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A case of polyparasitism in an 8-year-old female cat from Southern Brazil is reported. Among the described clinical signs, both gurltiosis and lagochilascariasis are of rare occurrence, being categorized as neglected diseases. The diagnosis of feline crural parasitic paraplegia was established through clinical signs, necropsy lesion observations, and the presence of Gurltia paralysans in histological sections of the spinal cord. Lagochilascaris minor was diagnosed with an ulcerated wound in the cervical region and further confirmed by coprology. In addition, other gastrointestinal parasites (i.e., Trichuris spp., Diphyllobothriidae, Toxocara cati, Ancylostoma spp., Cystoisospora spp., and Entamoeba spp.) were diagnosed through fecal examination and Sarcocystis felis by molecular analysis of muscle cysts. Aelurostrongylus abstrusus was detected in histological sections of lung parenchyma and confirmed by molecular analyses. The multiple parasitism detected in this case represents a unique report in terms of the number of parasites in the same individual, indicating the risk represented by stray cats as spreaders of zoonotic agents., Competing Interests: Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2 , encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral ( AAV ) vector-based approach. AAV9 /HPSE2, carrying human HPSE2 driven by CAG , was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9 /HPSE2 , the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9 /HPSE2 treatment. Therapeutically, AAV9 /HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy., Competing Interests: FL, CG, BJ, SA, AL, AG, WN, AW, NR No competing interests declared, SW is a co-founder of Bloomsbury Genetic Therapies and is a member of the SMAB of Forge Biologics, (© 2024, Lopes et al.)

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Objective: To assess regional and national mortality and years of life lost (YLL) related to adverse drug events in Brazil., Methods: This is an ecological study in which death records from 2009 to 2018 from the Mortality Information System were analyzed. Codes from the International Classification of Diseases 10th revision (ICD-10) that indicated drugs as the cause of death were identified. The number of deaths and the YLL due to adverse drug events were obtained. Crude, age- and gender-specific, and age-adjusted mortality rates and YLL rates per 100,000 inhabitants were formed by year, age group, gender, and Brazilian Federative Unit. Rate ratios were calculated by comparing rates from 2009 to 2018. A joinpoint regression model was applied for temporal analysis., Results: For the selected ICD-10 codes, a total of 95,231 deaths and 2,843,413 YLL were recorded. Mortality rates from adverse drug events increased by a mean of 2.5% per year, and YLL rates increased by 3.7%. Increases in rates were observed in almost all age groups for both genders. Variations in rates were found between Federative Units, with the highest age-adjusted mortality and YLL rates occurring in the Distrito Federal., Conclusions: The numbers and rates of deaths and YLL increased during the study period, and variations in rates of deaths and YLL were observed between Brazilian Federative Units. Information on multiple causes of death from death certificates can be useful for quantifying adverse drug events and analyzing them geographically, by age and by gender.

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation., (© 2024. The Author(s).)

Objective: Executive functions (EFs) are a multifaceted construct, important for several outcomes throughout life. The most commonly addressed executive components are inhibitory control, working memory, and cognitive flexibility. To map how other executive components are addressed conceptually and methodologically in the literature, a scoping review was carried out., Method: The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guideline was used. The database search (2017-2022) was carried out on the APA PsycInfo, Medline, Scopus, LILACS, and SciELO databases. A total of 3,473 articles were identified; 1,302 remained after screening. Given the large number of articles, a sample calculation was performed (95% CI and 5% error), with 297 articles randomly selected for full-text reading and 242 studies included for analysis., Results: There was a predominance of health application studies in adults and older adults and in developed countries. There is relative conceptual consensus that EF are a multidimensional construct; however, there is no explicit identification of the theoretical model used in the studies. A diversity of EF was evidenced, which broadens the understanding of the construct, its assessment, and intervention targets. Furthermore, there was a variety of instruments used to assess these skills, with a predominance of performance tests, often with construct-instrument ambivalence between studies., Conclusions: The mapping showed a diversity of skills referred to as EF in addition to the core components and identified the instruments used in their assessment. Greater conceptual and structural clarity and greater methodological care are fundamental to support the assessment of EF and their intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Congenital renal tract malformations (RTMs) are the major cause of severe kidney failure in children. Studies to date have identified defined genetic causes for only a minority of human RTMs. While some RTMs may be caused by poorly defined environmental perturbations affecting organogenesis, it is likely that numerous causative genetic variants have yet to be identified. Unfortunately, the speed of discovering further genetic causes for RTMs is limited by challenges in prioritising candidate genes harbouring sequence variants. Here, we exploited the computer-based artificial intelligence methodology of supervised machine learning to identify genes with a high probability of being involved in renal development. These genes, when mutated, are promising candidates for causing RTMs. With this methodology, the machine learning classifier determines which attributes are common to renal development genes and identifies genes possessing these attributes. Here we report the validation of an RTM gene classifier and provide predictions of the RTM association status for all protein-coding genes in the mouse genome. Overall, our predictions, whilst not definitive, can inform the prioritisation of genes when evaluating patient sequence data for genetic diagnosis. This knowledge of renal developmental genes will accelerate the processes of reaching a genetic diagnosis for patients born with RTMs., (© 2023. Springer Nature Limited.)

Cognitive-behavioral therapy (CBT) and neuropsychology are areas of psychology that have a common focus of interest on cognitive processing. The present study aimed to map and describe in a systematic way information about the association between CBT and neuropsychology by means of a scoping review. The systematic search for empirical articles published between 2010 and 2020, without language restriction, was carried out in the Medline, PsycInfo, LILACS, and SciELO databases. We found 3,723 articles, of which 198 were duplicates, which were excluded, and 3,525 articles went on to double-blind screening. For full text reading, we selected 323 articles, while 143 of them were selected for analysis. Results showed the characteristics, methodological aspects, and possible associations identified in the studies, which were as follows: neuropsychological assessment (NPA) and CBT assessment; NPA and CBT intervention; neuropsychological intervention and CBT intervention; and CBT strategy in neuropsychological intervention. The most used interventions were classic CBT, rehabilitation, and cognitive training, with the use of psychoeducation, cognitive restructuring, and problem solving, among others, applied, on the whole, to psychiatric and neurological conditions. We conclude that a greater understanding of the possible connections between the two areas can benefit patients from the psychiatric and neurological clinic.

Introduction: Urofacial, or Ochoa, syndrome (UFS) is an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. It also features an abnormal grimace. Half of individuals with UFS carry biallelic variants in HPSE2 , whereas other rare families carry variants in LRIG2. LRIG2 is immunodetected in pelvic ganglia sending autonomic axons into the bladder. Moreover, Lrig2 mutant mice have abnormal urination and abnormally patterned bladder nerves. We hypothesized that peripheral neurogenic defects underlie LRIG2 -associated bladder dysfunction., Methods: We describe a new family with LRIG2 -associated UFS and studied Lrig2 homozygous mutant mice with ex vivo physiological analyses., Results: The index case presented antenatally with urinary tract (UT) dilatation, and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with UT disease, characterizes UFS. Although HPSE2 sequencing was normal, he carried a homozygous, predicted pathogenic, LRIG2 stop variant (c.1939C>T; p.Arg647∗). Lrig2 mutant mice had enlarged bladders. Ex vivo physiology experiments showed neurogenic smooth muscle relaxation defects in the outflow tract, containing the urethra adjoining the bladder, and in detrusor contractility. Moreover, there were nuanced differences in physiological outflow tract defects between the sexes., Conclusion: Putting this family in the context of all reported UT disease-associated LRIG2 variants, the full UFS phenotype occurs with biallelic stop or frameshift variants, but missense variants lead to bladder-limited disease. Our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Analysis of differential gene expression from RNA-seq data has become a standard for several research areas. The steps for the computational analysis include many data types and file formats, and a wide variety of computational tools that can be applied alone or together as pipelines. This paper presents a review of the differential expression analysis pipeline, addressing its steps and the respective objectives, the principal methods available in each step, and their properties, therefore introducing an organized overview to this context. This review aims to address mainly the aspects involved in the differentially expressed gene (DEG) analysis from RNA sequencing data (RNA-seq), considering the computational methods. In addition, a timeline of the computational methods for DEG is shown and discussed, and the relationships existing between the most important computational tools are presented by an interaction network. A discussion on the challenges and gaps in DEG analysis is also highlighted in this review. This paper will serve as a tutorial for new entrants into the field and help established users update their analysis pipelines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)

This article describes the reporting characteristics of systematic reviews (SRs) in Psychology. The inclusion criteria were self-declared SRs in all branches of Psychology, published between 2019 and 2020. The search was performed in the PsycINFO and MEDLINE databases, from which 2487 records were identified, and 305 papers selected. There were many discrepancies in the reporting of Psychology SRs. Some PRISMA items, such as self-identification as an SR, description of the aim and the inclusion criteria, specification of the databases, and the description of the search and selection process using a flow diagram were reported in more than 90% of the SRs. Other items had lower coverage, such as the specification of the PICO framework, presentation of the complete search strategies, mention of the reporting guidelines, description of the exclusion criteria, performance of a risk of bias assessment, and analysis of the quality of the evidence, among others. The study highlights the need to improve the planning, performance and reporting of SR in Psychology.

Objective: To describe the frequency and characteristics of hospitalizations for/with adverse drug events in the Brazilian unified health system routine data., Methods: Nationwide retrospective study using data obtained from a period of ten years from the Brazil Hospital Information System (SIH-SUS), an administrative database that registers hospitalizations in the unified health system. We selected hospitalizations with primary and/or secondary diagnosis related to adverse drug events according to a list of validated International Classification Disease 10th edition (ICD-10) codes. These events were described according to year, age group, sex, length of hospital stay, mortality, hospital costs, Brazilian geographical region, and category of ICD-10 codes. Crude hospitalization rates of adverse drug events per 100,000 inhabitants were obtained and Joinpoint Regression was used to analyze temporal changes in these rates along the years. The most frequent ICD-10 codes were also identified., Results: Over ten years, 603,663 hospitalizations in Brazil were found in the database, out of which 2.5% of the patients died. Though 2009 had the highest prevalence of hospitalization per 100,000 inhabitants (32.57), no significant annual change in rates was found for the entire period. All age groups and sexes presented a jointpoint in temporal series; however, only women had a significative increase trend. The most frequent codes were from the chapter of mental and behavioral disorders (F19.2, F19.0, and F19.5 codes)., Conclusions: The database methodology can be useful to estimate frequencies of adverse drug events and perform characterization nationwide and to help monitor morbidity along the years.

Purpose: In glaucoma, initial visual field scotomas can be peripheral or central, whereas central scotomas are more severe and can disrupt daily activities. Individual anatomical features may influence the distribution of retinal nerve fibers and the starting site of visual field defects in glaucoma. In this study, we aimed to correlate myopia and hyperopia or anatomical variation of the disk-fovea angle with initial central or peripheral lesions in the visual field., Methods: This cross-sectional study included patients with primary open-angle glaucoma divided into a group of isolated central or peripheral scotomas in the visual field with MD > or equal to -6 dB, correlating with the degree of ametropia and anatomical variations, such as the disk-fovea angle., Results: We included 52 patients with glaucoma. Of 20 myopic patients, 6 (30%) had central scotomas, and 14 (70%) had peripheral scotomas. Of 32 hyperopic patients, 12 (37.5%) had central scotomas, and 20 (63.5%) had peripheral scotomas. Regarding the disk-fovea angle, 25 eyes had the disk-fovea angle of < -7°, with 9 (36%) eyes presenting with central scotoma, and 27 eyes presented with the disk-fovea angle of > -7°, with 9 (33.3%) eyes presenting with a central scotoma., Conclusion: This study showed an association between ametropia and scotomas on the perimetry in patients with glaucoma. Patients had a higher incidence of peripheral scotomas, but hyperopic patients had a greater number of central scotomas than myopic patients, and myopic patients had more peripheral scotomas than hyperopic patients. The disk-fovea angle was not correlated with scotomas in initial glaucoma.

Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) in 132 unrelated male PUV cases and 23,727 controls of diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (p=7.8 × 10 -12 ; OR 0.4) and rare variants at 6p21.1 (p=2.0 × 10 -8 ; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4151 controls. Fine mapping and functional genomic data mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7 , respectively, the encoded proteins of which were detected in the developing urinary tract of human embryos. We also observed enrichment of rare structural variation intersecting with candidate cis -regulatory elements, particularly inversions predicted to affect chromatin looping (p=3.1 × 10 -5 ). These findings represent the first robust genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate how a diverse ancestry seqGWAS can be used for disease locus discovery in a rare disease., Competing Interests: MC, OS, FL, AH, HS, CV, GB, WN, MZ, SW, YH, JC, DW, CM, AS, AK, RK, AW, DB, AL, DG No competing interests declared, (© 2022, Chan et al.)

Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2 , coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology., Competing Interests: Author ME was employed by the company Peak Proteins Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beaman, Lopes, Hofmann, Roesch, Promm, Bijlsma, Patel, Akinci, Burgu, Knijnenburg, Ho, Aufschlaeger, Dathe, Voelckel, Cohen, Yue, Stuart, Mckenzie, Elvin, Roberts, Woolf and Newman.)

The objective of this study is to conduct a systematic review and meta-analysis to assess the effect of psychosocial interventions in reducing problematic Internet use (PIU), anxiety, and depression symptoms in a sample of people. This review was registered on the PROSPERO database (CRD42020181912) and a total of 15 studies were included. Analyses of the effect of the interventions were conducted based on the standardized mean difference of the studied outcomes (PIU, anxiety, and depression). Most studies reported a positive effect of psychosocial interventions on reducing symptoms of PIU, depression, and anxiety among people with PIU. However, only one detected a robust effect in reducing symptoms of anxiety. For depression, this effect was more modest, and there was no difference between the different modalities of psychosocial interventions. The results suggest that psychosocial interventions are effective in reducing both symptoms of PIU and co-occurring symptoms of depression and anxiety in individuals with PIU., Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-022-00846-6., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

The physiological variations during the crustacean molting cycle have intrigued researchers for many years. Maintaining osmotic homeostasis in the face of hemolymph dilution and dealing with dynamic intracellular and extracellular calcium fluctuations are challenges these animals continuously confront. It has recently been shown that water channels present in the cell membrane (aquaporins) are essential for water uptake during premolt and postmolt. This study aims to investigate whether hypoosmotic shock and intracellular and extracellular calcium variations can lead to translocation of Aquaporin 1 (AQP-1) from the intracellular region to the plasma membrane during premolt and postmolt, thus allowing increased water flow in these stages. For this, we investigate in vitro the rapid change of AQP-1 positions in the abdominal muscle cells in the freshwater shrimp, Palaemon argentinus. Using cell volume analysis and immunohistochemistry, we show that hypoosmotic conditions and an elevation of the intracellular and extracellular calcium concentrations are concurrent with the translocation of AQP-1 to the plasma membrane. These results indicate that calcium flux and hypoosmotic shock may be regulators of AQP 1 in the translocation process., (© 2022 International Federation for Cell Biology.)

Introduction: Bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of anterior midline congenital malformations, involving the lower urinary tract. BEEC is usually sporadic, but families with more than one affected member have been reported, and a twin concordance study supported a genetic contribution to pathogenesis. Moreover, diverse chromosomal aberrations have been reported in a small subset of individuals with BEEC. The commonest are 22q11.2 microduplications, identified in approximately 3% of BEEC index cases., Objectives: We aimed to refine the chromosome 22q11.2 locus, and to determine whether the encompassed genes are expressed in normal developing and mature human urinary bladders., Results: Using DNA from an individual with CBE, the 22q11.2 duplicated locus was refined by identification of a maternally inherited 314 kb duplication (chr22:21,147,293-21,461,017), as depicted in this image. Moreover, the eight protein coding genes within the locus were found to be expressed during normal developing and mature bladders. To determine whether duplications in any of these individual genes were associated with CBE, we undertook copy number analyses in 115 individuals with CBE without duplications of the whole locus. No duplications of individual genes were found., Discussion: The current study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes are expressed in human bladders both during antenatal development and postnatally. Nevertheless, the precise biological explanation as to why duplication of the phenocritical region of 22q11 confers increased susceptibility to BEEC remains to be determined. The fact that individuals with CBE without duplications of the whole locus also lacked duplication of any of the individual genes suggests that in individuals with BEEC and duplication of the 22q11.2 locus altered dosage of more than one gene may be important in BEEC etiology., Conclusions: The study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes within this locus are expressed in human bladders., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: to assess the effects of an educational intervention on smoking cessation aimed at the nursing team., Method: this is a quasi-experimental study with 37 nursing professionals from a Brazilian hospital from May/2019 to December/2020. The intervention consisted of training nursing professionals on approaches to hospitalized smokers divided into two steps, the first, online, a prerequisite for the face-to-face/videoconference. The effect of the intervention was assessed through pre- and post-tests completed by participants. Smokers' medical records were also analyzed. For analysis, McNemar's chi-square test was used., Results: there was an increase in the frequency of actions aimed at smoking cessation after the intervention. Significant differences were found in guidelines related to disclosure to family members of their decision to quit smoking and the need for support, encouragement of abstinence after hospital discharge, and information on tobacco cessation and relapse strategies., Conclusion: the educational intervention proved to be innovative and with a great capacity for disseminating knowledge. The post-test showed a positive effect on the frequency of actions aimed at smoking cessation implemented by the nursing team.

Purpose: Adverse drug events are related to negative outcomes in healthcare, including hospitalization, increased duration of hospital stay and death. The aim of this study was to conduct a systematic review to evaluate hospitalizations and deaths related to adverse drug events worldwide, reported in studies with national coverage., Methods: The protocol was registered in PROSPERO (CRD42020157008). We performed a systematic search on Medline, Embase, CINAHL, LILACS, and the Cochrane Library (until March 2020) using pre-specified terms. We included published studies that reported data on hospitalizations and/or deaths related to adverse drug events from a national perspective and the use of secondary data as a source of information. Two reviewers independently extracted and synthesized data. The quality of the studies was assessed using an adapted version of the Joanna Briggs Institute critical appraisal checklist for prevalence studies. Narrative summaries of findings were undertaken., Results: Among 59,336 citations, 62 studies were included for data extraction and synthesis. Among these studies, 41 studies included the outcome of hospitalization, 16 included the death outcome, and five included both outcomes. Administrative databases regarding discharges and registries of vital statistics were the most common sources of information. The relative frequency of hospitalizations ranged from 0.03% to 7.3%, and from 9.7 to 383.0/100,000 population, whereas mortality rate ranged from 0.1 to 7.88/100,000 population., Conclusion: Our study highlights information about adverse drug events using large administrative databases in a national scenario and provides an overview of databases and methods implemented to detect adverse drug events., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We evaluated the association between risk behaviors and quality of life in 1,081 adolescents classified into the risk behavior (RB) or the non-risk behavior (nRB) group. The data were analyzed with logistic regression models, analysis of variance, and network analysis. The nRB group had higher quality-of-life scores, and having a religion (OR = .42) and better quality of life (OR = .95) significantly reduced the odds of risk behaviors. The network analysis identified that religion, gender, and type of school showed the best centrality and connectivity indices. These data showed a negative association between risk behaviors and lower quality-of-life levels.

The growth and popularization of platforms on scientific production has been the subject of several studies, producing relevant analyses of co-authorship behavior among groups of researchers. Researchers and their scientific productions can be analysed as co-authorship social networks, so researchers are linked through common publications. In this context, co-authoring networks can be analysed to find patterns that can describe or characterize them. This work presents the analysis and characterization of co-authorship networks of academic Brazilian graduate programs in computer science. Data from Brazilian researchers were collected and modeled as co-authoring networks among the graduate programs that researchers take part in. Each network topology was analysed with complex network measurements and three proposed qualitative indices that evaluate the publication's quality. In addition, the co-authorship networks of the computer science graduate programs were characterized in relation to the assessment received by CAPES, which attributes a qualitative grade to the graduate programs in Brazil. The results show the most relevant topological measurements for the program's characterization and the evaluations received by the programs in different qualitative degrees, relating the main topological patterns of the co-authorship networks and the CAPES grades of the Brazilian graduate programs in computer science., Competing Interests: The authors have declared that no competing interests exist.

The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1-independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U2OS cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover., (© 2021 Rusilowicz-Jones et al.)

Human urinary tract malformations can cause dysfunctional voiding, urosepsis and kidney failure. Other affected individuals, with severe phenotypes on fetal ultrasound screening, undergo elective termination. Currently, there exist no specific treatments that target the primary biological disease mechanisms that generate these urinary tract malformations. Historically, the pathogenesis of human urinary tract malformations has been obscure. It is now established that some such individuals have defined monogenic causes for their disease. In health, the implicated genes are expressed in either differentiating urinary tract smooth muscle cells, urothelial cells or peripheral nerve cells supplying the bladder. The phenotypes arising from mutations of these genes include megabladder, congenital functional bladder outflow obstruction, and vesicoureteric reflux. We contend that these genetic and molecular insights can now inform the design of novel therapies involving viral vector-mediated gene transfer. Indeed, this technology is being used to treat individuals with early onset monogenic disease outside the urinary tract, such as spinal muscular atrophy. Moreover, it has been contended that human fetal gene therapy, which may be necessary to ameliorate developmental defects, could become a reality in the coming decades. We suggest that viral vector-mediated gene therapies should first be tested in existing mouse models with similar monogenic and anatomical aberrations as found in people with urinary tract malformations. Indeed, gene transfer protocols have been successfully pioneered in newborn and fetal mice to treat non-urinary tract diseases. If similar strategies were successful in animals with urinary tract malformations, this would pave the way for personalized and potentially curative treatments for people with urinary tract malformations., Competing Interests: Conflicts of interest The authors have no conflict of interests to declare., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

MicroRNAs are small RNAs that negatively regulate gene expression and play an important role in fine-tuning molecular pathways during development. There is increasing interest in studying their function in the kidney, but the majority of studies to date use kidney cell lines and assess the total amounts of miRNAs of interest either by qPCR or by high-throughput methods such as next generation sequencing. However, this provides little information as to the distribution of the miRNAs in the developing kidney, which is crucial in deciphering their role, especially as there are multiple kidney cell types, each with its own specific transcriptome. Thus, we present a protocol for obtaining spatial information for miRNA expression during kidney development by in situ hybridization (ISH) of anti-miRNA, digoxigenin-labelled (DIG), Locked Nucleic Acid (LNA ® ) probes on (i) native human embryonic tissue and (ii) human pluripotent stem cell (hPSC)-derived 3D kidney organoids that model kidney development. We found that the method reveals the precise localization of miRNA in specific anatomical structures and/or cell types and confirms their absence from others, thus informing as to their specific role during development., Competing Interests: Competing interestsThe authors declare no competing interests., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

As consequence of the various genomic sequencing projects, an increasing volume of biological sequence data is being produced. Although machine learning algorithms have been successfully applied to a large number of genomic sequence-related problems, the results are largely affected by the type and number of features extracted. This effect has motivated new algorithms and pipeline proposals, mainly involving feature extraction problems, in which extracting significant discriminatory information from a biological set is challenging. Considering this, our work proposes a new study of feature extraction approaches based on mathematical features (numerical mapping with Fourier, entropy and complex networks). As a case study, we analyze long non-coding RNA sequences. Moreover, we separated this work into three studies. First, we assessed our proposal with the most addressed problem in our review, e.g. lncRNA and mRNA; second, we also validate the mathematical features in different classification problems, to predict the class of lncRNA, e.g. circular RNAs sequences; third, we analyze its robustness in scenarios with imbalanced data. The experimental results demonstrated three main contributions: first, an in-depth study of several mathematical features; second, a new feature extraction pipeline; and third, its high performance and robustness for distinct RNA sequence classification. Availability:https://github.com/Bonidia/FeatureExtraction&#95;BiologicalSequences., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy., (© 2021. The Author(s).)

Purpose: The development biosensing technologies capable of delivering fast and reliable analysis is a growing trend in drug quality control. Considering the emerging use of plant-based polyphenol oxidases (PPO) as biological component of electrochemical biosensors, this work reports the first Solanum lycocarpum PPO biosensor and its use in the pharmaceutical analysis of paracetamol in tablet formulations. Methods: The biosensor was optimized regarding fruit maturation (immature and mature-ripe), vegetal extract volume to be used in biosensor construction as well as optimal pH of electrochemical cell fluid. Results: Results evidenced that the extract which rendered the biosensor with best analytical performance was from immature fruits, and the biosensor produced using 100 µL of crude plant extract promoted better faradaic signal gathering. Moreover, when neutral pH media was used in the electrochemical cell, the biosensor showcased best faradaic signal output from the used redox probe (catechol), suggesting thence that the method presents high sensibility for phenolic compounds detection. Furthermore, the biosensor was able to quantify paracetamol in a linear range from 50 to 300 μM, showcasing LoD and LoQ of 3 μM and 10 μM, respectively. Conclusion: after careful evaluation, this biosensor might be a low-cost alternative for conventional pharmaceutical quality control methods., (©2021 The Authors.)

MicroRNAs (miRNAs) are gene expression regulators and they have been implicated in acquired kidney diseases and in renal development, mostly through animal studies. We hypothesized that the miR-199a/214 cluster regulates human kidney development. We detected its expression in human embryonic kidneys by in situ hybridization. To mechanistically study the cluster, we used 2D and 3D human embryonic stem cell (hESC) models of kidney development. After confirming expression in each model, we inhibited the miRNAs using lentivirally transduced miRNA sponges. This reduced the WT1 + metanephric mesenchyme domain in 2D cultures. Sponges did not prevent the formation of 3D kidney-like organoids. These organoids, however, contained dysmorphic glomeruli, downregulated WT1, aberrant proximal tubules, and increased interstitial capillaries. Thus, the miR-199a/214 cluster fine-tunes differentiation of both metanephric mesenchymal-derived nephrons and kidney endothelia. While clinical implications require further study, it is noted that patients with heterozygous deletions encompassing this miRNA locus can have malformed kidneys., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

This chapter provides two main contributions: (1) a description of computational tools and databases used to identify and analyze transposable elements (TEs) and circRNAs in plants; and (2) data analysis on public TE and circRNA data. Our goal is to highlight the primary information available in the literature on circular noncoding RNAs and transposable elements in plants. The exploratory analysis performed on publicly available circRNA and TEs data help discuss four sequence features. Finally, we investigate the association on circRNAs:TE in plants in the model organism Arabidopsis thaliana.

Mutations in PRKN are the most common cause of early onset Parkinson's disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in PRKN mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from PRKN mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Fibroblasts from 4 controls and 4 PRKN mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Direct conversion of control and PRKN mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a . This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC., (Copyright © 2020 Rieke, Zhang, Braun, Yilmaz, Japp, Lopes, Pleschka, Hilger, Schneider, Newman, Beaman, Nordenskjöld, Ebert, Promm, Rösch, Stein, Hirsch, Schäfer, Schmiedeke, Boemers, Lacher, Kluth, Gosemann, Anderberg, Barker, Holmdahl, Läckgren, Keene, Cervellione, Giorgio, Di Grazia, Feitz, Marcelis, Van Rooij, Bökenkamp, Beckers, Keegan, Sharma, Dakal, Wittler, Grote, Zwink, Jenetzky, Brusco, Thiele, Ludwig, Schweizer, Woolf, Odermatt and Reutter.)

Aquatic environments can be easily contaminated due to anthropogenic activities that may affect local biota. Microalgae are abundant and have an important role on the food chain. Consequently, they stand out as promising models for studies of contaminants. This study investigated the cytotoxic effects of atrazine and copper (separate and mixture) exposure in microalgae Desmodesmus communis, as well as its cellular defense due to ABC (ATP-binding cassette) proteins activity against the xenobiotics. We analyzed two different ABC proteins activity pathways: P-gp, which is responsible for nonspecific substance efflux, and MRP that is associated with metals efflux. It was observed that the microalgae exposure to atrazine (90 nM) and copper (141 nM) has been considered cytotoxic. When contaminants were mixed, only the combination of both highest concentrations tested was cytotoxic. The P-gp blocker, verapamil, demonstrated that the contaminants tested caused proteins inhibition. However, the MK-571 (MRP blocker) did not block pump activity. There was an inverse relationship between ABC protein activity and cytotoxicity; non-cytotoxic conditions suggest increased activity of microalgae defense proteins.

Objective: To describe the frequency and characteristics of adverse drug events in pediatric inpatients in a Brazilian tertiary teaching hospital., Methods: A cross-sectional study was conducted by retrospective and manual chart review of 240 pediatric admissions to identify adverse drug events using 17 triggers. When triggers were detected in the chart, reviewers investigated the chart in depth to decide whether an event occurred. Consensus about the occurrence of the event was obtained in meeting with a healthcare team. Events were classified by harm category and drugs were classified according to the Anatomical Therapeutic Chemical Classification. Patients who had suffered were compared to those who had not experienced events using the chi-squared test and the Mann-Whitney U test., Results: A total of 62 adverse events were found, and 18.8% of the patients had at least one event. Adverse events rates were 25.83 per 100 admissions, 20.27 per 1000 patient-days, 25.94 per 1000 drugs, and 2.12 per 1000 drug doses. All events found were classified as temporary harm, and cardiovascular drugs were most frequently related to events. Groups of patients with and without event were segregated (p<0.05) by the length of stay, number of drugs, and drug doses., Conclusion: The use of triggers demonstrated its utility in a pediatric setting by identifying harm. Adverse events rates were found to be higher than those of previous studies, but the harm rate was lower than other studies. This study enables the measurement of adverse events in order to define strategies to mitigate or reduce harm., (Copyright © 2019 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Objective: To evaluate aggressiveness in individuals receiving treatment for alcohol and crack cocaine use, both alone and in combination with one another, in order to compare them to control subjects with no history of drug problems, using the State-Trait Anger Expression Inventory. Method: The sample consisted of 67 men aged 18-65   years, divided into four groups: alcohol ( n  =   13); crack cocaine ( n  =   25); crack cocaine + alcohol ( n  =   16) and controls ( n  =   13). Participants completed the following instruments: socioeconomic questionnaire, the Wechsler Abbreviated Scale of Intelligence and the State-Trait Anger Expression Inventory. Results: Individuals with alcohol dependence alone, or comorbid with crack cocaine dependence, showed elevated levels of aggression and anger, though these varied according to the drug of abuse. Concurrent users of alcohol and crack cocaine had the highest levels of aggression, followed by isolated alcohol users, suggesting an association between alcohol consumption and aggression. Conclusion: The present findings suggest that alcohol and aggression levels may be associated with violent behavior. Concurrent use of alcohol and crack cocaine was related to higher levels of aggression, which may be associated with more severe alterations in behavior and impulse control.

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.

Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGFβ ligands, as well as Tgfbr1 and Tgfbr2 coding for TGFβ receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGFβ1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGFβ1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGFβ. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon-like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Purpose: Jenipapo fruit ( Genipa americana L) is a natural source of polyphenol oxidases (PPOs) whose potential in pharmaceutical analysis is noteworthy. Henceforth, this work reports the electrochemical study of a low-cost PPO-based biosensor produced from the crude extract of Jenipapo fruits and accounts a practical approach to employ this biosensor in the determination of methyldopa and paracetamol in pharmaceutical samples. Methods: In order to investigate the electrochemical properties of the biosensor, theoretical and practical approaches were employed, and both samples and the biosensor were analyzed through electrochemical impedance spectroscopy (EIS) and voltammetric techniques, namely: differential pulse voltammetry (DPV) and cyclic voltammetry (CV). Results: showcased that the biosensor presented good analytical features, as well as low detection limits (8 μmol L-1 for methyldopa and 5 μmol L-1 for paracetamol). The relative standard deviation was less than 5% mid-assay. Conclusion: The use of this biosensor is a reliable, low cost and useful alternative in the pharmaceutic determination of phenolic drugs (e.g. methyldopa and paracetamol)., (© 2019 The Author (s).)

Bradyrhizobium diazoefficiens CPAC 7 and Bradyrhizobium japonicum CPAC 15 are broadly used in commercial inoculants in Brazil, contributing to most of the nitrogen required by the soybean crop. These strains differ in their symbiotic properties: CPAC 7 is more efficient in fixing nitrogen, whereas CPAC 15 is more competitive. Comparative genomics revealed many transposases close to genes associated with symbiosis in the symbiotic island of these strains. Given the importance that insertion sequences (IS) elements have to bacterial genomes, we focused on identifying the local impact of these elements in the genomes of these and other related Bradyrhizobium strains to further understand their phenotypic differences. Analyses were performed using bioinformatics approaches. We found IS elements disrupting and inserted at regulatory regions of genes involved in symbiosis. Further comparative analyses with 21 Bradyrhizobium genomes revealed insertional polymorphism with distinguishing patterns between B. diazoefficiens and B. japonicum lineages. Finally, 13 of these potentially impacted genes are differentially expressed under symbiotic conditions in B. diazoefficiens USDA 110. Thus, IS elements are associated with the diversity of Bradyrhizobium, possibly by providing mechanisms for natural variation of symbiotic effectiveness., (© FEMS 2019.)

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853 ∗ ]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The urinary tract comprises the renal pelvis, the ureter, the urinary bladder, and the urethra. The tract acts as a functional unit, first propelling urine from the kidney to the bladder, then storing it at low pressure inside the bladder which intermittently and completely voids urine through the urethra. Congenital diseases of these structures can lead to a range of diseases sometimes associated with fetal losses or kidney failure in childhood and later in life. In some of these disorders, parts of the urinary tract are severely malformed. In other cases, the organs appear grossly intact yet they have functional deficits that compromise health. Human studies are beginning to indicate monogenic causes for some of these diseases. Here, the implicated genes can encode smooth muscle, neural or urothelial molecules, or transcription factors that regulate their expression. Furthermore, certain animal models are informative about how such molecules control the development and functional differentiation of the urinary tract. In future, novel therapies, including those based on gene transfer and stem cell technologies, may be used to treat these diseases to complement conventional pharmacological and surgical clinical therapies.

Background Drug-related problems are mostly preventable or predictable circumstances that may impact on health outcomes. Clinical pharmacy activities such as medication therapy management can identify and solve these problems, with potential to improve medication safety and effectiveness. Objective To evaluate ability of medication therapy management service to detect drug-related problems and prevent adverse drug events. This study also aimed to assess the risk factors for drugrelated problem occurrence. Setting Medical intensive care unit of a public tertiary hospital in Brazil. Methods Patients were evaluated by a clinical pharmacist, who provided medication therapy management service. Detected drug-related problems were categorized according to the Pharmaceutical Care Network Europe methodology and analyzed in multinomial regression to identify risk factors. Main outcome measure Potential risk factors for drug-related problem occurrence. Results The proposed medication therapy management service allowed detection of 170 drug-related problems that had potential to reach patients causing harm and other 50 unavoidable adverse events. Drug-related problems identified were more often associated with antibacterial use, caused by improper combinations or inadequate drug dosage. These problems required interventions that were accepted by the multidisciplinary team, resulting in more than 85% adherence and total problem solving. Main risk factors identified were previous diagnosis of kidney injury (OR = 8.38), use of midazolam (OR = 7.96), furosemide (OR = 5.87) and vancomycin (OR = 4.82). Conclusion Medication therapy management proved to be an effective method not only for drug-related problem detection, but also for adverse drug event prevention, contributing to improve patient safety.

Agribusiness has a great relevance in the world׳s economy. It generates a considerable impact in the gross national product of several nations. Hence, it is the major driver of many national economies. Nowadays, from each new planting to harvesting process it is mandatory and crucial to apply some kind of technology to optimize a given singular process, or even the entire cropping chain. For instance, digital image analysis joined with machine learning methods can be applied to obtain and guarantee a higher quality of the harvest, leading to not only a greater profit for producers, but also better products with lower cost to the final consumers. Thus, to provide this possibility this work describes a visual feature dataset from soybean seed images obtained from the tetrazolium test. This is a test capable to define how healthy a given seed is (e.g. how much the plant will produce, or if it is resistant to inclement weather, among others). To answer these questions we proposed this dataset which is the cornerstone to provide an effective classification of the soybean seed vigor (i.e. an extremely tiresome human visual inspection process). Besides, as one of the most prominent international commodity, the soybean production must follow rigid quality control process to be part of world trade. Hence, small mistakes in the seed vigor definition of a given seed lot can lead to huge losses.

In this work were studied the pH, thermal, and storage stability of free and immobilized laccases. Enzymes were produced by Pleurotus ostreatus on potato dextrose (PD) broth and potato dextrose modified (PDM) broth, and immobilized using Luffa cylindrica fibers as support. Both free and immobilized enzymes were assessed on their respective enzymatic activities and for 17α-ethinylestradiol (EE2) degradation. The optimum pH conditions concerning laccase activity ranged from 3.6 to 4.6, while temperature ranged between 30 °C and 50 °C for both free and immobilized enzyme. Laccase produced using PD broth presented greater storage stability and thermal stability than that of PDM. Best EE2 removals were of 79.22% and 75.00% for the free and immobilized enzymes, respectively. Removal rates were assessed during 8 h at pH 5. The removal of 17α-ethinylestradiol was stabilized in the fourth cycle of use. Results imply that immobilization promoted stability towards pH and temperature variations, although media played a decisive role in the enzymatic activity. Both free and immobilized laccases of P. ostreatus were able to degrade EE2, whereas immobilized laccase in PDM medium presented possible reuse applicability, albeit removal was not optimal when compared to other reports.

The ability to explant and then maintain embryonic tissues in organ culture makes it feasible to study the growth and differentiation of whole organs, or parts or combinations of them, in three dimensions. Moreover, the possible effects of biochemical manipulations or mutations can be explored by visualizing a growing organ. The mammalian renal tract comprises the kidney, ureter, and urinary bladder, and the focus of this chapter is organ culture of the embryonic mouse ureter in serum-free defined medium. Over the culture period, rudiments grow in length, smooth muscle differentiates, and the ureters then undergo peristalsis in a proximal to distal direction.

Objective: To describe the process of translation, adaptation, and validation of the Brazilian Portuguese version of the Pediatric Trigger Toolkit: Measuring Adverse Drug Events in the Children's Hospital., Methods: The validation process for the research instrument was carried out in five steps: (I) translation from English into Brazilian Portuguese by two independent translators; (II) synthesis of the translated versions; (III) adaptation of the triggers to the Brazilian context using a modified Delphi method carried out in two rounds; (IV) application of the research instrument in the review of 240 hospitalizations during 2014; and (V) back-translation from Brazilian Portuguese to English., Results: The translation step resulted in two versions, which were then synthesized to obtain equivalence within the Brazilian cultural context. The process of adapting the research instrument allowed the inclusion and adaptation of some triggers, as well as the exclusion of others, based on the consensus reached among experts during the Delphi step. The positive predictive value of the research instrument was 13.51%, and the antihistamine trigger presented the highest positive predictive value., Conclusion: The research instrument can be used to track the occurrence of adverse drug events in pediatric patients in Brazilian hospitals. Despite the adjustments made, triggers that were not identified or that had low positive predictive value can suggest the need for additional changes. However, more studies are needed before modifying or removing a trigger., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Objective: This study aimed to compare the use of trigger tools and non-targeted chart review as methods for the detection of adverse drug events in an intensive care unit considering the health system of a developing country., Methods: Patients were divided in groups that were submitted to different methods (trigger tool and non-targeted chart review) for adverse drug event detection. Medical records were retrospectively reviewed, and adverse drug events detected during the data collection were analyzed by a multidisciplinary team and classified according to their causality, predictability, severity and damage level., Results: The search for adverse events performed by trigger tools and non-targeted chart review allowed the identification of similar numbers of events (61.09 and 64.04 ADE/1000 patient-days, respectively), types of event and related drugs. In both groups, the most frequently detected adverse events were related to metabolic, gastrointestinal, cardiovascular and hematological systems. These organic systems matched the drugs most associated with adverse event occurrence: anti-infectives, antithrombotics and insulins. Events identified by non-targeted chart review presented higher causality relationships and were considered less severe than those observed by trigger tool use ( p  < 0.05)., Conclusion: The similar performance between these methods supports trigger tool applicability in the ICU routine, as this methodology requires less time to retrieve information from the medical records.

Glyphosate is the active component of many commonly used herbicides; it can reach bodies of water through irrigated rice plantations. In the present study, we evaluated the effect of glyphosate and Roundup ® (a glyphosate-based herbicide) in established culture of the zebrafish hepatocyte cell line ZF-L after 24 and 48 h of exposure to concentrations of 650 and 3250 µg/L. We observed a reduction in metabolic activity and lysosomal integrity, and an increase in cell number after 24 h of Roundup ® exposure at the highest concentration. An increase in active mitochondria and apoptotic cells was observed following 24 h exposure to glyphosate and Roundup ® , while only exposure to Roundup ® induced an increase in necrotic cells. Rhodamine B accumulation decreased after 48 h exposure to 650 µg/L of Roundup ® ; this reduction is indicative of increased activity of ABC pumps. Overall, the present findings highlighted the hazard of glyphosate exposure not only in the commercial formulation but also glyphosate alone, since both can induce damage in the ZF-L cell line primarily through the induction of apoptosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)