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Objectives: This study investigated regional trends in delays between the histological diagnosis of oral and oropharyngeal cancer and initiation of treatment across Brazil's federal units from 2013 to 2019., Methods: A retrospective, observational study was conducted using secondary data from the Brazilian Health System Database (DATASUS) for the years 2013-2019. Variables collected included the year of treatment, sex, age group, anatomical location, disease stage, treatment method, and federal unit of Brazil. Thematic maps were generated, and time series were analyzed using joint-point regression., Results: A total of 72,062 cases were included in the study. Majority of cases were of men (79.32%) and individuals older than 45 years (91.15%). Treatment was initiated earlier in younger patients, in cases of lip cancer, and among those who had undergone surgery. In 11 states, a significant decrease was observed in initiating treatment for oral cancer 60 days from diagnosis, whereas a significant increase was observed in three states. For oropharyngeal cancer, a significant decrease was observed in initiating treatment at 60 days from diagnosis in three states, whereas a significant increase was observed in five states., Conclusions: The findings revealed a high degree of heterogeneity in treatment delays for oral and oropharyngeal cancer across Brazil from 2013 to 2019. The northern states of Brazil exhibited a high percentage of treatment delays exceeding 60 days., (© 2025 American Association of Public Health Dentistry.) more...

Introduction: The erector spinae plane block (ESPB) has recently emerged as a regional anesthesia technique for perioperative pain management in pediatric cardiac surgery. However, evidence comparing its effectiveness with intravenous (IV) opioid-based analgesia is limited. We aimed to evaluate and compare the analgesic efficacy of ESPB versus IV opioids in this setting., Methods: We systematically reviewed and meta-analyzed studies comparing ESPB with IV opioid analgesia in pediatric cardiac surgeries with midline sternotomy. Primary outcomes were intraoperative fentanyl consumption and intensive care unit (ICU) length of stay (LOS). Secondary outcomes included postoperative opioid consumption, time to first rescue analgesia, pain scores, postoperative vomiting and other complications, extubation time, and hospital LOS. Statistical analyses were performed using RStudio version 4.2.3., Results: Five studies with 384 patients were included, with 178 receiving ESPB. ESPB significantly reduced intraoperative fentanyl use (MD -1.90 μg.kg -1 ; 95% CI -3.15 to -0.66 μg.kg -1 ; p = .003; I 2  = 58%) and ICU LOS (MD -3.50 h; 95% CI -4.32 to -2.69 h; p < .0001; I 2  = 0%). No significant differences were found in the remaining outcomes., Conclusion: Our findings suggest the ESPB might be an important adjunct to enhancing analgesia for midline sternotomies in pediatric cardiac surgery, potentially reducing intraoperative opioid requirements and ICU LOS., Prospero Registration: CRD 42024526961., (© 2024 The Author(s). Pediatric Anesthesia published by John Wiley & Sons Ltd.) more...

Introduction: Eating disorders can be irreversible and, in many cases, fatal. However, the symptoms full recovery is possible, and early diagnosis is one, of many, important factors for the success of treatment. In this sense, the screening of risk behaviours arises as a relevant alternative to improve the prognosis of patients. This review will analyse the diagnostic accuracy of self-administered screening tests for eating disorders in adolescent and adult users of primary healthcare., Methods and Analysis: A systematic review will be performed by independent reviewers. The databases used will be Medline, Embase, the Latin American and Caribbean Health Sciences Literature, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, PsycINFO, ProQuest Dissertations and Theses Database and Google Scholar without restrictions on the year of publication and language. Studies that compared the results of self-administered screening tests for eating disorders in adolescents and adults in primary care with the results of clinical interviews will be included. Data extraction will consist of the identification of the publication, study and participant characteristics, general information about the tools and data on the diagnostic accuracy properties. The risk of bias in the studies will be assessed via the Quality Assessment of Diagnostic Accuracy Studies. Qualitative data will be presented in narrative form. The meta-analysis will be conducted via the random effects model with the metadata command of Stata. The summary statistics for sensitivity and specificity, as well as their 95% CI, will be generated., Ethics and Dissemination: This systematic review is based on published literature; therefore, submission to an ethics committee is not necessary. The dissemination of the study will be carried out through technical reports, scientific articles, posters, meeting presentations, specific forums, national congresses and international media., Prospero Registration Number: CRD42023476156., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.) more...

This study aimed to investigate the static and dynamic rheological properties of an ultra-processed powdered goat milk beverage containing carboxymethyl cellulose (CMC), guar gum (GG), and xanthan gum (XG), using a mixture design. Fourteen samples were evaluated, in addition to the original beverage. The flow curves classified the fluids as non-Newtonian and characterized all the reconstituted beverages with pseudoplastic behavior, precisely due to the addition of hydrocolloids that increased the viscosity, and the fresh beverage sample showed the behavior of a dilatant fluid. The stress sweep verified the changes in the storage module (G') and the loss module (G″), the G' ranged from 1.97 to 20.36 (Pa) and the G″ ranged from 5.94 to 11.30 (Pa), demonstrating that there was the formation of beverages with elastic and viscous behaviors. The results showed a synergistic effect between the texture improvers, and the formulations with GG identified a greater effect on the tension. The frequency sweep tests showed that the behavior of the samples was that of a weak gel; however, when subjected to a certain frequency, the values of G' exceeded the value of G″, becoming a sample with more elastic characteristics and consequently, presenting the behavior of a stronger gel. Finally, according to the data presented, it is assumed that formulations containing GG and xanthan gum may produce desirable consumer properties for the reconstituted goat milk drink. Samples with a higher concentration of GG exhibited improved rheological performance, characterized by greater consistency, increased resistance to tension, and higher viscosity at low frequencies. PRACTICAL APPLICATION: The powdered goat milk drink is an innovative product that meets the demands of the food industry and consumers by offering a nutritious and sustainable beverage alternative., (© 2024 Institute of Food Technologists.) more...

Background: Elderly patients comprise an increasing proportion of patients undergoing surgery, and they require special attention due to age-related physiological changes. Propofol is the traditional agent for anaesthesia, and recently, remimazolam, a novel ultra-short-acting benzodiazepine, has emerged as an alternative to propofol in general anaesthesia., Objectives: We aim to compare remimazolam vs . propofol for general anaesthesia in elderly patients regarding hypotension, induction characteristics, haemodynamics and recovery outcomes., Design: Meta-analysis with sensitivity and trial sequential analyses (TSA) to assess inconsistencies. Risk ratios and mean differences with 95% confidence intervals (95% CIs) were computed using a random effects model. Subgroups and meta-regression according to anaesthesia methods were also performed., Data Sources: We systematically searched MEDLINE, Embase and Cochrane for randomised controlled trials (RCTs) up to January 1, 2024., Eligibility Criteria: Patients at least 60 years old, comparing remimazolam vs . propofol for general anaesthesia., Results: Eleven RCTs (947 patients) were included. Compared with propofol, remimazolam was associated with lower postinduction and intra-operative hypotension (RR 0.41, 95% CI 0.27 to 0.62, P  < 0.001) and incidence of bradycardia (risk ratio 0.58, 95% CI 0.34 to 0.98, P  = 0.04), with a higher heart rate ( P  = 0.01). The incidence of injection pain was lower ( P  < 0.001), but remimazolam was associated with a longer time to loss of consciousness ( P  < 0.001) and a higher bispectral index at loss of consciousness ( P  = 0.04). No differences were found for mean arterial pressure, emergence time, extubation time and incidence of emergence agitation. The TSA was consistent and achieved the required information size for hypotension., Conclusions: Remimazolam significantly reduced the risk of hypotension, bradycardia and injection pain, despite an increase in the time to loss of consciousness. Remimazolam appears to be an effective and well tolerated alternative to propofol in elderly patients undergoing general anaesthesia., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology.) more...

Supplementing swine diets with phytase increases phosphorus release by approximately 50% from cereal phytates. The increase in phosphorus availability allows for a reduction in dietary phosphorus supplementation from mineral sources and decreases the environmental impact of pork production through a decrease in phosphorus excretion. Superdosing phytase has been reported to boost swine productivity, improve the digestibility of other nutrients, and mitigate the antinutritional effects of phytates. However, there are significant cost differences among phytase products. Bacterial phytases are considered more modern, often with a higher cost of inclusion. A study was conducted with 288 piglets that were 21 d of age and weighed 6.43 ± 0.956 kg. Pigs were divided into four groups. Each group of pigs was fed a different experimental diet varying in phytase source and level: fungal phytase ( Aspergillus niger ) at 500 FTU/kg of diet, fungal phytase at 2,000 FTU/kg, bacterial phytase ( Escherichia coli ) at 500 FTU/kg, and bacterial phytase at 2,000 FTU/kg. No differences were found for phytase sources or doses on productivity at 14 and 21 d postweaning. However, piglets supplemented with 2,000 FTUs/kg of phytase in the diet during the first 21 d of nursery exhibited a 5.8% better feed conversion ( P  = 0.02). An interaction between phytase source and dose was observed for average live weight and daily weight gain over the 42-d nursery period ( P  < 0.05). Supplementing the diet with 2,000 FTU/kg of fungal phytase improved daily weight gain and live weight throughout the experimental period compared to piglets supplemented with 500 FTU/kg of the same phytase source. Additionally, it resulted in better final weights compared to piglets supplemented with 500 FTU/kg of bacterial phytase. Phytase inclusion at 2,000 FTU/kg improved feed conversion by 2.07% over the 42-d nursery period. The most economically favorable feed conversion ratios were observed when supplementing the diet with fungal phytase at 2,000 FTUs/kg., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science.) more...

Purpose: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases., Methods: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6 KozakGAL4 allele to assess the expression pattern of dYkt6., Results: Two individuals are homozygous for YKT6 [NM&#95;006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM&#95;006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes., Conclusion: The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys)., Competing Interests: Conflict of Interest BCM and Miraca Holdings have formed a joint venture with shared ownership and governance of BG, which performs clinical microarray analysis, clinical ES (cES), and clinical biochemical studies. James R. Lupski serves on the Scientific Advisory Board of the BG. James R. Lupski has stock ownership in 23andMe, is a paid consultant for Genomics International, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. Nhu Thao Nguyen Galván serves as a consultant for 3DSystems. Davut Pehlivan provides consulting service for Ionis Pharmaceuticals. Wendy K. Chung is on the Board of Directors of Prime Medicine and Rallybio. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.) more...

Background: To evaluate the influence of previous physical activity (PA) during childhood, adolescence, and current PA practice on the production of antibodies and inflammatory response between the first and second doses of the COVID-19 vaccine., Methods: Fifty-nine men and 56 women were evaluated before the first vaccine, and 12 weeks later, blood samples were taken to quantify production of anti-severe acute respiratory syndrome coronavirus-2 immunoglobulin G antibodies and cytokines. Previous PA during childhood and adolescence was self-referred, and current PA was assessed using the International Physical Activity Questionnaire., Results: A positive and significant association was observed only between PA practice during adolescence and an increase in antibody production in adulthood (β = 2012.077, 95% confidence interval, 257.7953-3766.358, P = .025). Individuals who practiced PA during adolescence showed higher production of antibodies between the first and second vaccine dose compared to nonpractitioners (P = .025) and those that accumulated ≥150 minutes per week of current moderate-vigorous PA (MVPA), and presented higher antibody production in relation to who did <150 minutes per week of MVPA (P = .046). Individuals that were practitioners during childhood produced higher G-CSF (P = .047), and those that accumulated ≥150 minutes per week of current MVPA demonstrated lower IP-10 levels (P = .033). However, PA practitioners during adolescence presented higher G-CSF (P = .025), IL-17 (P = .038), IL-1RA (P = .005), IL-1β (P = .020), and IL-2 (P = .026) levels., Conclusion: Our results suggest that adults that accumulated at least 150 minutes of MVPA per week or practiced PA during adolescence developed an improved immune and inflammatory response against COVID-19 vaccination. more...

The increased utilization of clinical genomic sequencing in the past decade has ushered in the era of genomic medicine, requiring genetics providers to acquire new skills and adapt their practices. The change in workplace responsibilities of clinical/medical geneticists (CMGs) and genetic counselors (GCs) in North America, due to the evolution of genetic testing, has not been studied. We surveyed CMGs (n = 80) and GCs (n = 127) with experience in general/pediatric genetics to describe their current practice of clinical tasks and the change in regularity of performing these tasks over the past 5-10 years. Currently, complementarity of responsibilities between CMGs and GCs clearly exists but providers who have been in the field for longer have noted role changes. Trends indicate that fewer experienced CMGs perform physical exams and select genetic tests than before and fewer experienced GCs complete requisitions and write result letters. The frequency of CMGs and GCs who investigate genetic test results, however, has increased. This study provides insight into the changing landscape of clinical genetics practice. Our findings suggest that the roles and responsibilities of CMGs and GCs have shifted in the past decade., (© 2023 Wiley Periodicals LLC.) more...

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy., Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician., Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants., Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG., (© 2023 International League Against Epilepsy.) more...

Mandacaru is a cactus with great socioeconomic potential, but lack of information about its cultivation hinders its domestication. Here, we aimed to evaluate the acclimatization and vegetative development of mandacaru under different substrates and irrigation levels. For this, seeds inoculated in vitro were grown for 120 days, being transplanted to pots containing four types of substrate (S1-caatinga soil + gravel; S2-washed sand + organic matter + soil + charcoal; S3-washed sand + cattle manure + soil + sand; S4-commercial organic substrate). Pots were irrigated with 100% of the field capacity (FC) once-a-week, or with 50% FC twice-a-week, and kept in a greenhouse for six months. The experimental design was completely randomized, in a 4 × 2 factorial scheme, with six replications. Plant height and diameter, axial and radial growth rate, fresh and dry mass of stem and root, water content, and photosynthetic pigments were determined. Growth was affected mainly by the substrate, with S4 resulting in higher growth and pigment content, while S1 was impaired and S2 and S3 resulted in intermediate growth. The use of S4 and 100% FC once per week was the best condition for mandacaru., (© 2023. The Author(s).) more...

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort., Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays., Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD., Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., Competing Interests: Conflict of Interest Renee Bend and Julie Rath are employees of PreventionGenetics, part of Exact Sciences. Michelle M. Morrow and Francisca Millan are employees of GeneDx, LLC. All other authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...

The aetiology of anorexia nervosa (AN) presents a puzzle for researchers. Recent research has sought to understand the behavioural and neural mechanisms of these patients' persistent choice of calorie restriction. This scoping review aims to map the literature on the contribution of habit-based learning to food restriction in AN. PRISMA-ScR guidelines were adopted. The search strategy was applied to seven databases and to grey literature. A total of 35 studies were included in this review. The results indicate that the habit-based learning model has gained substantial attention in current research, employing neuroimaging methods, scales, and behavioural techniques. Food choices were strongly associated with dorsal striatum activity, and habitual food restriction based on the self-report restriction index was associated with clinical impairment in people chronically ill with restricting AN. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and Regulating Emotions and Changing Habits (REaCH) have emerged as potential treatments. Future research should employ longitudinal studies to investigate the time required for habit-based learning and analyse how developmental status, such as adolescence, influences the role of habits in the progression and severity of diet-related illnesses. Ultimately, seeking effective strategies to modify persistent dietary restrictions controlled by habits remains essential. more...

Autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is a rare Mendelian disorder resulting from biallelic loss of function variants in Tubulin-Gamma Complex Associated Protein 6 (TUBGCP6, MIM#610053). Clinical features of this disorder include microcephaly, cognitive impairment, dysmorphic features, and variable ophthalmological anomalies including chorioretinopathy. Microcephaly can be recognized prenatally and visual impairment becomes evident during the first year of life. The clinical presentation resembles the findings in some acquired conditions such as congenital toxoplasmosis and cytomegalovirus infections; thus, it is important to recognize and diagnose this syndrome in view of its impact on patient health management and familial reproductive plans. To date, only seven molecularly confirmed patients from five unrelated families have been reported. We report an additional four unrelated patients with TUBGCP6 variants including one prenatal diagnosis and review the clinical phenotypes and genotypes of all the known cases. This report expands the molecular and phenotypic spectrum of TUBGCP6 and includes additional prenatal findings associated with MCCRP1., (© 2023 Wiley Periodicals LLC.) more...

The growing interest in a healthy lifestyle has contributed to disseminating perspectives on more sustainable natural resource management. This review describes promising aspects of using cacti in the food industry, addressing sustainable, nutritional, and functional aspects of the plant's production. Our study provides an overview of the potential of cacti for the food industry to encourage the sustainable cultivation of underutilized cactus species and their commercial exploitation. The commercial production of cacti has advantages over other agricultural practices by mitigating damage to ecosystems and encouraging migration to sustainable agriculture. The application of cactus ingredients in food development has been broad, whether in producing breads, jellies, gums, dyes, probiotics, and postbiotic and paraprobiotic foods. However, in the field of probiotic foods, future research should focus on technologies applied in processing and researching interactions between probiotics and raw materials to determine the functionality and bioactivity of products. more...

Staphylococcus lugdunensis produces lugdulysin, a metalloprotease that may contribute to its virulence. This study aimed to evaluate the biochemical aspects of lugdulysin and investigate its effect on Staphylococcus aureus biofilms. The protease was isolated and characterized for its optimal pH and temperature, hydrolysis kinetics, and influence of metal cofactor supplementation. The protein structure was determined via homology modeling. The effect on S. aureus biofilms was assessed by the micromethod technique. The protease optimal pH and temperature were 7.0 and 37 °C, respectively. EDTA inhibited protease activity, confirming it as a metalloprotease. Lugdulysin activity was not recovered by divalent ion supplementation post-inhibition, and supplementation with divalent ions did not change enzymatic activity. The isolated enzyme was stable for up to 3 h. Lugdulysin significantly inhibited the formation and disrupted preestablished protein-matrix MRSA biofilm. This preliminary study indicates that lugdulysin has a potential role as a competition mechanism and/or modulation of staphylococcal biofilm., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.) more...

Objective: Rare inherited missense variants in SLC32A1, the gene that encodes the vesicular gamma-aminobutyric acid (GABA) transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarify if de novo missense variants in SLC32A1 can also cause epilepsy with impaired neurodevelopment., Methods: Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathy and de novo missense variants in SLC32A1. To assess causality, we performed functional evaluation of the identified variants in a murine neuronal cell culture model., Results: The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the vesicular gamma-aminobutyric acid N-terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high-frequency stimulation. Thus, variants in vesicular gamma-aminobutyric acid can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity., Interpretation: This work establishes de novo missense variants in SLC32A1 as a novel cause of a developmental and epileptic encephalopathy. SUMMARY FOR SOCIAL MEDIA IF PUBLISHED: @platzer&#95;k @lemke&#95;johannes @RamiJamra @Nirgalito @GeneDx The SLC family 32 Member 1 (SLC32A1) is the only protein identified to date, that loads gamma-aminobutyric acid (GABA) and glycine into synaptic vesicles, and is therefore also known as the vesicular GABA transporter (VGAT) or vesicular inhibitory amino acid transporter (VIAAT). Rare inherited missense variants in SLC32A1, the gene that encodes VGAT/vesicular inhibitory amino acid transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarify if de novo missense variants in SLC32A1 can also cause epilepsy with impaired neurodevelopment. We report on four individuals with de novo missense variants in SLC32A1 and a developmental and epileptic encephalopathy with infantile onset epilepsy. We establish causality of the variants via in silico modeling and their functional evaluation in a murine neuronal cell culture model. SLC32A1 variants represent a novel genetic etiology in neurodevelopmental disorders with epilepsy and a new GABA-related disease mechanism. ANN NEUROL 2022;92:958-973., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.) more...

Ehlers-Danlos syndrome, hypermobility type (hEDS) is a heritable connective tissue disorder that currently does not have a known molecular etiology. Previous studies have explored the complex symptomology, clinical diagnosis, and psychological aspects of hEDS. Genetics providers currently aid in the diagnosis and management guidance of patients with hEDS, but there is limited data describing the needs and expectations of individuals with hEDS from a clinical genetics appointment. Our study sought to explore these items through the use of an online survey to assess participants' beliefs, needs and expectations (BNE) for genetic counseling as well as questions about demographics, hEDS symptoms, and current medical care. A total of 460 respondents with hEDS completed the survey. Most participants felt joint pain/weakness (n = 392; 88%) was one of the most disruptive symptoms of hEDS and 63% (n = 289) reported having psychiatric conditions. BNE scores were highest in two domains: expectations to have psychosocial concerns addressed during a genetic counseling appointment (mean score = 4.4/5; SD = 0.56) and desire for positive feelings after a genetic counseling session (mean score = 4.3/5; SD = 0.59). Participants who previously had genetic counseling felt less unsure about their diagnosis (p = 0.02) and had lower need for information about hEDS (p < 0.001). Majority of participants did not feel that their doctors were knowledgeable about hEDS (n = 269; 58%) and strongly supported a multidisciplinary approach to their care (n = 445; 97%). This research provides a framework for genetics providers and other healthcare professionals to assess the needs and expectations of patients with hEDS and consider re-structuring their appointment formats to service this population., (© 2022 Wiley Periodicals LLC.) more...

Anorexia nervosa (AN) and restrained eating behaviour (REB) are characterised by reduced food intake to achieve body weight loss. This scope review aimed to describe the existing evidence on the association between AN, restrictive eating behaviour and food consumption. Studies with children and adolescents of both sexes of all races and ethnicities were included. Experimental and observational studies, systematic reviews, meta-analysis, case reports or series, conference abstracts, dissertations and theses were also included. The search was conducted in ten electronic databases and grey literature without language restriction on 14 November 2020. Twenty-four studies met the inclusion criteria. Most studies included girls and identified lower intake of energy content, fat and certain micronutrients. There was also a higher intake of caffeine, fibre, vegetables, legumes and fruits and a lower intake of low-quality snack, fast food, sweets and foods with high carbohydrate and fat contents. The need to improve the quality of the diet among study participants was also identified. Thus, it is recommended that the evaluation of food consumption be careful to develop effective prevention strategies for the development of AN/REB and minimise nutritional deficiencies in these individuals. more...

Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown., Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID)., Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition., Conclusion: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism., Competing Interests: Conflict of Interest E.T., K.M., K.R., I.M.W., K.G.M., and L.R. are employees of GeneDx, LLC. K.R. is a shareholder of OPKO Health, Inc. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.) more...

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres., Competing Interests: The 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 Dharmadhikari, Pereira, Andrews, Macera, Harkavy, Wapner, Jobanputra, Levy, Ganapathi and Liao.) more...

Royal jelly is an essential substance for the development of bees from larval to adult stages. Studies have identified a group of key proteins in royal jelly, denominated major royal jelly proteins (MRJPs). The group currently consists of nine proteins (MRJP1-MRJP9), with MRJP1 being the most abundant and MRJP3 being used as a microsatellite marker for the selection of queens with a greater production of royal jelly. The diet of bees is mostly composed of proteins, and supplementing this intake to encourage a higher production of their primary product is important for producers. It is estimated that, by adding probiotic and prebiotic organisms to their diets, the benefits to bees will be even greater, both for their immune systems and primary responses to stress. Circumstances that are adverse compared to those of the natural habitat of bees eventually substantially interfere with bee behavior. Stress situations are modulated by proteins termed heat shock proteins (HSPs). Among these, HSP70 has been shown to exhibit abundance changes whenever bees experience unusual situations of stress. Thus, we sought to supplement A. mellifera bee colony diets with proteins and prebiotic and probiotic components, and to evaluate the expression levels of MRJP3 and HSP70 mRNAs using qRT-PCR. The results revealed that differences in the expression of MRJP3 can be attributed to the different types of feed offered. Significant differences were evident when comparing the expression levels of MRJP3 and HSP70, suggesting that protein supplementation with pre/probiotics promotes positive results in royal jelly synthesis carried out by honey bee nurses. more...

Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The ATP6AP1 gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in ATP6AP1 have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations. Although the most striking and common clinical feature is hepatopathy, the phenotypic and genotypic spectrum of ATP6AP1-CDG continues to expand. Here, we report identical twins who presented with acute liver failure and jaundice. Prenatal features included cystic hygroma, atrial septal defect, and ventriculomegaly. Postnatal features included pectus carinatum, connective tissue abnormalities, and hypospadias. Whole-exome sequencing (WES) revealed a novel de novo in-frame deletion in the ATP6AP1 gene (c.230&#95;232delACT;p.Tyr77del). Although both twins have the commonly reported clinical feature of hepatopathy seen in other individuals with ATP6AP1-CDG -related disorder, they do not have neurological sequelae. This report expands the phenotypic spectrum of ATP6AP1-CDG- related disorder with both probands exhibiting unique prenatal and postnatal features, including fetal ventriculomegaly, umbilical hernia, pectus carinatum, micropenis, and hypospadias. Furthermore, this case affirms that neurological features described in the initial case series on ATP6AP1-CDG do not appear to be central, whereas the prenatal and connective tissue manifestations may be more common than previously thought. This emphasizes the importance of long-term clinical follow-up and variant interpretation using current updated recommendations., (© 2022 Barua et al.; Published by Cold Spring Harbor Laboratory Press.) more...

The quest for an ideal biomaterial perfectly matching the microenvironment of the surrounding tissues and cells is an endless challenge within biomedical research, in addition to integrating this with a facile and sustainable technology for its preparation. Engineering hydrogels through click chemistry would promote the sustainable invention of tailor-made hydrogels. Herein, we disclose a versatile and facile catalyst-free click chemistry for the generation of an innovative hydrogel by combining chondroitin sulfate (CS) and polyethylene glycol (PEG). Various multi-armed PEG-Norbornene (A-PEG-N) with different molecular sizes were investigated to generate crosslinked copolymers with tunable rheological and mechanical properties. The crosslinked and mechanically stable porous hydrogels could be generated by simply mixing the two clickable Tetrazine-CS (TCS) and A-PEG-N components, generating a self-standing hydrogel within minutes. The leading candidate (TCS-8A-PEG-N (40 kD)), based on the mechanical and biocompatibility results, was further employed as a scaffold to improve wound closure and blood flow in vivo. The hydrogel demonstrated not only enhanced blood perfusion and an increased number of blood vessels, but also desirable fibrous matrix orientation and normal collagen deposition. Taken together, these results demonstrate the potential of the hydrogel to improve wound repair and hold promise for in situ skin tissue engineering applications. more...

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability. more...

Background: Weight stigma is a phenomenon associated with adverse behavioural and psychological consequences. Although experts suggest that its increase during the COVID-19 pandemic may be associated with worse health outcomes for people with obesity, a thorough analysis of the main findings and gaps is still needed when relating to this subject., Objective: We aim to answer three questions: (1) How does weight stigma manifest in the COVID-19 pandemic? (2) How can weight stigma affect people with overweight or obesity in times of COVID-19? (3) What are the perceptions and experiences of weight stigma during the pandemic in individuals who experience overweight or obesity?, Methods: We conducted a scoping review of studies addressing weight stigma and the COVID-19 pandemic in electronic databases (Medline/PubMed, CINAHL, Embase, PsycInfo, BVS/Lilacs, Scopus, Web of Science, Google Scholar, and OpenGrey) published until 10th August 2021. All relevant studies were reviewed in full by two researchers. In addition, a narrative synthesis of the data was performed., Results: The results included 35 studies out of 8,090 records and identified 13 original research publications, 14 text and opinion papers, and 6 narrative reviews. The results revealed the presence of weight stigma in the media, healthcare settings, interpersonal relationships, and public campaigns during the COVID-19 pandemic. The evidence of increasing weight stigma in the COVID-19 outbreak is limited, though. Many weight discrimination consequences were described during this time, such as impairment in accessing healthcare, worst COVID-19 outcomes, and maladaptive eating. However, only maladaptive behaviours and decline in mental health outcomes were demonstrated empirically in all age groups. This effect occurred regardless of body mass index, but people with high body weight were more likely to experience weight stigma. For some people with obesity, weight stigma in the pandemic has made activities of daily routine difficult., Conclusions: The results suggest that weight stigma in the COVID-19 pandemic occurs in several settings; moreover, although weight discrimination impacts mental health, whether before or during the pandemic, this influence between the pandemic and pre-pandemic scenario is still unclear. Therefore, more research is required in this field while the pandemic lasts, especially with people with obesity. Overall, people with overweight or obesity are more vulnerable to weight stigma than individuals without overweight. In addition, weight stigma refers to discrimination or prejudice based on a person's weight and relates to several consequences, for instance, poor healthcare treatment and mental health problems. In the COVID-19 outbreak, these weight stigma effects tend to become even more critical because they may be associated with unfavourable COVID-19 outcomes and eating disorder risks. Thus, it is crucial to investigate how weight stigma occurs during the pandemic and its impact on health, mainly for the most affected people. We investigated 35 studies published between 2019 and 2021 to map and explore how weight stigma was manifested and the related consequences for people with overweight or obesity in the COVID-19 pandemic. Only about a third of them were quantitative or qualitative, limiting the evidence of weight stigma in the COVID-19 context. The available evidence suggests that weight stigma manifests in several settings such as media, healthcare, public campaigns, and is more common in people with excess weight. However, weight discrimination experiences before or during the pandemic were associated with adverse psychological and behavioural consequences across all age groups, regardless of body weight. For some people with obesity, for instance, weight stigma made it difficult to accomplish their activities of daily routine. Nevertheless, it remains unclear whether weight stigma has increased in the pandemic, thus, more studies are required, especially about people with overweight or obesity., (© 2022. The Author(s).) more...

Background: Overlapping microdeletions of chromosome 3q26-3q28 have been reported in eight individuals. The common phenotype observed in these individuals include intrauterine growth restriction, short stature, microcephaly, feeding difficulties, facial dysmorphisms, limb abnormalities and developmental delay. The most striking clinical features shared among all reported cases is prenatal and postnatal growth restriction and neurodevelopmental abnormalities., Case Presentation: We identified two additional individuals with overlapping deletions and shared clinical features by high-resolution SNP oligonucleotide microarray, and refined the smallest region of overlap (SRO) to a 1.2 Mb genomic location in chromosome 3q27.1 by reviewing and comparing all published cases. We evaluated the SRO using ACMG/ClinGen current recommendations for classifying copy number variants (CNVs), and discussed the contribution of the genes deleted in the SRO to the abnormal phenotype observed in these individuals., Conclusions: This study provides further evidence supporting the existence of a novel 3q27.1 microdeletion syndrome and suggests that haploinsufficiency of potential candidate genes, DVL3, AP2M1, and PARL in the SRO in 3q27.1 is responsible for the phenotype., (© 2022. The Author(s).) more...

Lecithin-cholesterol acyltransferase (LCAT), an enzyme that participates in lipoprotein metabolism, plays an important role in cholesterol homeostasis. Mutations in the LCAT gene can cause two rare genetic disorders: familial LCAT deficiency (FLD), which is characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure, and fish-eye disease (FED), which causes dyslipidemia and progressive corneal opacities. Herein, we report six suspected cases of FLD in the backlands of Piauí, located in northeast Brazil. A genetic diagnosis was performed in index cases. Among these, a further investigation was performed to identify new cases in the families. In addition, molecular analyses were performed to verify the levels of consanguinity within families and the existence of a genetic relationship between them. All six index cases were confirmed as FLD with an identical mutation (c.803G > A, p.R268H). The genetic investigation confirmed another 7 new cases of FLD, 52 heterozygous and 6 individuals without mutations. The rate of consanguinity revealed that marriages within the family did not contribute to the high number of FLD cases within the restricted region. The elders of each family (patriarchs and matriarchs) were subjected to a kinship analysis and were more genetically related to each other than the control group. Bayesian analysis was implemented to confirm the hypothesis of connectivity among patriarchs and matriarchs and indicated that they were genetically more related to each other than would be randomly expected, thus suggesting the occurrence of a possible founder effect in these families., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors.) more...

Hypertensive disorders of pregnancy are closely associated with prematurity, stillbirth, and maternal morbidity and mortality. The onset of hypertensive disorders of pregnancy (HDP) is generally noticed after the 20th week of gestation, limiting earlier intervention. The placenta is directly responsible for modulating local and systemic physiology by communicating using mechanisms such as the release of extracellular vesicles, especially exosomes. In this study, we postulated that an analysis of exosome-enriched maternal plasma could provide a more focused and applicable approach for diagnosing HDP earlier in pregnancy. Therefore, the peripheral blood plasma of 24 pregnant women (11 controls, 13 HDP) was collected between 20th and 24th gestational weeks and centrifuged for exosome enrichment. Exosome-enriched plasma samples were analyzed by Raman spectroscopy and by proton nuclear magnetic resonance metabolomics ( 1 H NMR). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to analyze the Raman data, from the spectral region of 600-1,800 cm -1 , to determine its potential to discriminate between groups. Using principal component analysis, we were able to differentiate the two groups, with 89% of all variances found in the first three principal components. In patients with HDP, most significant differences in Raman bands intensity were found for sphingomyelin, acetyl CoA, methionine, DNA, RNA, phenylalanine, tryptophan, carotenoids, tyrosine, arginine, leucine, amide I and III, and phospholipids. The 1 H NMR analysis showed reduced levels of D-glucose, L-proline, L-tyrosine, glycine, and anserine in HDP, while levels of 2-hydroxyvalerate, polyunsaturated fatty acids, and very-low-density lipoprotein (VLDL) were increased. 1 H NMR results were able to assign an unknown sample to either the control or HDP groups at a precision of 88.3% using orthogonal partial least squares discriminant analysis and 87% using logistic regression analysis. Our results suggested that an analysis of exosome-enriched plasma could provide an initial assessment of placental function at the maternal-fetal interface and aid HDP diagnosis, prognosis, and treatment, as well as to detect novel, early biomarkers for HDP., Competing Interests: The 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 © 2021 Weingrill, Paladino, Souza, Pereira, Marques, Silva, da Silva Fonseca, Ursulino, Aquino, Bevilacqua, Urschitz, Silva and Borbely.) more...

Biological electroporation is a process of opening pores in the cell membrane when exposed to intense electric fields. This work provides results for validation of a dynamic model of electroporation on biological tissues. Computational simulations were carried out and results for the electrical current through the tissue and increase of the tissue temperature were compared to experimental results. Two calculation methods were used: Equivalent Circuit Method and Finite Element Method. With Equivalent Circuit Method the dielectric dispersion present in biological tissues was included. Liver, kidney and heart of rabbit were used in the experiments. Voltage pulse protocols and voltage ramps were applied using stainless steel needles electrodes. There is good agreement between the simulated and experimental results with mean errors below 15%, with the simulated results within the experimental standard deviation. Only for the protocol with fundamental frequency of 50 kHz, the simulation performed by the Finite Element Method using a commercial software did not correctly represent the current, with errors reaching 50%. The justification for the error found is due to the dielectric dispersion that was not included in this simulator., (© 2021. Biomedical Engineering Society.) more...

Artificial intelligence (AI)-based systems applied to histopathology whole-slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI-based automated prostate cancer detection system, Paige Prostate, when applied to independent real-world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required). We assessed the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) of a local pathologist, two central pathologists, and Paige Prostate in the diagnosis of 600 transrectal ultrasound-guided prostate needle core biopsy regions ('part-specimens') from 100 consecutive patients, and to ascertain the impact of Paige Prostate on diagnostic accuracy and efficiency. Paige Prostate displayed high sensitivity (0.99; CI 0.96-1.0), NPV (1.0; CI 0.98-1.0), and specificity (0.93; CI 0.90-0.96) at the part-specimen level. At the patient level, Paige Prostate displayed optimal sensitivity (1.0; CI 0.93-1.0) and NPV (1.0; CI 0.91-1.0) at a specificity of 0.78 (CI 0.64-0.89). The 27 part-specimens considered by Paige Prostate as suspicious, whose final diagnosis was benign, were found to comprise atrophy (n = 14), atrophy and apical prostate tissue (n = 1), apical/benign prostate tissue (n = 9), adenosis (n = 2), and post-atrophic hyperplasia (n = 1). Paige Prostate resulted in the identification of four additional patients whose diagnoses were upgraded from benign/suspicious to malignant. Additionally, this AI-based test provided an estimated 65.5% reduction of the diagnostic time for the material analyzed. Given its optimal sensitivity and NPV, Paige Prostate has the potential to be employed for the automated identification of patients whose histologic slides could forgo full histopathologic review. In addition to providing incremental improvements in diagnostic accuracy and efficiency, this AI-based system identified patients whose prostate cancers were not initially diagnosed by three experienced histopathologists. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.) more...

Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca 2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2-blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins-antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats., (Copyright © 2020. Published by Elsevier B.V.) more...

Context: Zinc is an essential trace mineral required for the function of brain and neural structures. The role of zinc supplementation in the prevention and treatment of depression has been suggested in clinical studies that reported a reduction in depressive symptoms., Objective: The aim of this review was to determine whether zinc supplementation vs placebo can prevent or improve depressive symptoms in children, adolescents, or adults., Data Sources: Five electronic databases were searched, and studies published until September 2019 were included without language restriction., Study Selection: Randomized, controlled, crossover trials that evaluated the effect of zinc supplementation vs a comparator for prevention or improvement of depressive symptoms in children, adolescents, or adults were eligible for inclusion., Data Extraction: Two authors independently performed data extraction and risk-of-bias assessment., Results: The initial search identified 12 322 studies, 5 of which were eligible for meta-analysis. The standardized mean difference (SMD) showed an average reduction of 0.36 point (95%CI, -0.67 to -0.04) in the intervention group compared with the placebo group. Forstudies in which the mean age of participants was ≥ 40 years, the SMD was reduced by 0.61 point (95%CI, -1.12 to -0.09) in the intervention group vs the placebo group. The meta-analysis by sample size (< 60 individuals and  ≥ 60 individuals) did not show an effect of zinc supplementation in reducing depressive symptoms (SMD -0.28; 95%CI, -0.67 to -0.10; and SMD -0.52; 95%CI, -1.10 to 0.06)., Conclusion: Zinc supplementation may reduce depressive symptoms in individuals treated with antidepressant drugs for clinical depression., Systematic Review Registration: PROSPERO registration number CRD42018081691., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

It is well known that intake of probiotic brings health benefits. Lactic bacteria with probiotic potential have aroused the interest of the industry in developing food products that incorporate such benefits. However, incorporating probiotic bacteria into food is a challenge for the industry, given the sensitivity of probiotic cultures to process conditions. Therefore, the objective of this study is to evaluate gelatin- and inulin-based filmogenic solutions as a potential vehicle for incorporating probiotics into food products and to model the fermentation kinetics. L. salivarius ( Lactobacillus salivarius ) growth in filmogenic solutions was analyzed under the influence of a variety gelatin concentrations (1.0-3.0%) and inulin concentrations (4.0-6.0%) and fermented under the effect of different temperatures (25-45 °C). A full 2 3 factorial plan with three replicates at the central point was used to optimize the process. The impacts of process conditions on cell development are fundamental to optimize the process and make it applicable by the industry. The present study showed that the optimal conditions for the development of probiotic cells in filmogenic solutions are a combination of 1.0% gelatin with 4.0% inulin and fermentation temperature of 45 °C. It was observed that the maximum cell growth occurred in an estimated time of about 4 h of fermentation. L. salivarius cell production and substrate consumption during the fermentation of the filmogenic solution were well simulated by a model proposed in this article, with coefficients of determination of 0.981 (cell growth) and 0.991 (substrate consumption). more...

Objective: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene., Methods: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca 2+ imaging., Results: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca 2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function., Interpretation: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca 2+ homeostasis in disease pathogenesis., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.) more...

Background: Excess Weight and Cardiovascular Diseases are health problems with increasing prevalence among children and adolescents, hence the need to investigate the issues related to them to better deal with the problem., Objective: To investigate the influence of excess adiposity on the levels of apolipoprotein B and A1 in children and adolescents., Methods: A systematic search was conducted in the PubMed, Embase, Lilacs, Web of Science, Ovid and Science direct databases, searching for cohort eligible studies and evaluating their results, methodological quality and risk of bias; combinable studies with good quality and low risk of bias were evaluated by meta-analysis. The summary measure used was the weighted mean difference (WMD) with its respective 95% confidence interval., Results: 8 articles attended the eligibility criteria including individuals with age mean varying from 9 to 15.7 years of age. The meta-analysis included 4 articles with a total of 7,974 children and adolescents. It was observed a mean increase of 4,94mg/dL (95%CI: 4,22 to 5,67) in the ApoB levels in individuals with excess of body adiposity. For the ApoA1, we identified a mean reduction of -8,13mg/dL (95%CI: -9,09 to -7,17 mg/dL) in its levels in children and adolescents with higher body adiposity. Beside this, the influence of excess adiposity on the ApoB and ApoA1 levels was higher between adolescents than children., Conclusions: The excess of body adiposity influenced both the reduction of ApoA1 values and the increase of ApoB levels, being these changes more relevant among adolescents. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0). more...

We report a case of a newly recognized primary immunodeficiency due to biallelic mutations in CARMIL2 manifesting as an actinic prurigo-like photodermatitis, allergic diathesis and recurrent infections in a child. We present this case to highlight a rare phenotype seen in this T-cell immunodeficiency and provide an overview of other dermatologic manifestations among published reports of this condition., (© 2020 Wiley Periodicals, LLC.) more...

Purpose: Exome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population., Methods: We undertook an SER to identify primary literature from January 2007 to March 2019 describing health, clinical, reproductive, and psychosocial outcomes resulting from ES/GS in patients with CA/DD/ID. A narrative synthesis of results was performed., Results: We retrieved 2654 publications for full-text review from 7178 articles. Only 167 articles met our inclusion criteria, and these were primarily case reports or small case series of fewer than 20 patients. The most frequently reported outcomes from ES/GS were changes to clinical management or reproductive decision-making. Two studies reported on the reduction of mortality or morbidity or impact on quality of life following ES/GS., Conclusion: There is evidence that ES/GS for patients with CA/DD/ID informs clinical and reproductive decision-making, which could lead to improved outcomes for patients and their family members. Further research is needed to generate evidence regarding health outcomes to inform robust guidelines regarding ES/GS in the care of patients with CA/DD/ID. more...

Objective: to present the indicators for monitoring and evaluation of oral health actions in the Brazilian National Health System (SUS), proposed in the period 2000-2017., Methods: documental research conducted on the Ministry of Health website regarding government guidelines on oral health monitoring and evaluation systems; the indicators were classified according to the following categories: access to care; resolutive capacity and continuity; and availability of oral health services., Results: oral health indicators were identified in the following guidelines: 'Health Services Performance Evaluation Methodology Project', 'SUS Qualification Evaluation Program', 'National Program for Improving Primary Care Access and Quality', and 'SUS Performance Index'; most of them refer to access to services and resolutive capacity and continuity of care., Conclusion: oral health indicators in the four government guidelines identified provide important input for health management, but new indicators are needed for effective monitoring and evaluation of oral health actions. more...

Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring., (© 2019 Wiley Periodicals, Inc.) more...