taurine deficiencies that do occur can result in serious health issues, such as dilated cardiomyopathy. The objective of this study was to determine the circulating concentrations of plasma and whole blood taurine, indispensable and dispensable amino acid concentrations in the plasma, and taurine and creatinine concentrations in the urine of adult dogs fed a green lentil diet. Twelve adult, intact, female beagles were randomly assigned to a diet containing 45% green lentils (GLD) or a poultry byproduct meal diet (CON) for 90 d. Fresh urine samples were collected every 30 d and analyzed for taurine and creatinine concentrations. A blood sample was also collected every 30 d and analyzed for amino acids including taurine. Animal procedures were approved by the University of Illinois Institutional Animal Care and Use Committee. All diets were formulated to meet or exceed the nutrient requirements for adult dogs at maintenance. The concentrations of taurine in the plasma and whole blood showed no differences (P > 0.05) between dietary treatments or across time points. Similarly, no differences (P > 0.05) in plasma methionine concentrations were observed between treatments or across time points. A treatment effect (P < 0.05) showed dogs fed GLD had higher total primary fecal bile acid excretion compared with dogs fed CON. The differential abundance of fecal microbial communities showed Firmicutes as the predominant phyla in dogs fed both GLD and CON, with Bacteroidaceae, Erysipelotrichaceae, and Lactobacillaceae as predominant families in dogs fed GLD. The α-diversity of dogs fed GLD (P < 0.05) was lower than in dogs fed CON. These data suggest that the inclusion of 45% green lentil in extruded diets does not lower whole blood and plasma taurine concentrations during a 90-d period and is appropriate for use in a complete and balanced formulation for dogs.
Resisted adduction sit-up test (RASUT) as a screening tool for pelvic versus hip pathology
Authors: Galano Gregory J , Tyler Timothy F , Stubbs Trevor , Ashraf Ali , Roberts Michael , McHugh Malachy P , Zoland Mark P , Nicholas Stephen J
Published: November 2021

Groin pain is a common symptom in hip and pelvic pathology and differentiating between the two remains a challenge. The purpose of this study was to examine whether a test combining resisted adduction with a sit-up (RASUT) differentiates between pelvic and hip pathology. The RASUT was performed on 160 patients with complaints of hip or groin pain who subsequently had their diagnosis confirmed by magnetic resonance imaging (MRI) or surgery. Patients were categorized as having pelvic pathology (athletic pubalgia or other) or hip pathology (intra-articular or other). Athletic pubalgia was defined as any condition involving the disruption of the pubic aponeurotic plate. Sensitivity, specificity, positive predictive accuracy, negative predictive accuracy and diagnostic odds ratios were computed. Seventy-one patients had pelvic pathology (40 athletic pubalgia), 81 had hip pathology and 8 had both. The RASUT was effective in differentiating pelvic from hip pathology; 50 of 77 patients with a positive RASUT had pelvic pathology versus 29 of 83 patients with a negative test (P < 0.001). RASUT was diagnostic for athletic pubalgia (diagnostic odds ratio 6.08, P < 0.001); 35 of 45 patients with athletic pubalgia had a positive RASUT (78% sensitivity) and 73 of 83 patients with a negative RASUT did not have athletic pubalgia (88% negative predictive accuracy). The RASUT can be used to differentiate pelvic from hip pathology and to identify patients without athletic pubalgia. This is a valuable screening tool in the armamentarium of the sports medicine clinician.
Bacterial Communities of Lab and Field Northern House Mosquitoes (Diptera: Culicidae) Throughout Diapause
Authors: Didion Elise M , Doyle Megan , Benoit Joshua B
Published: November 2021

Diapause is a hormonally driven response which is triggered by environmental cues that signal impending adverse conditions and prompts metabolic, developmental, and behavioral changes to allow survival until the return of favorable conditions. Microbial symbionts have been shown to influence the metabolism, development, and behavior of their host organisms, all of which are common diapause-associated characteristics. Surveys of bacterial components in relation to diapause have been examined in few systems, of which the species are usually inactive during dormancy, such as eggs or pupae. This is specifically intriguing as adult female diapause in Culex pipiens (Diptera: Culicidae) can last between 4 and 7 mo and females remain mobile within their hibernacula. Furthermore, it is unknown how microbiota changes associated with prolonged dormancy are different between the lab and field for insect systems. This study aims to characterize how the microbiota of C. pipiens changes throughout diapause under both field and lab settings when provided identical food and water resources. Based on these studies, C. pipiens microbiota shifts as diapause progresses and there are considerable differences between field and lab individuals even when provided the same carbohydrate and water sources. Specific bacterial communities have more association with different periods of diapause, field and lab rearing conditions, and nutritional reserve levels. These studies highlight that diapausing mosquito microbiota studies ideally should occur in field mesocosms and at multiple locations, to increase applicability to wild C. pipiens as prolonged exposure to artificial rearing conditions could impact metrics related to diapause-microbiome interactions. Additionally, these findings suggest that it would be worthwhile to establish if the microbiota shift during diapause impacts host physiology and whether this shift is critical to diapause success.
Are pharmacists well equipped to deal with global health emergencies? Burnout during COVID-19
Authors: Al-Haqan Asmaa , Alenezi Farah , Al-Mutairi Shriefa , Al-Taweel Dalal
Published: November 2021

Objectives

This study aimed to evaluate and assess the burnout effect among pharmacists during COVID-19 pandemic in Kuwait.

Methods

A cross-sectional study using an online self-administered questionnaire was conducted from September 2020 to January 2021. The questionnaire included demographic questions as well as items from the Copenhagen Burnout Inventory (CBI) to assess burnout in three domains: personal burnout, work-related burnout and client-related burnout. Descriptive statistics, correlations and comparative analysis were performed.

Key findings

A total of 277 completed responses were received. The overall mean (SD) score for the respondents’ burnout was 52.8 (19.1). The mean (SD) burnout scores for the three CBI domains (personal, work-related and client-related) were 56.6 (21.7), 53.9 (21.4) and 47.0 (23.8), respectively. It was found that younger age, female, Kuwaiti, Kuwait University graduates and less experienced participants had higher personal, work-related, client-related burnout scores. Personal and work-related scores were more strongly correlated (r = 0.81); in comparison with their correlation with the client-related score (r ≈ 0.55).

Conclusions

High burnout scores for pharmacists in Kuwait on a personal, work-related and client-related level during the COVID-19 pandemic were found. Strategies for early identification of burnout and recognition of modifiable factors that affect pharmacists’ work in Kuwait are needed to promote pharmacists’ psychological well-being.
Measuring Skin Color: Consistency, Comparability, and Meaningfulness of Rating Scale Scores and Handheld Device Readings
Authors: Gordon Rachel A , Branigan Amelia R , Khan Mariya Adnan , Nunez Johanna G
Published: November 2021

As US society continues to diversify and calls for better measurements of racialized appearance increase, survey researchers need guidance about effective strategies for assessing skin color in field research. This study examined the consistency, comparability, and meaningfulness of the two most widely used skin tone rating scales (Massey–Martin and PERLA) and two portable and inexpensive handheld devices for skin color measurement (Nix colorimeter and Labby spectrophotometer). We collected data in person using these four instruments from forty-six college students selected to reflect a wide range of skin tones across four racial-ethnic groups (Asian, Black, Latinx, White). These college students, five study staff, and 459 adults from an online sample also rated forty stock photos, again selected for skin tone diversity. Our results—based on data collected under controlled conditions—demonstrate high consistency across raters and readings. The Massey–Martin and PERLA scale scores were highly linearly related to each other, although PERLA better differentiated among people with the lightest skin tones. The Nix and Labby darkness-to-lightness (L*) readings were likewise linearly related to each other and to the Massey–Martin and PERLA scores, in addition to showing expected variation within and between race ethnicities. In addition, darker Massey–Martin and PERLA ratings correlated with online raters’ expectations that a photographed person experienced greater discrimination. In contrast, the redness (a*) and yellowness (b*) undertones were highest in the mid-range of the rating scale scores and demonstrated greater overlap across race-ethnicities. Overall, each instrument showed sufficient consistency, comparability, and meaningfulness for use in field surveys when implemented soundly (e.g., not requiring memorization). However, PERLA might be preferred to Massey–Martin in studies representing individuals with the lightest skin tones, and handheld devices may be preferred to rating scales to reduce measurement error when studies could gather only a single rating.
A Rescaling Bootstrap Approach For Imputed Survey Data
Authors: Mashreghi Zeinab , Deng Huiqi
Published: November 2021

Imputation is usually used to deal with item nonresponse in surveys. Treating the imputed values as true observations may obviously lead to serious underestimation of the variance of point estimators. In this article, we propose a new bootstrap method under the rescaling bootstrap approach for estimating the variance of an imputed estimator obtained after applying deterministic regression or random hot-deck imputation. A novel technique is used to rescale the original data set through solving certain systems of linear equations. The proposed procedure can handle unequal response probabilities and large sampling fractions. Some simulation studies are conducted to show the great performance of the proposed method in terms of relative bias, relative efficiency, and coverage probability, for both population mean and median.
Modelling multiwavelength emission of Ultra-luminous X-ray Sources accreting above the Eddington limit
Authors: Ambrosi E , Zampieri L , Pintore F , Wolter A
Published: November 2021

We model the multiwavelength properties of binaries accreting at super-critical rates with the aim to better understand the observational properties of Ultra-luminous X-ray Sources (ULXs). We calculate an extended grid of binary systems which evolve through Roche Lobe Overflow and undergo case A mass transfer from massive donors (up to 25 ${\rm M}_{\odot } \,$) on to massive black holes (BHs) (up to 100 ${\rm M}_{\odot } \,$). Angular momentum loss with the ejection of mass through an outflow is incorporated. We apply our super-Eddington accretion model to these systems, computing their evolutionary tracks on the colour–magnitude diagram (CMD) for the Johnson and Hubble Space Telescope photometric systems. We found that the tracks occupy specific positions on the CMD depending on the evolutionary stage of the donor and of the binary. Moreover, their shapes are similar, regardless the BH mass. More massive BHs lead to more luminous tracks. We additionally compute their optical-through-X-ray spectral energy distribution considering the effects of a Comptonizing corona that surrounds the innermost regions of the disc. We apply our model to four ULXs: NGC 4559 X-7, NGC 5204 X-1, Holmberg II X-1, and NGC 5907 ULX-2. We found that accretion on to BHs with mass in the range of 35–55 ${\rm M}_{\odot }$ is consistent with to the observational properties of these sources. We finally explore and discuss the possibility to extend our model also to ULXs powered by accreting pulsars (PULXs).
Radio and X-ray spectral properties of gamma-ray bursts and pulsar wind nebulae
Authors: Zhu Bo-Tao , Lu Fang-Wu , Zhou Bing , Fang Jun , Zhang Li
Published: November 2021

Both gamma-ray bursts (GRBs) and pulsar wind nebula (PWNe) are energetic outflows that are produced in powerful high-energy astrophysical environments. Based on the correlations between the radio luminosity LR and X-ray luminosity LX as well as between the multiband spectral slope αRX and radio flux FR for compiled GRB and PWN samples, the radio and X-ray spectral properties are statistically investigated. The results show that (1) the correlations between LR and LX are consistent for GRBs and PWNe, within the uncertainties; and (2) for the whole sample, FR is related to αRX, and GRBs have lower αRX than PWNe. It may be concluded that GRBs and PWNe have the same or similar particle acceleration mechanisms and radiation processes, i.e. synchrotron radiation, to produce the radio-to-X-ray band emission.
Angular clustering properties of the DESI QSO target selection using DR9 Legacy Imaging Surveys
Authors: Chaussidon Edmond , Yèche Christophe , Palanque-Delabrouille Nathalie , de Mattia Arnaud , Myers Adam D , Rezaie Mehdi , Ross Ashley J , Seo Hee-Jong , Brooks David , Gaztañaga Enrique , Kehoe Robert , Levi Michael E , Newman Jeffrey A , Tarlé Gregory , Zhang Kai
Published: November 2021

The quasar target selection for the upcoming survey of the Dark Energy Spectroscopic Instrument (DESI) will be fixed for the next 5 yr. The aim of this work is to validate the quasar selection by studying the impact of imaging systematics as well as stellar and galactic contaminants, and to develop a procedure to mitigate them. Density fluctuations of quasar targets are found to be related to photometric properties such as seeing and depth of the Data Release 9 of the DESI Legacy Imaging Surveys. To model this complex relation, we explore machine learning algorithms (random forest and multilayer perceptron) as an alternative to the standard linear regression. Splitting the footprint of the Legacy Imaging Surveys into three regions according to photometric properties, we perform an independent analysis in each region, validating our method using extended Baryon Oscillation Spectroscopic Survey (eBOSS) EZ-mocks. The mitigation procedure is tested by comparing the angular correlation of the corrected target selection on each photometric region to the angular correlation function obtained using quasars from the Sloan Digital Sky Survey (SDSS) Data Release 16. With our procedure, we recover a similar level of correlation between DESI quasar targets and SDSS quasars in two-thirds of the total footprint and we show that the excess of correlation in the remaining area is due to a stellar contamination that should be removed with DESI spectroscopic data. We derive the Limber parameters in our three imaging regions and compare them to previous measurements from SDSS and the 2dF QSO Redshift Survey.
Spatio-temporal bands of coronal bright points and their relation to solar torsional oscillations
Authors: Tsinamdzgvrishvili Tamar , Chargeishvili B B , Shergelashvili Bidzina M , Mghebrishvili Irakli
Published: November 2021

Using automatic processing of daily fits files from SOHO_EIT, we studied the temporal evolution of the latitudinal distribution of bright coronal points from 1995 to 2020. The study revealed homogeneous and inhomogeneous components of the latitudinal distribution. The homogeneous component has cyclical variations with a significant phase shift compared to the number of sunspots. The residual inhomogeneous component manifests itself as migration of the centre of increased density from high to low latitudes. The bands of the residual density of coronal bright points (CBP) reflect solar torsional oscillations. It should be associated with the strengthening of the local alpha-omega dynamo. However, the cyclical nature of the number of CBP is explained by the diffusion of large-scale magnetic fluxes.
The impact of primordial binary on the dynamical evolution of intermediate massive star clusters
Authors: Wang Long , Tanikawa Ataru , Fujii Michiko S
Published: November 2021

Observations found that star clusters contain a large fraction of binaries. Tight binaries are an important heating source that influences the long-term dynamical evolution of star clusters. However, due to the limitation of N-body tool, previous theoretical modelling for globular clusters (GCs) by using direct N-body simulations has not investigated how a large fraction of primordial binaries affect their long-term evolution. In this work, by using the high-performance N-body code, petar, we carry out star-by-star models for intermediate massive GCs (N = 100 000) with the primordial binary fraction varying from 0 to 1. We find that when a stellar-mass black hole (BH) subsystem exists, the structural evolution of GCs (core and half-mass radii) only depends on the properties of massive primordial binaries, because they affect the number of BH binaries (BBHs), which dominate the binary heating process. Low-mass binaries including double white dwarf binaries (BWDs) have almost no influence on the dynamics. Meanwhile, only gravitational wave mergers from BBHs are strongly affected by dynamical interactions, while low-mass mergers from BWDs show no difference in the isolated environment (field) and in GCs. Low-mass binaries become important only after most BHs escape and the core collapse of light stars occurs. Our result suggests that for N-body modelling of GCs with a BH subsystem dominating binary heating, it is not necessary to include low-mass binaries. These binaries can be studied separately by using standalone binary stellar evolution codes. This way can significantly reduce the computing cost.
GenBank
Authors: Sayers Eric W , Cavanaugh Mark , Clark Karen , Pruitt Kim D , Schoch Conrad L , Sherry Stephen T , Karsch-Mizrachi Ilene
Published: November 2021

GenBank® (https://www.ncbi.nlm.nih.gov/genbank/) is a comprehensive, public database that contains 15.3 trillion base pairs from over 2.5 billion nucleotide sequences for 504 000 formally described species. Recent updates include resources for data from the SARS-CoV-2 virus, including a SARS-CoV-2 landing page, NCBI Datasets, NCBI Virus and the Submission Portal. We also discuss upcoming changes to GI identifiers, a new data management interface for BioProject, and advice for providing contextual metadata in submissions.
OUHP: an optimized universal hairpin primer system for cost-effective and high-throughput RT-qPCR-based quantification of microRNA (miRNA) expression
Authors: He Fang , Ni Na , Wang Hao , Zeng Zongyue , Zhao Piao , Shi Deyao , Xia Yinglin , Chen Connie , Hu Daniel A , Qin Kevin H , Wagstaff William , Qin David , Hendren-Santiago Bryce , Ho Sherwin H , Haydon Rex C , Luu Hue H , Reid Russell R , Shen Le , Gan Hua , Fan Jiaming , He Tong-Chuan
Published: November 2021

MicroRNAs (miRNAs or miRs) are single-stranded, ∼22-nucleotide noncoding RNAs that regulate many cellular processes. While numerous miRNA quantification technologies are available, a recent analysis of 12 commercial platforms revealed high variations in reproducibility, sensitivity, accuracy, specificity and concordance within and/or between platforms. Here, we developed a universal hairpin primer (UHP) system that negates the use of miRNA-specific hairpin primers (MsHPs) for quantitative reverse transcription PCR (RT-qPCR)-based miRNA quantification. Specifically, we analyzed four UHPs that share the same hairpin structure but are anchored with two, three, four and six degenerate nucleotides at 3′-ends (namely UHP2, UHP3, UHP4 and UHP6), and found that the four UHPs yielded robust RT products and quantified miRNAs with high efficiency. UHP-based RT-qPCR miRNA quantification was not affected by long transcripts. By analyzing 14 miRNAs, we demonstrated that UHP4 closely mimicked MsHPs in miRNA quantification. Fine-tuning experiments identified an optimized UHP (OUHP) mix with a molar composition of UHP2:UHP4:UHP6 = 8:1:1, which closely recapitulated MsHPs in miRNA quantification. Using synthetic LET7 isomiRs, we demonstrated that the OUHP-based qPCR system exhibited high specificity and sensitivity. Collectively, our results demonstrate that the OUHP system can serve as a reliable and cost-effective surrogate of MsHPs for RT-qPCR-based miRNA quantification for basic research and precision medicine.
VID22counteracts G-quadruplex-induced genome instability
Authors: Galati Elena , Bosio Maria C , Novarina Daniele , Chiara Matteo , Bernini Giulia M , Mozzarelli Alessandro M , García-Rubio Maria L , Gómez-González Belén , Aguilera Andrés , Carzaniga Thomas , Todisco Marco , Bellini Tommaso , Nava Giulia M , Frigè Gianmaria , Sertic Sarah , Horner David S , Baryshnikova Anastasia , Manzari Caterina , D’Erchia Anna M , Pesole Graziano , Brown Grant W , Muzi-Falconi Marco , Lazzaro Federico
Published: November 2021

Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.
Decoding the effects of synonymous variants
Authors: Zeng Zishuo , Aptekmann Ariel A , Bromberg Yana
Published: November 2021

Synonymous single nucleotide variants (sSNVs) are common in the human genome but are often overlooked. However, sSNVs can have significant biological impact and may lead to disease. Existing computational methods for evaluating the effect of sSNVs suffer from the lack of gold-standard training/evaluation data and exhibit over-reliance on sequence conservation signals. We developed synVep (synonymous Variant effect predictor), a machine learning-based method that overcomes both of these limitations. Our training data was a combination of variants reported by gnomAD (observed) and those unreported, but possible in the human genome (generated). We used positive-unlabeled learning to purify the generated variant set of any likely unobservable variants. We then trained two sequential extreme gradient boosting models to identify subsets of the remaining variants putatively enriched and depleted in effect. Our method attained 90% precision/recall on a previously unseen set of variants. Furthermore, although synVep does not explicitly use conservation, its scores correlated with evolutionary distances between orthologs in cross-species variation analysis. synVep was also able to differentiate pathogenic vs. benign variants, as well as splice-site disrupting variants (SDV) vs. non-SDVs. Thus, synVep provides an important improvement in annotation of sSNVs, allowing users to focus on variants that most likely harbor effects.
SCoV2-MD: a database for the dynamics of the SARS-CoV-2 proteome and variant impact predictions
Authors: Torrens-Fontanals Mariona , Peralta-García Alejandro , Talarico Carmine , Guixà-González Ramon , Giorgino Toni , Selent Jana
Published: November 2021

SCoV2-MD (www.scov2-md.org) is a new online resource that systematically organizes atomistic simulations of the SARS-CoV-2 proteome. The database includes simulations produced by leading groups using molecular dynamics (MD) methods to investigate the structure-dynamics-function relationships of viral proteins. SCoV2-MD cross-references the molecular data with the pandemic evolution by tracking all available variants sequenced during the pandemic and deposited in the GISAID resource. SCoV2-MD enables the interactive analysis of the deposited trajectories through a web interface, which enables users to search by viral protein, isolate, phylogenetic attributes, or specific point mutation. Each mutation can then be analyzed interactively combining static (e.g. a variety of amino acid substitution penalties) and dynamic (time-dependent data derived from the dynamics of the local geometry) scores. Dynamic scores can be computed on the basis of nine non-covalent interaction types, including steric properties, solvent accessibility, hydrogen bonding, and other types of chemical interactions. Where available, experimental data such as antibody escape and change in binding affinities from deep mutational scanning experiments are also made available. All metrics can be combined to build predefined or custom scores to interrogate the impact of evolving variants on protein structure and function.
Regional Parliaments and Democratic Crises: The Performance of ECOWAS and MERCOSUR Parliaments in the Democracy Protection Agenda
Authors: Luciano Bruno Theodoro , Ramanzini Júnior Haroldo
Published: November 2021

This article aims to examine regional parliaments of two prominent regional organisations in South America (Southern Common Market) and Western Africa (Economic Community of West African States), by focusing on their performance in the agenda of democracy protection. We comparatively assess the performance of regional parliamentary agents in contributing to the mediation and conflict resolution in cases of democratic breakdown as well as the conditions and factors that affect parliamentary performance. We argue that regional parliaments have exerted relevant agency in democratic crises, despite their low decision-making competencies and the strong intergovernmental features of Global South regional organisations.
The miRNome function transitions from regulating developmental genes to transposable elements during pollen maturation
Authors: Oliver Cecilia , Annacondia Maria Luz , Wang Zhenxing , Jullien Pauline E , Slotkin R Keith , Köhler Claudia , Martinez German
Published: November 2021

Animal and plant microRNAs (miRNAs) are essential for the spatio-temporal regulation of development. Together with this role, plant miRNAs have been proposed to target transposable elements (TEs) and stimulate the production of epigenetically active small interfering RNAs. This activity is evident in the plant male gamete containing structure, the male gametophyte or pollen grain. How the dual role of plant miRNAs, regulating both genes and TEs, is integrated during pollen development and which mRNAs are regulated by miRNAs in this cell type at a genome-wide scale are unknown. Here, we provide a detailed analysis of miRNA dynamics and activity during pollen development in Arabidopsis thaliana using small RNA and degradome parallel analysis of RNA end high-throughput sequencing. Furthermore, we uncover miRNAs loaded into the two main active Argonaute (AGO) proteins in the uninuclear and mature pollen grain, AGO1 and AGO5. Our results indicate that the developmental progression from microspore to mature pollen grain is characterized by a transition from miRNAs targeting developmental genes to miRNAs regulating TE activity.
Origins of the Opioid Crisis and its Enduring Impacts
Authors: Alpert Abby , Evans William N , Lieber Ethan M J , Powell David
Published: November 2021

Overdose deaths involving opioids have increased dramatically since the 1990s, leading to the worst drug overdose epidemic in U.S. history, but there is limited empirical evidence about the initial causes. In this article, we examine the role of the 1996 introduction and marketing of OxyContin as a potential leading cause of the opioid crisis. We leverage cross-state variation in exposure to OxyContin's introduction due to a state policy that substantially limited the drug's early entry and marketing in select states. Recently unsealed court documents involving Purdue Pharma show that state-based triplicate prescription programs posed a major obstacle to sales of OxyContin and suggest that less marketing was targeted to states with these programs. We find that OxyContin distribution was more than 50% lower in “triplicate states” in the years after the drug's launch. Although triplicate states had higher rates of overdose deaths prior to 1996, this relationship flipped shortly after the launch and triplicate states saw substantially slower growth in overdose deaths, continuing even 20 years after OxyContin's introduction. Our results show that the introduction and marketing of OxyContin explain a substantial share of overdose deaths over the past two decades.
AGE-DEPENDENT DOSE DUE TO INTAKE OF 40K, 228RA, 226RA IN SPRING WATER IN PETRA DISTRICT, JORDAN
Authors: Qwasmeh Ahmed Ali Husein
Published: November 2021

A HpGe detector was used to measure radioactivity concentrations of 40K, 228Ra and 226Ra in spring water from villages in Petra district in southern Jordan. The concentrations of 40K, 228Ra, 226Ra were 0.64–2.72 Bq/l, 0.05–0.08 Bq/l and 0.15–0.22 Bq/l, respectively. These values were compared to the concentrations of the corresponding radionuclides in studies from Jordan and near countries. The annual effective doses (${D}_{\mathrm{eff}}$) due to the intake of 40K, 228Ra and 226Ra, for the different age groups were calculated. The highest ${D}_{\mathrm{eff}}$ values due to the intake of 226Ra and 228Ra were found in the infants age group, whereas the lowest were found in the adults age group in every site. The annual effective doses in this study were compared to the committed annual effective doses from ingestion in UNSCEAR. The annual effective doses in this study were much higher than the committed values in UNSCEAR. The life time risk for radiation-induced cancer for the whole population was calculated for every sample and it revealed no extra risk over the one recommended by WHO.
Development and Internal Validation of Novel Risk Tools to Predict Subsequent Shoulder Surgery After Proximal Humerus Fractures
Authors: Nowak Lauren L. , Hall Jeremy , Davis Aileen M. , McKee Michael D. , Mamdani Muhammad , Beaton Dorcas , Schemitsch Emil H.
Published: November 2021

Objective:

To (1) identify predictors of subsequent surgery after initial treatment of proximal humerus fractures (PHFs) and (2) generate valid risk prediction tools to predict subsequent surgery.

Methods:

We identified patients ≥50 years with PHF from 2004 to 2015 using health data sets in Ontario, Canada. We used procedural codes to classify patients into treatment groups of (1) surgical fixation, (2) shoulder replacement, and (3) conservative. We used procedural and diagnosis codes to capture subsequent surgery within 2 years after fracture. We developed regression models for two-thirds of each group to identify predictors of subsequent surgery and the regression equations to develop risk tools to predict subsequent surgery. We used the final third of each cohort to evaluate the discriminative ability of the risk tools using c-statistics.

Results:

We identified 20,897 patients with PHF, 2414 treated with fixation, 1065 with replacement, and 17,418 treated conservatively. Predictors of reoperation after fixation included bone grafting and nail or wire fixation versus plate fixation, whereas poor bone quality was associated with reoperation after initial replacement. In conservatively treated patients, more comorbidities were associated with subsequent surgery, whereas age 70+ and discharge home after presentation lowered the odds of subsequent surgery. The risk tools were able to discriminate with c-statistics of 0.75–0.88 (derivation) and 0.51–0.79 (validation).

Conclusions:

Our risk tools showed good to strong discriminative ability for patients treated conservatively and with fixation. These data may be used as the foundation to develop a clinically informative tool.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Association Between Migraine and Dry Eye: A Systematic Review and Metaanalysis
Authors: Chen Hanlin , Chen Aiming , Wang Shibin , Zou Minjie , Young Charlotte Aimee , Zheng Danying , Jin Guangming
Published: November 2021

Purpose:

The purpose of this study was to assess whether migraine might be associated with the increased risk of dry eye disease and to determine the strength of the association between migraine and dry eye disease.

Methods:

We searched EMBASE, PubMed, Web of Science databases and China National Knowledge Infrastructure, WanFang, and VIP databases for studies that investigated the association between dry eye and migraine from inception to September 8, 2020. Relevant data were extracted by 2 investigators independently. Publication bias and heterogeneity were evaluated. Odds ratio (OR) and 95% confidence interval (CI) were computed by metaanalysis using random-effects models.

Results:

Of the 565 studies identified, 7 studies met the inclusion criteria and were included in this metaanalysis. Patients with migraine had significantly higher morbidity of dry eye compared with the control group (OR = 1.55; 95% CI = 1.32–1.82; P < 0.001). Subgroup analysis showed that the association between dry eye and migraine was stronger in hospital-based studies (OR = 1.97, P = 0.036) than population-based studies (OR = 1.42, P < 0.001). In addition, differences in geographic location and diagnostic criteria have no effect on the results.

Conclusions:

There was a significant association between dry eye and migraine. Patients with migraine are more prone to suffer from dry eye than subjects without migraine, and the association strength varies among populations studied.
Cytokeratin 13 Is a New Biomarker for the Diagnosis of Limbal Stem Cell Deficiency
Authors: Liang Qingfeng , Le Qihua , Wang Leying , Cordova Daniel , Baclagon Elfren , Garrido Sheyla González , Levin Mary , Jin Yusheng , Tseng Chi-hong , Rao Jianyu , Deng Sophie X.
Published: November 2021

Purpose:

The purpose of this study was to evaluate the expression of cytokeratin (K) 13 on the corneal surface and to validate its application in the diagnosis of limbal stem cell deficiency (LSCD).

Methods:

This prospective comparative study included 26 corneal impression cytology (IC) specimens from patients diagnosed with LSCD. Twenty-three IC specimens from normal donors served as controls. K12 and K13 expression were detected on the IC specimens by immunohistochemistry study. The number of K12+ or K13+ cells in all areas of the IC was quantified using ImageJ software.

Results:

The epithelial cells harvested from IC specimens from control corneas were all K12+. In eyes with LSCD, K13+ and K12+/K13+ cells accounted for 93.8% and 2.6%, respectively, in the cornea. In eyes with sectoral LSCD, the median number of K13+ cells in the clinically affected area was higher than that in the unaffected area (810.0 vs. 115.0 cells/mm2; P < 0.001). No significant correlation was found between the LSCD severity and the number of K12+ cells (r = −0.284, P = 0.16) or K13+ cells (r = −0.011, P = 0.95). The presence of at least 16 K13+ cells/mm2 was suggestive of LSCD.

Conclusions:

Identification of K13+ cells on IC specimens provides a simple and reliable method to detect conjunctival epithelial cells on the cornea. K13 is a marker for diagnosing LSCD and localizing the involved area in sectoral LSCD.
Conjunctival Myxoma: High-Resolution Optical Coherence Tomography Findings of a Rare Tumor
Authors: Alvarado-Villacorta Rosa , Davila-Alquisiras Jesus H. , Ramos-Betancourt Nallely , Vazquez-Romo Kristian A. , Hernández-Ayuso Ivette , Ríos y Valles-Valles Dolores , Rodríguez-Reyes Abelardo A.
Published: November 2021

Purpose:

The purpose of this study was to describe 2 cases of biopsy-proven conjunctival myxomas and present their optical signs on high-resolution optical coherence tomography (HR-OCT) with clinical and histopathological correlations.

Methods:

Two middle-aged female patients with a clinical diagnosis of conjunctival cysts were referred for surgical treatment. Clinical assessment, photographs, ultrasound biomicroscopy, and HR-OCT images were obtained. Excisional biopsies were performed, and specimens were sent for histopathological and immunohistochemical analyses.

Results:

Clinically, these patients presented with a well-circumscribed, semitranslucent, yellow–pinkish mass. Ultrasound biomicroscopy showed a dome-shaped epibulbar mass with medium-to-high internal reflectivity. No compromise of the underlying sclera was noted. HR-OCT showed a normal conjunctival epithelium, a subepithelial nonhomogeneous mass with hyperreflective and hyporeflective areas lined by a highly hyperreflective band, and mild posterior shadowing. Histopathological findings and immunoreactivity for CD34 and vimentin confirmed the diagnosis of conjunctival myxoma.

Conclusions:

The HR-OCT optical signs found in our 2 cases strongly correlated with the microscopic findings. Disclosing the optical signs observed on HR-OCT can help clinicians diagnose and differentiate this lesion, guiding its management. However, more studies with a larger number of patients comparing conjunctival myxoma and other ocular surface tumors are needed to enlighten readers about the unique pattern observed by HR-OCT.
A Meta-analysis of the Effect of Motivational Interviewing on Depression, Anxiety, and Quality of Life in Stroke Patients
Authors: Qiqi Ni , Hangting Li , Jia Wu , Jiaoni Shen , Xinrui Wan , Guijuan He
Published: November 2021

BACKGROUND: Motivational interviewing has become a popular approach for relieving mood disturbances. We aimed to investigate whether motivational interviewing can effectively improve depression, anxiety, and quality of life among stroke patients. METHODS: Seven electronic databases were searched from inception to March 15, 2021. Other potentially related studies were identified through manually searching the reference lists of empirical articles and relevant review articles. Randomized controlled trials that investigated the effects of motivational interviewing on stroke patients with mood disturbances were deemed eligible. The Cochrane Handbook 5.1.0 was used to assess the risk of bias. Meta-analyses were conducted using the Review Manager Version 5.3. RESULTS: Six articles with 1419 participants were included. The subgroup analysis revealed that motivational interviewing was associated with improvement of depression (P < .00001) and quality of life (P = .0007) among patients having stroke at less than 12 months of follow-up. No significant differences were detected for improving depression (P = .40) and quality of life (P = .38) at 12 months of follow-up. Furthermore, the meta-analysis showed that motivational interviewing was not associated with alleviation of anxiety (P = .81) among stroke patients. CONCLUSION: This meta-analysis indicated that motivational interviewing might have beneficial effects on depression and quality of life in stroke patients at less than 12 months of follow-up. However, large and well-designed randomized controlled trials are needed to confirm these findings.
“But it feels swollen!”: the frequency and clinical characteristics of people with knee osteoarthritis who report subjective knee swelling in the absence of objective swelling
Authors: Tanaka So , Nishigami Tomohiko , Ohishi Koji , Nishikawa Kazutaka , Wand Benedict M. , Stanton Tasha R. , Yamashita Hirofumi , Mibu Akira , Tokunaga Masami , Yoshimoto Takaaki , Ushida Takahiro
Published: November 2021

Introduction:

There are complex interactions between pain and perceptions of the painful body part in musculoskeletal disorders, and disruption of various body representations in people with chronic pain.

Objectives:

The purpose of this study was to investigate how frequently people with knee osteoarthritis (OA) complain of swelling without objective evidence of swelling, and describe the clinical characteristics of this population.

Methods:

Forty-six people with knee OA (68.1 ± 8.8 years) participated in this cross-sectional study. Subjective and objective swelling was evaluated by knee-specific body perception questionnaire and ultrasonography, respectively. Pain intensity, disability, pain-related beliefs, 2-point discrimination threshold, and quadriceps muscle strength were also evaluated.

Results:

Approximately 1/3 of participants (n = 15) had subjective feelings of knee swelling in the absence of objective swelling (S only). Fifteen participants had both subjective and objective knee swelling (S + O group) and 16 had neither subjective nor objective knee swelling (No S/O group). Participants in the S only group had similar pain or disability as those in the S + O group but had more severe pain or disability than those with in the No S/O group. Those in the S only group also had larger 2-point discrimination distance threshold at the medial knee (impaired tactile acuity) than those in the S + O group and had more dysfunctional pain catastrophizing and pain-related self-efficacy than both other groups.

Conclusion:

Our results suggest that about 30% of people with knee OA perceive swelling of the knee in the absence of any objective swelling and that this is accompanied by severe pain and functional disability. Considering altered body image of the knee may reveal relevant treatment-based subgroups in people with knee OA.