Miracle-dz/UniFAR-FTUs huggingface dataset:
Euthanasia of dogs and cats by veterinarians in New Zealand: protocols, procedures and experiences

ABSTRACT Aims To collect data on protocols used by New Zealand veterinarians to perform euthanasia of dogs and cats, and to explore opinions towards the training they received in euthanasia during veterinary school. Methods A cross-sectional survey was administered to all veterinarians registered with the Veterinary Council of New Zealand. The survey asked respondents about their practices’ policies for euthanasia; protocols for performing euthanasia of dogs and cats; opinions towards euthanasia training received in veterinary school; and subsequent experiences with euthanasia in practice. Descriptive statistics were provided for all quantitative study variables and thematic analysis was performed on the free-text comments. Results The survey was completed by 361/1,448 (24.9%) veterinarians in companion or mixed animal practice. The mean numbers of dogs and cats euthanised each month were 7.2 (median 5; min 0; max 60) and 7.9 (median 5; min 0; max 60), respectively. Fewer than half of respondents reported that their clinic had a standard protocol for euthanising dogs (147/361; 40.7%) or cats (157/361; 43.5%). For euthanasia of dogs, 119/361 (32.9%) always used sedation while 71/361 (19.7%) indicated that they would not use sedation. For euthanasia of cats, 170/361 (47.1%) always used sedation while 53/361 (14.7%) indicated that they would not use sedation. Placement of IV catheters, methods for patient restraint, preferences towards the presence of owners during euthanasia, services provided with euthanasia, and discussions with owners were also highly variable and handled case-by-case depending on the client, patient, and clinical scenario. When asked about the euthanasia training received at veterinary school, it was generally ranked as below satisfactory, with approximately one-third of respondents indicating that they received no training in dealing with emotional clients (113/361; 31.3%), sedation protocols for euthanasia (107/361; 29.6%), or managing compassion fatigue (132/361; 36.6%). Most respondents (268/361; 74.2%) received no formal training in euthanasia after graduation and learned from experience or discussions with colleagues. Providing animals and owners with a good experience during the euthanasia process was highlighted as important for managing compassion fatigue. Conclusions Euthanasia is a common procedure in companion animal practice and there is considerable variation in how veterinarians approach both the technical and non-technical elements. Training provided during veterinary school was generally considered below satisfactory, particularly regarding managing compassion fatigue and clients’ emotional needs. Clinical relevance Providing veterinarians with additional training on adapting their euthanasia protocols to different clinical scenarios may improve the experience for patients, owners and veterinary staff.
An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis

ABSTRACT Introduction Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. Areas covered Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. Expert opinion S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.
Ongoing increasing trends in central precocious puberty incidence among Korean boys and girls from 2008 to 2020

Background Over the last few decades, there has been growing evidence of earlier onset and progression of puberty worldwide. This population-based longitudinal cohort study aimed to analyze the change in the annual incidence rate of central precocious puberty (CPP) among Korean children over the most recent decade, using the national registry data. Method The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and insurance claims for gonadotropin-releasing hormone agonist (GnRHa) treatment were used to identify CPP patients who were using the Korean Health Insurance Review & Assessment Service (HIRA) database between 2008 and 2020. Patients who began GnRHa therapy before the age of 9 and 10 for girls and boys, respectively, were included in the study. Results A total of 6,906 boys and 126,377 girls were diagnosed with CPP between 2008 and 2020. The annual incidence of CPP increased by 83.3 times in boys (from 1.2 to 100 per 100,000 persons) and by 15.9 times in girls (from 88.9 to 1414.7 per 100,000 persons). The age-specific annual incidence of CPP increased remarkably more in older children than in younger ones; the 2020 CPP incidence among 9-year-old boys and 8-year-old girls reached 705.2 and 7,967.3 per 100,000 persons, respectively. The annual prevalence of CPP in boys and girls increased from 2.7 to 206.5 (76.5 times) and from 141.8 to 3439.9 (24.3 times) per 100,000 persons, respectively. Conclusion Based on GnRHa treatment insurance claims, our study suggests that the annual incidence of CPP has substantially increased in Korea during the past 13 years. These findings highlight the importance of meticulous judgment by doctors in determining GnRHa treatment.
OutSingle: a novel method of detecting and injecting outliers in RNA-Seq count data using the optimal hard threshold for singular values

Abstract Motivation Finding outliers in RNA-sequencing (RNA-Seq) gene expression (GE) can help in identifying genes that are aberrant and cause Mendelian disorders. Recently developed models for this task rely on modeling RNA-Seq GE data using the negative binomial distribution (NBD). However, some of those models either rely on procedures for inferring NBD’s parameters in a nonbiased way that are computationally demanding and thus make confounder control challenging, while others rely on less computationally demanding but biased procedures and convoluted confounder control approaches that hinder interpretability. Results In this article, we present OutSingle (Outlier detection using Singular Value Decomposition), an almost instantaneous way of detecting outliers in RNA-Seq GE data. It uses a simple log-normal approach for count modeling. For confounder control, it uses the recently discovered optimal hard threshold (OHT) method for noise detection, which itself is based on singular value decomposition (SVD). Due to its SVD/OHT utilization, OutSingle’s model is straightforward to understand and interpret. We then show that our novel method, when used on RNA-Seq GE data with real biological outliers masked by confounders, outcompetes the previous state-of-the-art model based on an ad hoc denoising autoencoder. Additionally, OutSingle can be used to inject artificial outliers masked by confounders, which is difficult to achieve with previous approaches. We describe a way of using OutSingle for outlier injection and proceed to show how OutSingle outperforms its competition on 16 out of 18 datasets that were generated from three real datasets using OutSingle’s injection procedure with different outlier types and magnitudes. Our methods are applicable to other types of similar problems involving finding outliers in matrices under the presence of confounders. Availability and implementation The code for OutSingle is available at https://github.com/esalkovic/outsingle.
Comparison of perioperative outcomes and anesthetic-related complications of morbidly obese and super-obese parturients delivering by cesarean section

Abstract Objective To compare the perioperative outcomes and anesthetic-related complications of morbidly obese and super-obese parturients delivering by cesarean section. Methods A retrospective analysis of 6 years of data was performed. Exclusions were cases with gestational ages <24 weeks, placenta accreta spectrum, polyhydramnios, or multiple gestations. Results The study included 494 patients whose body mass index (BMI) exceeded 40 kg/m2 at delivery. Of these, 469 were morbidly obese (BMI 40–49.9; mean, 42.9 ± 2.4), and 25 were super obese (BMI >50; mean, 54.5 ± 4.2). Twenty-four (5.1%) morbidly obese women received general anesthesia. The other 445 patients (94.9%) in the morbid obesity group underwent cesarean delivery under regional anesthesia; however, some (2.2%; 10/445) received general anesthesia after regional anesthesia failed. In the super-obesity group, 23 patients (92.0%) received regional anesthesia, while two patients (8.0%) received general anesthesia. There were no cases of pulmonary aspiration, maternal deaths, or difficult or failed intubation. There was one episode of cardiac arrest in a patient with a BMI of 47.9. Among the morbidly obese and super-obese women given regional anesthesia, the super-obese patients had significantly greater volumes of ephedrine and norepinephrine consumption (p = 0.027 and 0.030), intravenous fluids (p = 0.006), and bleeding during surgery (p = 0.017). They also had more hypotensive episodes (p = 0.038). The two groups’ incidences of neonatal birth asphyxia, postpartum hemorrhage, blood transfusion, and uterine atony did not differ significantly. The lengths of stay in the hospital were also comparable. Conclusions Among the women receiving regional anesthesia, the super-obese parturients had greater intraoperative bleeding, a higher proportion of hypotensive episodes, and a greater vasopressor requirement than the morbidly obese parturients. Anesthesiologists must prepare for the adverse perioperative events that such women risk experiencing during a delivery by cesarean section. Trial registration www.clinicaltrials. gov ID: NCT04657692. KEY MESSAGES Super obesity parturients are at a significantly higher risk of intraoperative bleeding, maternal hypotension, and higher vasopressor requirement compared to parturients with morbid obesity undergoing cesarean delivery. We additionally found a weak positive correlation between patient body weight and intraoperative blood loss in a patient with morbid obesity regardless of anesthetic technique.
Syntactic Network Analysis in Schizophrenia-Spectrum Disorders.

BACKGROUND Language anomalies are a hallmark feature of schizophrenia-spectrum disorders (SSD). Here, we used network analysis to examine possible differences in syntactic relations between patients with SSD and healthy controls. Moreover, we assessed their relationship with sociodemographic factors, psychotic symptoms, and cognitive functioning, and we evaluated whether the quantification of syntactic network measures has diagnostic value. STUDY DESIGN Using a semi-structured interview, we collected speech samples from 63 patients with SSD and 63 controls. Per sentence, a syntactic representation (ie, parse tree) was obtained and used as input for network analysis. The resulting syntactic networks were analyzed for 11 local and global network measures, which were compared between groups using multivariate analysis of covariance, considering the effects of age, sex, and education. RESULTS Patients with SSD and controls significantly differed on most syntactic network measures. Sex had a significant effect on syntactic measures, and there was a significant interaction between sex and group, as the anomalies in syntactic relations were most pronounced in women with SSD. Syntactic measures were correlated with negative symptoms (Positive and Negative Syndrome Scale) and cognition (Brief Assessment of Cognition in Schizophrenia). A random forest classifier based on the best set of network features distinguished patients from controls with 74% cross-validated accuracy. CONCLUSIONS Examining syntactic relations from a network perspective revealed robust differences between patients with SSD and healthy controls, especially in women. Our results support the validity of linguistic network analysis in SSD and have the potential to be used in combination with other automated language measures as a marker for SSD.
The quasi-one-dimensional frustrated XY model

A quasi-one-dimensional version of the frustrated XY model used to describe Josephson junction arrays and granular superconductors is described. It is shown that there are two distinct types of ground state, depending on whether the frustration is greater than or less than a critical amount. The small fluctuations around the weak frustration ground state are analysed by diagonalising the Hessian matrix; this gives an expression for the low-temperature specific heat of the network. By an extension of this analysis to include the effect of twisted boundary conditions, the critical current of the system is calculated in the low-flux regime. Finally the effect of diamagnetic screening currents is included.
Inhibition of Integrin αvβ3-FAK-MAPK signaling constrains the invasion of T-ALL cells

ABSTRACT The role of adhesion receptor integrin αvβ3 in T-ALL was unclear. Firstly, we performed quantitative real-time PCR to assess medullary expression of integrin β3(ITGB3) in T-ALL patients and high ITGB3 expression was relevant with the central nervous system leukemia(CNSL) incidence. Decreasing of cell invasion was observed in Jurkat and Molt4 treated with integrin αvβ3 specific antibody and inhibitor as well as cells with ITGB3 interference. Further, phosphorylation of FAK, cRAF, MEK and ERK decreased in cells with integrin αvβ3 inhibition or interference. Invasion decreased in T-ALL cells treated with FAK and ERK inhibitors. In conclusion, inhibition of integrin αvβ3 signals significantly limits the cell invasion of T-ALL cells.
Characterization of the Impact of Merkel Cell Polyomavirus-Induced Interferon Signaling on Viral Infection

Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. ABSTRACT Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.
Viral metagenomics unveils MW (Malawi) polyomavirus infection in Brazilian pediatric patients with acute respiratory disease

Viral metagenomics has been extensively applied for the identification of emerging or poorly characterized viruses. In this study, we applied metagenomics for the identification of viral infections among pediatric patients with acute respiratory disease, but who tested negative for SARS‐CoV‐2. Twelve pools composed of eight nasopharyngeal specimens were submitted to viral metagenomics. Surprisingly, in two of the pools, we identified reads belonging to the poorly characterized Malawi polyomavirus (MWPyV). Then, the samples composing the positive pools were individually tested using quantitative polymerase chain reaction for identification of the MWPyV index cases. MWPyV‐positive samples were also submitted to respiratory virus panel testing due to the metagenomic identification of different clinically important viruses. Of note, MWPyV‐positive samples tested also positive for respiratory syncytial virus types A and B. In this study, we retrieved two complete MWPyV genome sequences from the index samples that were submitted to phylogenetic inference to investigate their viral origin. Our study represents the first molecular and genomic characterization of MWPyV obtained from pediatric patients in South America. The detection of MWPyV in acutely infected infants suggests that this virus might participate (coparticipate) in cases of respiratory symptoms. Nevertheless, future studies based on testing of a larger number of clinical samples and MWPyV complete genomes appear to be necessary to elucidate if this emerging polyomavirus might be clinically important.
T-cell–rich, large B-cell lymphoma in the brain of a horse

T-cell–rich, large B-cell lymphoma (TCRLBCL) is the most commonly diagnosed type of lymphoma in horses. Here we describe the clinical signs, neuropathology, immunohistochemistry (IHC), and PCR for antigen receptor rearrangement (PARR) analysis results of a TCRLBCL in the brain of an 8-y-old male Quarter Horse that was euthanized after acute anorexia, tremors, head pressing, falling, blindness, incoordination, and seizures. Autopsy revealed a firm, smooth, pale-yellow mass that expanded both lateral ventricles and the adjacent subcortical white matter. Histologically, the mass consisted of a densely cellular neoplasm composed of large, CD79+ neoplastic B-lymphocytes admixed with sheets of small, CD3+ reactive T-lymphocytes, Iba1+ histiocytes, MUM1+ plasma cells, and rare eosinophils supported by a fine fibrovascular stroma. Formalin-fixed, paraffin-embedded tissue scrolls were retrieved and subjected to PARR analysis, which revealed a clonal reaction in the immunoglobulin gene and a polyclonal reaction for the T-lymphocyte receptor gene, consistent with a neoplastic B-lymphocyte and reactive T-lymphocyte proliferation. The diagnosis of TCRLBCL was suspected histologically and confirmed based on IHC and PARR analysis.
Mechanism of assembly of type 4 filaments: everything you always wanted to know (but were afraid to ask)

Type 4 filaments (T4F) are a superfamily of filamentous nanomachines – virtually ubiquitous in prokaryotes and functionally versatile – of which type 4 pili (T4P) are the defining member. T4F are polymers of type 4 pilins, assembled by conserved multi-protein machineries. They have long been an important topic for research because they are key virulence factors in numerous bacterial pathogens. Our poor understanding of the molecular mechanisms of T4F assembly is a serious hindrance to the design of anti-T4F therapeutics. This review attempts to shed light on the fundamental mechanistic principles at play in T4F assembly by focusing on similarities rather than differences between several (mostly bacterial) T4F. This holistic approach, complemented by the revolutionary ability of artificial intelligence to predict protein structures, led to an intriguing mechanistic model of T4F assembly.
Withdrawal of antiseizure medications – for whom, when, and how?

ABSTRACT Introduction Epilepsy is a chronic disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. Most patients can achieve complete seizure control (seizure freedom) with antiseizure medications (ASMs). In some of them, the withdrawal of ASMs can be considered. Guidance is required to identify patients in whom drug discontinuation can be safely attempted and to inform when and how ASM withdrawal can be done. Areas covered In this perspective, the authors discuss the evidence on ASM withdrawal in epilepsy patients who are seizure-free and provide some suggestions on how to do it effectively in clinical practice, minimizing the risk of seizure recurrence. Expert opinion The decision of discontinuing ASMs in epilepsy patients should rely on an accurate estimate of seizure recurrence risk. Whenever possible, such a risk should be assessed on an individual basis. The decision should also consider the psychosocial and personal consequences of seizure relapse. No robust evidence is available on the safest tapering regimen.