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Objective: Approximately 6 to 13% of women suffer from antenatal depression (AD) around the world. AD can lead to several health problems for mother-baby. Vitamin D is a molecule that appears to have great preventive/therapeutic potential against neuropsychiatric disorders. The present study aimed to analyze the association between deficiency of vitamin D and AD in pregnant women in a city in the south of Brazil (Pelotas, RS). We hypothesize that pregnant women with a positive AD diagnosis have deficient levels of 25-hydroxyvitamin D (25(OH)D)., Methods: This cross-sectional study was conducted in a cohort study (CEP/UCPEL 47807915.4.0000.5339). From this cohort, 180 pregnant women at up to 24 weeks gestation were selected (130 non-depressed and 50 depressed), and the diagnosis of depression was made using the MINI-Plus. Blood was collected and stored for the later analysis of vitamin D (25(OH)D) by chemiluminescence method. The SPSS program was used for data analysis, and p<0.05 was considered statistically significant., Results: In our study, we showed a significant association between Major Depressive Episode current in the antenatal period and vitamin D deficiency (OR: 0.9; CI 95%: 0.9;1.0, p=0.003)., Conclusion: Our results demonstrate that vitamin D deficiency may be involved in major depressive disorder in the antenatal period, in this way it advised a follow-up of vitamin D levels in the pregnancy-puerperal cycle to minimize mental health problems in women and prevent developmental deficits in children., Competing Interests: No conflicts of interest declared concerning the publication of this article.

The use of recreational waters is a widespread activity worldwide, and one of the risks associated with this practice is the exposure of bathers to microorganisms that may arise due to pollution caused by inadequate infrastructure and sanitation. In the present work, we isolated Candida spp. (n = 24) from five recreational beaches in Rio de Janeiro, Brazil, in order to evaluate their susceptibility to antifungals, the production of virulence attributes and the in vivo virulence using Tenebrio molitor larvae as a model. The ITS1-5.8S-ITS2 gene sequencing identified thirteen isolates (54.1 %) as C. tropicalis, seven (29.1 %) as C. krusei (Pichia kudriavzevii), one (4.2 %) as C. rugosa (Diutina rugosa), one (4.2 %) as C. mesorugosa (Diutina mesorugosa), one (4.2 %) as C. utilis (Cyberlindnera jadinii) and one (4.2 %) as C. parapsilosis. C. tropicalis isolates showed resistance to azoles and susceptibility to amphotericin B, flucytosine and caspofungin. C. krusei isolates were resistant to fluconazole, caspofungin and itraconazole, with 42.8 % resistance to flucytosine, besides susceptibility to voriconazole and amphotericin B. The remaining species were susceptible to all tested antifungals. All Candida isolates adhered to abiotic surfaces and formed biofilm on polystyrene, albeit to varying degrees, and produced aspartic protease and hemolytic activity, which are considered fungal virulence attributes. C. tropicalis, C. krusei and C. utilis isolates produced phytase, while the only esterase producer was C. tropicalis. Regarding resistance to osmotic stress, all isolates of C. tropicalis, C. parapsilosis and C. mesorugosa grew up to 7.5 % NaCl; the remaining isolates grew up to 1.87-3.75 % NaCl. The mortality caused by fungal challenges in T. molitor larvae was variable, with C. tropicalis, C. utilis and C. parapsilosis being more virulent than C. krusei and C. rugosa complex. Collectively, the presence of these yeasts, particularly the virulent and resistant isolates, in recreational waters can pose a significant health risk to bathers., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Leishmaniasis represents a severe global health problem. In the last decades, there have been significant challenges in controlling this disease due to the unavailability of licensed vaccines, the high toxicity of the available drugs, and an unrestrained surge of drug-resistant parasites, and human immunodeficiency virus (HIV)-Leishmania co-infections. Leishmania spp. preferentially invade macrophage lineage cells of vertebrates for replication after subverting cellular functions of humans and other mammals. These early events in host-parasite interactions are likely to influence the future course of the disease. Thus, there is a continuing need to discover a simple cellular model that reproduces the in vivo pathogenesis. Acanthamoeba spp. are non-mammalian phagocytic amoeba with remarkable similarity to the cellular and functional aspects of macrophages. We aimed to assess whether the similarity reported between macrophages and Acanthamoeba spp. is sufficient to reproduce the infectivity of Leishmania spp. Herein, we analyzed co-cultures of Acanthamoeba castellanii or Acanthamoeba polyphaga with Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania braziliensis. Light and fluorescence microscopy revealed that the flagellated promastigotes attach to the A. castellanii and/or A. polyphaga in a bipolar and or random manner, which initiates their uptake via pseudopods. Once inside the cells, the promastigotes undergo significant changes, which result in the obligatory amastigote-like intracellular form. There was a productive infection with a continuous increase in intracellular parasites. However, we frequently observed intracellular amastigotes in vacuoles, phagolysosomes, and the cytosol of Acanthamoeba spp. Our findings corroborate that Leishmania spp. infects Acanthamoeba spp. and replicates in them but does not cause their rapid degeneration or lysis. Overall, the evidence presented here confirms that Acanthamoeba spp. have all prerequisites and can help elucidate how Leishmania spp. infect mammalian cells. Future work exposing the mechanisms of these interactions should yield novel insights into how these pathogens exploit amoebae., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tuberculosis (TB), exceeded in mortality only by COVID-19 among global infectious diseases, is caused by Mycobacterium tuberculosis (Mtb). The pathogenicity of Mtb is largely attributed to its complex cell envelope, which includes a class of glycolipids called phosphatidyl-myo-inositol mannosides (PIMs), found uniquely in mycobacteria and its related corynebacterineae. These glycolipids maintain the integrity of the mycobacterial cell envelope, regulate its permeability, and mediate host-pathogen interactions. PIMs consist of a phosphatidyl-myo-inositol core decorated with one to six mannose residues and up to four acyl chains. The mannosyltransferase PimE catalyzes the transfer of the fifth PIM mannose residue from a polyprenyl phosphate-mannose (PPM) donor. This step in the biosynthesis of higher-order PIMs contributes to the proper assembly and function of the mycobacterial cell envelope; however, the structural basis for substrate recognition and the catalytic mechanism of PimE remain poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of PimE from Mycobacterium abscessus captured in its apo form and in a product-bound complex with the reaction product Ac1PIM5 and the by-product polyprenyl phosphate (PP), determined at 3.0 Å and 3.5 Å, respectively. The structures reveal the active site within a distinctive binding cavity that accommodates both donor and acceptor substrates/products. Within the cavity, we identified residues involved in substrate coordination and catalysis, which we confirmed through in vitro enzymatic assays and further validated by in vivo complementation experiments. Molecular dynamics simulations were applied to identify the access pathways and the dynamics involved in substrate binding. Integrating structural, biochemical, genetic, and computational experiments, our study provides comprehensive insights into how PimE functions, opening potential avenues for development of novel anti-TB therapeutics.

Purpose: Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese., Method: This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated off and on optimal medication. Inferential analyses included Disease (controls vs. PwPD) and Language (French vs. Portuguese) as factors, and random decision forest algorithms identified relevant acoustic variables able to distinguish participants: (a) by language (French vs. Portuguese) and (b) by clinical status (PwPD on and off medication vs. controls)., Results: French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative., Conclusions: Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive.

Objectives: We aimed to identify determinants of health-related quality of life (HRQoL) and global functioning and health (GH) in axial SpA (axSpA), peripheral SpA (pSpA) and (PsA)., Methods: The ASAS-perSpA study data were analysed. Models for the three patient groups were run separately to explore factors associated with HRQoL and GH, assessed by EQ-5D and ASAS-HI, respectively., Results: The analyses included 4185 patients: 2719 with axSpA, 433 with pSpA, and 1033 with PsA.In axSpA, disease activity (β = -0.061), physical function (β = -0.041), female sex (β = -0.019) and fibromyalgia (FM) (β = -0.068) were associated with worse HRQoL; age (β = 0.001) and university education (β = 0.014) were associated with better HRQoL. In pSpA, disease activity (β = -0.04) and physical function (β = -0.054) were associated with worse HRQoL. In PsA, disease activity (β = -0.045), physical function (β = -0.053), axial disease (β = -0.041) and female sex (β = -0.028) were associated with worse HRQoL. In axSpA, disease activity (β = 0.889), physical function (β = 0.887), peripheral disease (β = 0.564), female sex (β = 0.812) and FM (β = 1.639) were associated with worse GH; age (β = -0.013) and university education (β = -0.274) were associated with better GH. In pSpA, physical function (β = 1.142) and female sex (β = 1.060) were associated with worse GH; university education (β = -0.611) was associated with better GH. In PsA, disease activity (β = 0.703), physical function (β = 1.025), axial involvement (β = 0.659), female sex (β = 0.924) and FM (β = 1.387) were associated with worse GH; age (β = -0.024) and university education (β = -0.856) were associated with better GH., Conclusion: Disease activity and physical function are major HRQoL and GH determinants across SpA types, and clinical characteristics and sociodemographic factors play an important role, highlighting the importance of a holistic approach for individual patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We aimed to estimate the proportions of childhood parental neglect, abuse, and rejection and to evaluate the co-occurrence of these experiences among transgender women in Rio de Janeiro, Brazil. This was a cross-sectional study with a convenience sample enrolled between July 2019 and March 2020, using an adapted version of the Childhood Trauma Questionnaire. Proportions and corresponding confidence intervals (CI) were calculated. Kendall correlation with Tau-b estimator was used in the bivariate analyses. We gathered data from 139 participants. The most prevalent types of childhood traumas were emotional abuse (60.43%, 95% CI [51.79, 68.62]), physical abuse (57.55%, 95% CI [48.90, 65.89]) and sexual abuse (44.60%, 95% CI [36.18, 53.27]). Severe to extreme physical and emotional abuse occurred among 40.29% (95% CI [32.06, 48.93]) and 5.75% (95% CI [2.51, 11.02]) of participants, respectively. The proportion of parental rejection (eviction) was 32.37% (95% CI [25.04, 40.69]) and occurred with the other forms of abuse, except sexual abuse. Multiple types of childhood abuse, neglect, and parental rejection were observed among transgender women in our sample. The harmful effects of childhood abuse on the mental and physical health of people in the transgender population are of concern, particularly considering the cumulative effect produced by the co-occurrence of such events and their harmful lifetime effects. It is urgently necessary to debate and formulate public policies to ensure the right to gender expression from childhood., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Repressor element-1 silencing transcription factor (REST) is required for the formation of mature neurons. REST dysregulation underlies a key mechanism of neurodegeneration associated with neurological disorders. However, the mechanisms leading to alterations of REST-mediated silencing of key neurogenesis genes are not known. Here, we show that BRCA1 Associated ATM Activator 1 (BRAT1), a gene linked to neurodegenerative diseases, is required for the activation of REST-responsive genes during neuronal differentiation. We find that INTS11 and INTS9 subunits of Integrator complex interact with BRAT1 as a distinct trimeric complex to activate critical neuronal genes during differentiation. BRAT1 depletion results in persistence of REST residence on critical neuronal genes disrupting the differentiation of NT2 cells into astrocytes and neuronal cells. We identified BRAT1 and INTS11 co-occupying the promoter region of these genes and pinpoint a role for BRAT1 in recruiting INTS11 to their promoters. Disease-causing mutations in BRAT1 diminish its association with INTS11/INTS9, linking the manifestation of disease phenotypes with a defect in transcriptional activation of key neuronal genes by BRAT1/INTS11/INTS9 complex. Finally, loss of Brat1 in mouse embryonic stem cells leads to a defect in neuronal differentiation assay. Importantly, while reconstitution with wild-type BRAT1 restores neuronal differentiation, the addition of a BRAT1 mutant is unable to associate with INTS11/INTS9 and fails to rescue the neuronal phenotype. Taken together, our study highlights the importance of BRAT1 association with INTS11 and INTS9 in the development of the nervous system., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Globally, the counting of deaths based on gender identity and sexual orientation has been a challenge for health systems. In most cases, non-governmental organizations have dedicated themselves to this work. Despite these efforts in generating information, the scarcity of official data presents significant limitations in policy formulation and actions guided by population needs. Therefore, this manuscript aims to evaluate the accuracy, potential, and limits of probabilistic data relationships to yield information on deaths according to gender identity and sexual orientation in the State of Rio de Janeiro., Methods: This study evaluated the accuracy of the probabilistic record linkage to obtain information on deaths according to gender and sexual orientation. Data from two information systems were used from June 15, 2015 to December 31, 2020. We constructed nine probabilistic data relationship strategies and identified the performance and cutoff points of the best strategy., Results: The best data blocking strategy was established through logical blocks with the first and last names, birthdate, and mother's name in the pairing strategy. With a population base of 80,178 records, 1556 deaths were retrieved. With an area under the curve of 0.979, this strategy presented 93.26% accuracy, 98.46% sensitivity, and 90.04% specificity for the cutoff point ≥ 17.9 of the data relationship score. The adoption of the cutoff point optimized the manual review phase, identifying 2259 (90.04%) of the 2509 false pairs and identifying 1532 (98.46%) of the 1556 true pairs., Conclusion: With the identification of possible strategies for determining probabilistic data relationships, the retrieval of information on mortality according to sexual and gender markers has become feasible. Based on information from the daily routine of health services, the formulation of public policies that consider the LGBTQ + population more closely reflects the reality experienced by these population groups., (© 2024. The Author(s).)

The gut microbiome reflects health and predicts possible disease in hosts. A holistic view of this community is needed, focusing on identifying species and dissecting how species interact with their host and each other, regardless of whether their presence is beneficial, inconsequential, or detrimental. The distribution of gut-associated eukaryotes within and across non-human primates is likely driven by host behavior and ecology. To ascertain the existence of free-living amoebae (FLA) in the gut of wild and captive non-human primates, 101 stool samples were collected and submitted to culture-dependent microscopy examination and DNA sequencing. Free-living amoebae were detected in 45.4% (46/101) of fecal samples analyzed, and their morphological characteristics matched those of Acanthamoeba spp., Vermamoeba spp., heterolobosean amoeboflagellates and fan-shaped amoebae of the family Vannellidae. Sequence analysis of the PCR products revealed that the suspected amoebae are highly homologous (99% identity and 100% query coverage) with Acanthamoeba T4 genotype and Vermamoeba vermiformis amoebae. The results showed a great diversity of amoebae in the non-human primate's microbiome, which may pose a potential risk to the health of NHPs. To our knowledge, this is the first report of free-living amoebae in non-human primates that are naturally infected. However, it is unknown whether gut-borne amoebae exploit a viable ecological niche or are simply transient residents in the gut.

Introduction: Epilepsy, a neurological disorder characterized by recurring unprovoked seizures due to excessive neuronal excitability, is primarily attributed to genetic factors, accounting for an estimated 70 % of cases. Array-comparative genomic hybridization (aCGH) is a crucial genetic test for detecting copy number variants (CNVs) associated with epilepsy. This study aimed to analyze a cohort of epilepsy patients with CNVs detected through aCGH to enhance our understanding of the genetic underpinnings of epilepsy., Methods: A retrospective cross-sectional study was conducted using the aCGH database from the Genetics Department of the Faculty of Medicine of the University of Porto, encompassing 146 patients diagnosed with epilepsy, epileptic encephalopathy, or seizures. Clinical data were collected, and aCGH was performed following established guidelines. CNVs were classified based on ACMG standards, and patients were categorized into four groups according to their clinical phenotype., Results: Among the 146 included patients, 94 (64 %) had at least one CNV, with 22 (15.1 %) classified as pathogenic or likely pathogenic. Chromosomes 1, 2, 16, and X were frequently implicated, with Xp22.33 being the most reported region (8 CNVs). The phenotype "Epilepsy and global developmental delay/intellectual disability" showed the highest prevalence of clinically relevant CNVs. Various CNVs were identified across different groups, suggesting potential roles in epilepsy., Conclusions: This study highlights the significance of aCGH in unraveling the genetic basis of epilepsy and tailoring treatment strategies. It contributes valuable insights to the expanding knowledge in the field, emphasizing the need for research to elucidate the diverse genetic causes of epilepsy., Competing Interests: Declaration of competing interest 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., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Declaration of competing interest None.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients ( n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3 , the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

Objectives: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis., Methods: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference., Results: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented., Conclusions: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.

Introduction: Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD., Methods: Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP., Results/case Report: Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed., Conclusion: In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The inclusion of the "gender identity" field in the Brazilian violence surveillance system, although representing a step forward, still has limitations that may compromise epidemiological data validity. Existing response options for victims' identities do not adequately cover the diversity of this analysis category, resulting in classification biases. Additionally, the absence of options for cisgender identities reflects an approach that naturalizes these identities, while trans identities are considered deviant and subject to surveillance. To overcome these limitations, it is imperative to adopt a broader understanding of gender as a social and performative construction. This requires a reassessment of social structures and data collection instruments. In this context of discussion, this theoretical-methodological essay aims to reflect on gender identity measurement in the Reporting Diseases System interpersonal and self-inflicted violence surveillance system, taking as frameworks the theoretical conceptions about gender as a performative act and the foundations of validity in epidemiological investigations.

Glucose homeostasis is essential for energy production and the central nervous system function, depending on glycogen metabolism. Glycogen storage diseases (GSD) are caused by enzymatic defects of the glycogen degradation and mainly involve the liver since the inhibition of hepatic glycogen breakdown results in its excessive storage and hepatomegaly. Other findings are hypoglycemia and hyperlactatemia and consequent neurological symptoms. GSD Type Ia is a severe disease with clinical manifestations usually occurring in the first months. Morbidity and mortality are high, when not treated. The patient was a male newborn, with nonconsanguineous couple, born by eutocic delivery and weight 3760 g. On Day 2, weight loss >10% and jaundice were noticed, and physical examination was as normal. The investigation showed low glucose that only respond to iv glucose, metabolic acidosis, hyperlactatemia and elevated liver enzymes. Considering his inherited metabolic disease, he was transferred to the Reference Center. Complementary tests showed hypertriglyceridemia and absence of ketone bodies. Abdominal US revealed a liver in the upper limit of normal. Most likely clinical diagnosis was GSD type Ia, confirmed by genetic test. He needed iv glucose, but then stabilized with formula without galactose, supplemented with dextrin every 2 hours. He is now 7 months old, has flash glucose self-monitoring system, maintaining frequent feedings, with sporadic hypoglycemia with normal physical development and no hepatomegaly. Hypoglycemia and early weight loss in newborns are red flags for metabolic diseases or other conditions. When accompanied by other metabolic findings, such as hyperlactatemia and metabolic acidosis, associated with short fasting periods, glycogen metabolism disorders must be considered. Patients with GSD Type Ia generally appear normal at birth and an early presentation is not frequent within the first hours after birth. Moreover, avoiding fasting and hypoglycemia are of vital importance for better cognitive outcome, global prognosis, and prevention of other metabolic abnormalities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

Objective: To compare the 2-year retention rate between a second tumor necrosis factor alpha inhibitor (TNFi) and secukinumab (SEK) or ustekinumab (UST), in Psoriatic Arthritis (PsA) patients with previous inadequate response to their first TNFi., Methods: Prospective longitudinal cohort study with a follow-up period of 2 years using the Nationwide Portuguese Reuma.pt database. Patients with a clinical diagnosis of PsA who also fulfill the CASPAR classification criteria, with previous treatment failure to a first-line TNFi and having started a second biotechnological drug (TNFi, SEK or UST) were included. The Cycling group was defined as switching from a first TNFi to a second TNFi, and the Swapping group as switching from a first TNFi to SEK or UST. Sociodemographic data, disease characteristics, disease activity scores and physical function at baseline and after 6, 12 and 24 months were recorded. Cox-proportional hazards regression was used to compare retention rates between Cycling and Swapping groups. To obtain a predictor model of 2-year discontinuation, a multivariable Cox regression model was performed., Results: In total, 439 patients were included, 58% were female, with a mean age (standard deviation) of 49 (12) years. Globally, 75.6% initiated a second TNFi (Cycling group), and 24.4% started SEK/UST (Swapping group). The retention rates after 6, 12 and 24 months were 72%/66%/59% in the Cycling group; and 77%/66%/59% in the Swapping group. There were no significant differences in retention rates between both strategies (HR: 1.06, 95% CI 0.72-1.16). After 2 years of follow-up, 34.4% of patients discontinued their second biologic, mainly due to inefficacy (72.8%), with no differences found between groups. Baseline treatment with glucocorticoids was the only predictor of discontinuation after 2 years of follow-up (HR:1.668, 95% CI 1.154-2.409)., Conclusions: After failure of a first TNF inhibitor, Cycling and Swapping strategies result in similar retention rates suggesting that both are acceptable in the management of patients with psoriatic arthritis.

Objectives: Chronic low back pain (CLBP) is a common health problem and in most patients it is not possible to identify a specific cause (non-specific CLBP). Spondyloarthritis is a musculoskeletal disorder characterized by (often inflammatory) back pain and spinal stiffness. The impact of CLBP and spondyloarthritis on patients' physical function may be different. This study aims to compare physical disability in patients with spondyloarthritis and CLBP, in a population-based setting. Furthermore, we aim to identify modifiable risk factors for physical disability among these two populations., Methods: Data from EpiReumaPt, a national health cohort with 10 661 individuals, conducted from September 2011 to December 2013, was used. Physical function was accessed by the Health Assessment Questionnaire Disability Index (HAQ-DI) and by the physical function dimension of the 36-Item Short Form Survey (SF-36). Univariable and multivariable linear regression analyses were used to assess the differences between groups. Factors associated with physical disability were explored for both diseases., Results: We evaluated 92 patients with spondyloarthritis, 1376 patients with CLBP and 679 subjects without rheumatic and musculoskeletal diseases (RMDs). Spondyloarthritis and CLBP patients reported significantly higher levels of disability in HAQ-DI (ß=0.33; p < 0.001 and ß=0.20; p < 0.001, respectively) than subjects without RMDs. In comparison to CLBP patients, spondyloarthritis patients reported higher disability (ß=0.14; p=0.03). The physical domains of SF-36, bodily pain and general health, where more affected in spondyloarthritis patients than in CLBP patients (ß=-6.61; p=0.02 and ß=-5.94; p=0.001, respectively). Spondyloarthritis and CLBP patients had a worse physical summary score (PCS) than mental summary score (MCS), and only PCS was significantly worse in comparison to subjects without RMDs. Factors associated with physical disability in CLBP were low back pain intensity, older age, obesity, multimorbidity, and retirement. Similarly, in spondyloarthritis physical disability was associated with retirement and multimorbidity. Factors associated with lower disability were alcohol consumption and male gender in CLBP, and regular physical exercise was associated with lower disability in both disorders., Conclusions: In this nationwide cohort, spondyloarthritis and CLBP patients reported significant physical disability. Regular physical exercise was associated with lower disability in both diseases.

Abnormal prion proteins (PrP Sc ) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrP Sc by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrP Sc patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrP Sc IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrP Sc immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.

Objectives: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA)., Methods: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression., Results: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19., Conclusion: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics., Competing Interests: Competing interests: PMM has received honoraria from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). MS reports a joint, unconditional grant from a consortium of 14 companies supporting the German RABBIT register (AbbVie, Amgen, BMS, Fresenius Kabi, Galapagos, Hexal, Lilly, MSD, Pfizer, Roche, Samsung, Sanofi, Viatris and UCB). SKM reports departmental income from AbbVie, Almirall, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, UCB, outside the submitted work. JL has nothing to disclose. LG reports personal consultant fees/honoraria/travelling support from AbbVie, Amgen, Bristol-Myers Squibb, Biogen, Celgene, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, and UCB, and grants from Sandoz and UC, all unrelated to this manuscript. ND has nothing to disclose. AP has nothing to disclose. AS reports a joint, unconditional grant from a consortium of 14 companies supporting the German RABBIT register (AbbVie, Amgen, BMS, Fresenius Kabi, Galapagos, Hexal, Lilly, MSD, Pfizer, Roche, Samsung, Sanofi, Viatris and UCB) and personal fees from lectures for AbbVie, Amgen, Celltrion, MSD, Janssen, Lilly, Roche, BMS and Pfizer, all unrelated to this work. ACR reports a joint, unconditional grant from a consortium of 12 companies supporting the German RABBIT-SpA register (AbbVie, Amgen, Biogen, Celltrion, Hexal, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, Viatris and UCB) and personal fees from lectures for Novartis, Roche, and Pfizer, all unrelated to this work. BF has nothing to disclose. CGA has nothing to disclose. CGSS has nothing to disclose. CEMG reports grants and/or personal fees from AbbVie, Almirall, Amgen, Anaptysbio, BMS, Boehringer-Ingelheim, Evelo Bioscience, Inmagene, GSK, Janssen, Kyowa Kirin, LEO, Lilly, Novartis, ONO Pharmaceutical, Pfizer and UCB Pharma, outside the submitted work. CL has nothing to disclose. CM-R has nothing to disclose. DW has received personal speaker/consultant fees from AbbVie, BMS, MSD, Pfizer, Roche Chugai, Amgen, Nordic Pharma, UCB, Novartis, Janssen, Lilly, Sandoz, Grunenthal, Galapagos. DAR is Scientific Advisor for GSK, unrelated to this work. DW has nothing to disclose. EFM has received personal consultant fees from Boehringer Ingelheim Portugal, Lda; LPCDR received support for specific activities: grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal S.A., MSD, Medac and from A. Menarini Portugal-Farmacêutica, S.A.; grants and non-financial support from Pfizer, and non-financial support from Grünenthal GmbH, outside the submitted work. ES has nothing to disclose. ESR reports grants/contracts from Novartis, Pfizer, Amgen and Elea, honoraria from Amgen, Abbvie, BMS, Eli Lilly, Janssen, Novartis, Pfizer, Sandoz, and UCB, support for attending meetings from Abbvie, Pfizer, UCB, and Janssen, and participation on data safety monitoring board or advisory board from Abbvie, Janssen, Pfizer, Amgen, Sandoz and Novartis. FMR has nothing to disclose. FO has nothing to disclose. FRM has nothing to disclose. HS has nothing to disclose. JD has nothing to disclose. JNB reports grants and/or personal fees from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Meyers-Squibb, J&J, LEO Pharma, Lilly, Novartis, Pfizer, Samsung, Sun Pharma, and UCB, outside of the submitted work. JH has nothing to disclose. KLH has received non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. LG has received consulting fees and/or research support from Abbvie, Acelyrin, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer and UCB, all unrelated to this manuscript, and research support from UCB. LS has nothing to disclose. LJ has nothing to disclose. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, S.A., Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal GmbH and UCB Pharma. MMP has nothing to disclose. MDZ has nothing to disclose. MdlAS has nothing to disclose. MY has nothing to disclose. MD has nothing to disclose. NG-S has nothing to disclose. NR has nothing to disclose. NH has received consulting fees from Abbvie, Eli Lilly, Janssen, Novartis and UCB. PS has nothing to disclose. RG has received consulting/speaker’s fees from Abbvie, Janssen, Novartis, Pfizer, and Cornerstones, all unrelated to this manuscript, and travel grants from Pfizer and Janssen. RH reports consulting fees from AbbVie, GSK, Novartis, Pfizer, Amgen, Biogen, BMS, Galapagos, Lilly, Mylan, Gilead, Janssen, TAKEDA/Shire, Roche/Chugai, research grant from Pfizer, all unrelated to this manuscript. SL-T has nothing to disclose. SB reports consulting fees from AbbVie, Horizon, Novartis, and Pfizer, and is an employee of Pfizer, Inc. TP reports personal consultant fees from Abbvie, Amgen, Biogen, BMS, Celgene, Celltrion, Fresenius-Kabi, Galapagos, Gilead, Janssen, Lilly, MSD, Nordic, Novartis, Pfizer, Roche-Chugai, Sandoz, Sanofi and UCB, all unrelated to this manuscript. TO reports consultancy fees from Merck Sharp & Dohme, unrelated to the present work. WBM has received personal speaker/consultant fees from AbbVie, Pfizer, Amgen, Novartis, Janssen, Lilly, Biopas. ZSW has nothing to disclose. ZZNY has nothing to disclose. JY is supported by NIH/NIAMS K24 AR07534 and AHRQ R01HS028024. She has received research grants from Gilead, Aurinia, BMS Foundation and Astra Zeneca and performed consultation for Astra Zeneca, Pfizer, and Aurinia. PCR has nothing to disclose. CHS reports grants from AbbVie, Sanofi, Novartis, and Pfizer and through consortia with multiple academic partners (psort.org.uk, BIOMAP-IMI.eu), outside the submitted work; she is a member of the British Association of Dermatologists Guideline committee on biologics in psoriasis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

MicroRNA (miRNA) homeostasis is crucial for the posttranscriptional regulation of their target genes during development and in disease states. miRNAs are derived from primary transcripts and are processed from a hairpin precursor intermediary to a mature 22-nucleotide duplex RNA. Loading of the duplex into the Argonaute (AGO) protein family is pivotal to miRNA abundance and its posttranscriptional function. The Integrator complex plays a key role in protein coding and noncoding RNA maturation, RNA polymerase II pause-release, and premature transcriptional termination. Here, we report that loss of Integrator results in global destabilization of mature miRNAs. Enhanced ultraviolet cross-linking and immunoprecipitation of Integrator uncovered an association with duplex miRNAs before their loading onto AGOs. Tracing miRNA fate from biogenesis to stabilization by incorporating 4-thiouridine in nascent transcripts pinpointed a critical role for Integrator in miRNA assembly into AGOs.

Background: Copy number variations (CNVs) on chromosome 2 are associated with a variety of human diseases particularly neurodevelopmental disorders. Array comparative genomic hybridization (aCGH) constitutes an added value for the diagnosis of neurodevelopmental or neuropsychiatric diseases. This study aims to establish a genotype-phenotype correlation, reporting CNVs on the chromosome 2, contributing for a better characterization of the molecular significance of rare CNVs in this chromosome., Methods: To accomplish this, a cross-sectional study was performed using genetic information included in a database of the Department of Genetics of the Faculty of Medicine and clinical data from Hospital database. CNVs were classified as pathogenic, benign, variants of unknown significance, and likely pathogenic or likely benign, in accordance with the ACMG Standards and Guidelines., Results: A total of 2897 patients were studied using aCGH, 32 with CNVs on chromosome 2, 24 classified as likely pathogenic, and 8 as pathogenic. Genomic intervals with a higher incidence were one 2p25.3 and 2q13 regions., Conclusions: This study will help to establish new genotype-phenotype correlations, allowing update of databases and literature and the improvement of diagnosis and genetic counseling which could be an added value for prenatal genetic counseling., Competing Interests: None., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of PBJ-Associação Porto Biomedical/Porto Biomedical Society. All rights reserved.)

Purpose: Both spondyloarthritis and chronic low back pain (CLBP) significantly impact health-related quality of life (HRQoL). It is important to clarify whether these disorders have different impacts on the several domains of HRQoL as different mechanisms may necessitate different treatment interventions. Moreover, the factors associated with HRQoL can inform more targeted group interventions to promote HRQoL., Methods: We used data from EpiReumaPt, a population-based survey conducted from September 2011 to December 2013. HRQoL was assessed with EuroQoL-5-Dimensions (EQ-5D). Spondyloarthritis was diagnosed by expert opinion (rheumatologist) and predefined criteria. CLBP was diagnosed if low back pain was present on the day of the interview and persisted for > 90 days. Univariable and multivariable linear regression analyses compared HRQoL among subjects with spondyloarthritis, CLBP, and no rheumatic diseases. Multivariable linear regression analyses evaluated HRQoL factors in spondyloarthritis and CLBP subjects., Results: We included 92 spondyloarthritis patients, 1376 CLBP patients, and 679 subjects without rheumatic diseases. HRQoL was similarly affected in spondyloarthritis and CLBP (ß =  - 0.03, 95% CI [- 0.08; 0.03]) in all EQ5D dimensions. A much lower HRQoL was found in spondyloarthritis and CLBP patients compared with subjects without rheumatic diseases (ß =  - 0.14, 95% CI [- 0.19; - 0.10]; ß =  - 0.12, 95% CI [- 0.14; - 0.09], respectively). In spondyloarthritis subjects, multimorbidity and active disease were associated with worse HRQoL (ß =  - 0.18; 95% CI [- 0.24; 0.03]; ß =  - 0.13; 95% CI [- 0.29; - 0.05], respectively), and regular physical exercise was associated with better HRQoL (ß = 0.18; 95% CI [0.10; 0.30]). In CLBP subjects, multimorbidity (β =  - 0.11; 95% CI [- 0.14; - 0.08]), obesity (β =  - 0.04; 95% CI [- 0.08; - 0.01]), and low back pain intensity (β =  - 0.02; 95% CI [- 0.03; - 0.02]) were associated with worse HRQoL, and regular physical exercise (β = 0.08; 95% CI [0.05; 0.11]) was significantly associated with better HRQoL., Conclusion: Spondyloarthritis and CLBP subjects reported similar levels of impairment in the mental, physical, and social domains of HRQoL. Future health plans should address modifiable factors associated with HRQoL in these conditions to achieve better outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Violence is a major social problem in Brazil, with severe repercussions on the health care sector. Primary health care professionals, especially community health workers (CHWs), are at high risk of violence at facilities and in the socially vulnerable area where they work. This study analyzed the relationships between adverse working conditions and dimensions of localized violence on the prevalence of common mental disorders (CMD) among CHWs in Fortaleza, a state capital in Northeastern Brazil. Information was collected with a self-report questionnaire containing items on sociodemographic data, work-related violence, psychoemotional signs and symptoms (Self-Reporting Questionnaire-20), mental health care, and absence from work due to general or mental health issues. Based on the responses of 1,437 CHWs, the prevalence of CMD (32.75%) was associated with perceived, witnessed, or suffered violence in the work area. In the hierarchical analysis, CMD were associated with age, sex, religious identity, years of experience as a CHW with the Family Health Strategy (FHS), work neighborhood, activities in the community, considering the lack of bonding with families as an obstacle, having suffered domestic violence, use of medication for emotional dysregulation, identifying the neighborhood as violent, considering violence a physical or mental health determinant, and identifying impunity as a cause of violence. Thus, the work and mental health of CHWs were significantly affected by violence dimensions. Our findings are relevant to the adoption of strategies to mitigate the effects of violence on the work and mental health of CHWs.

Introduction: Pathogenic variants in HIVEP2 have been associated with a neurodevelopmental disorder mainly characterized by intellectual disability, severe language impairment, and motor developmental delay. Since its first description in 2016, only 15 patients have been described in the literature., Methods: Here, we report 2 additional unrelated Portuguese children presenting intellectual disability and motor delay in whom de novo nonsense pathogenic variants in HIVEP2 have been identified by next-generation sequencing analysis., Results: In patient 1, the variant c.2827C>T, p.(Arg943*) was detected, whereas patient 2 carried the variant c.6667C>T, p.(Arg2223*). Interestingly, patient 1 presented with a rapid growth of the occipitofrontal diameter in the first months of life due to external hydrocephalus, a feature that, as far as we know, has never been reported in patients with HIVEP2 pathogenic variants., Conclusion: This report expands the phenotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported affected individuals., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

The purpose of this article is to analyse the circumstances in which the National Health Policy for Persons with Disabilities (PNSPCD) came into place in 2002 and the factors supporting or impeding its implementation from 2002 to 2018. The analysis was based on the Comprehensive Policy Analysis Model proposed by Walt and Gilson and focussed on understanding the context, process, content and actors involved in the formulation and implementation of the Policy. Data were obtained from two sources: document analysis of the key relevant documents and seven key informant interviews. Content analysis was undertaken using the Condensation of Meanings technique. The research demonstrates that the development and implementation of PNSPCD is marked by advances and retreats, determined, above all, by national and international macro-political decisions. The policy was formulated during Fernando Henrique's governments, under pressure from social movements and the international agenda and constituted a breakthrough for the rights of persons with disabilities. However, progress on implementation only took place under subsequent centre-left governments with the establishment of a care network for people with disabilities and a defined specific budget. These developments resulted from the mobilization of social movements, the ratification of the United Nations Convention on the rights of people with disabilities and the adherence of these governments to the human rights agenda. The coming to power of ultra-right governments triggered fiscal austerity, a setback in the implementation of the care network and a weakening in the content of various social policies related to the care of people with disabilities. During this era, the political approach changed, with the attempt to evade the role of the State, and the perspective of guaranteeing social rights. Undoubtedly, the neoliberal offensive on social policies, especially the Unified Health System, is the main obstacle to the effective implementation of the PNPCD in Brazil., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Objectives: In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries., Methods: Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data., Results: The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97-0.98), men vs. women: 1.88 (1.60-2.22), current vs. non-smoking: 0.76 (0.63-0.91), HLA-B27 positive vs. negative: 1.51 (1.20-1.91), TNF start year 2015-2018 vs. 2009-2014: 1.24 (1.06-1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25-1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58-1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99-1.00) and 0.99 (0.99-1.99), respectively CONCLUSION: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations., Competing Interests: Declaration of Competing Interest LMØ, LL, SG and SHR: research grants from Novartis; UL: none; DDG none; JKW: consultant of AbbVie, Amgen, Celgene, Eli Lilly and Novartis; BG: research grants from Pfizer, Abbvie and BMS; LP: consultant of Novartis Finland, UCB Pharma, Pfizer, Sanofi, BMS, AbbVie, Amgen, Celgene, Eli Lilly, Boehringer-Ingelheim, Mylan; KL: consulting and/or speaking fees from Amgen, Johnson and Johnson and Novartis; ACo: research grants, consulting and/or speaking fees from Amgen, Lilly, Pfizer, Boehringer Ingelheim; KP: speaker and consulting fees from Pfizer, MSD, BMS, UCB, Amgen, Egis, Roche, AbbVie; JZ: speaker and consulting fees from Abbvie, Elli-Lilly, Sandoz, Novartis, Egis, UCB; EKK: none; NA: speaking fees from Pfizer; ÖSG: none; HS: research grant from Sociedade Portuguesa de Reumatologia and speaker and/or consultancy fees from Abbvie, Janssen, Lilly, Novartis and Pfizer; MJN: consulting and/or speaking fees from AbbVie, Eli Lilly, Janssens, Novartis and Pfizer; BM: research grant from Novartis; GTJ: research grants from AbbVie, Pfizer, UCB, Amgen, GSK. Speaker fee from Janssen; HR: consulting and/or speaking fees from Abbvie, Celgene, Pfizer, UCB, and Viatris; MT: consulting and/or speaking fees from Abbvie, Amgen, Biogen, Eli Lilly, Janssen, Medis, MSD, Novartis, Pfizer, Sanofi, Sandoz-Lek; AJG: none; IHB: Consultant for Abbvie, UCB, MSD, Novartis, Lilly, unrestricted Grants received for investigator initiated studies from: MSD, Pfizer, AbbVie, UCB, fees received for Lectures from BMS, AbbVie, Pfizer, MSD ; JA: PI for agreements between Karolinska Institutet and Abbvie, Astra-Zeneca, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB; FI: consulting and/or speaking from Abbvie, Amgen, AstraZeneca, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; AGL: Research Grant from Novartis, and speaker and/or consultancy fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and UCB; ACi: consulting and/or speaking fees from AbbVie, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer; MJS: speaker fees from Abbvie, AstraZeneca, Lilly, Novartis and Pfizer; CC: Speaker and consultancy fees from AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer; ZR: speaker or consultancy fees from Abbvie, Novartis, MSD, Medis, Biogen, Eli Lilly, Pfizer, Sanofi, Lek, Janssen; BjG: consulting and/or speaking fees from Amgen and Novartis; MØ: research grants from Abbvie, BMS, Merck, Celgene and Novartis, and speaker and/or consultancy fees from Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB; MLH: Research grants from Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Medac, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Health literacy evaluation is considered a priority issue in the health literacy research field. The complexity of the multiple definitions of health literacy and the diversity of instruments to evaluate health literacy has become a challenge to the establishment of comparisons across different studies. This work aimed to provide a systematic literature review of the existing measurement instruments adapted or developed for different groups of the Portuguese population., Methods: A comprehensive search of digital databases was conducted to systematize and understand the available knowledge about health literacy measurement in Portugal and to identify assessment tools and studies developed. The selection process was based on PRISMA guidelines., Results: A total of 17 publications were analysed regarding different aspects, which resulted in the identification of 11 different instruments, that were adapted or developed to measure health literacy in different groups of the Portuguese population, mainly adults, adolescents, and young adults. Seven instruments focusing on general health literacy (including e-health), 2 on mental health literacy, and the other 2 on oral health literacy were identified., Discussion/conclusion: This study presents the first general overview of health literacy measurement in Portugal and clearly shows that to deepen our knowledge of health literacy in the Portuguese population it is essential to broaden the scope and the target of health literacy assessment to have a comprehensive understanding that will allow transforming our reality regarding health and disease., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel on behalf of NOVA National School of Public Health.)

Objective: There is a lack of real-life studies on interleukin-17 (IL-17) inhibition in psoriatic arthritis (PsA). We assessed real-life 6- and 12-month effectiveness (i.e., retention, remission, low disease activity [LDA], and response rates) of the IL-17 inhibitor secukinumab in PsA patients overall and across 1) number of prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), 2) years since diagnosis, and 3) European registries., Methods: Thirteen quality registries in rheumatology participating in the European Spondyloarthritis Research Collaboration Network provided longitudinal, observational data collected as part of routine care for secondary use. Data were pooled and analyzed with Kaplan-Meier plots, log rank tests, Cox regression, and multiple linear and logistic regression analyses., Results: A total of 2,017 PsA patients started treatment with secukinumab between 2015 and 2018. Overall secukinumab retention rates were 86% and 76% after 6 and 12 months, respectively. Crude (LUNDEX adjusted) 6-month remission/LDA (LDA including remission) rates for the 28-joint Disease Activity Index for Psoriatic Arthritis, the Disease Activity Score in 28 joints using the C-reactive protein level, and the Simplified Disease Activity Index (SDAI) were 13%/46% (11%/39%), 36%/55% (30%/46%), and 13%/56% (11%/47%), and 12-month rates were 11%/46% (7%/31%), 39%/56% (26%/38%), and 16%/62% (10%/41%), respectively. Clinical Disease Activity Index remission/LDA rates were similar to the SDAI rates. Six-month American College of Rheumatology 20%/50%/70% improvement criteria responses were 34%/19%/11% (29%/16%/9%); 12-month rates were 37%/21%/11% (24%/14%/7%). Secukinumab effectiveness was significantly better for b/tsDMARD-naive patients, similar across time since diagnosis (<2/2-4/>4 years), and varied significantly across the European registries., Conclusion: In this large real-world study on secukinumab treatment in PsA, 6- and 12-month effectiveness was comparable to that in previous observational studies of tumor necrosis factor inhibitors. Retention, remission, LDA, and response rates were significantly better for b/tsDMARD-naive patients, were independent of time since diagnosis, and varied significantly across the European countries., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Mammals are threatened worldwide, with ~26% of all species being included in the IUCN threatened categories. This overall pattern is primarily associated with habitat loss or degradation, and human persecution for terrestrial mammals, and pollution, open net fishing, climate change, and prey depletion for marine mammals. Mammals play a key role in maintaining ecosystems functionality and resilience, and therefore information on their distribution is crucial to delineate and support conservation actions. MAMMALS IN PORTUGAL is a publicly available data set compiling unpublished georeferenced occurrence records of 92 terrestrial, volant, and marine mammals in mainland Portugal and archipelagos of the Azores and Madeira that includes 105,026 data entries between 1873 and 2021 (72% of the data occurring in 2000 and 2021). The methods used to collect the data were: live observations/captures (43%), sign surveys (35%), camera trapping (16%), bioacoustics surveys (4%) and radiotracking, and inquiries that represent less than 1% of the records. The data set includes 13 types of records: (1) burrows | soil mounds | tunnel, (2) capture, (3) colony, (4) dead animal | hair | skulls | jaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8), observation in shelters, (9) photo trapping | video, (10) predators diet | pellets | pine cones/nuts, (11) scat | track | ditch, (12) telemetry and (13) vocalization | echolocation. The spatial uncertainty of most records ranges between 0 and 100 m (76%). Rodentia (n =31,573) has the highest number of records followed by Chiroptera (n = 18,857), Carnivora (n = 18,594), Lagomorpha (n = 17,496), Cetartiodactyla (n = 11,568) and Eulipotyphla (n = 7008). The data set includes records of species classified by the IUCN as threatened (e.g., Oryctolagus cuniculus [n = 12,159], Monachus monachus [n = 1,512], and Lynx pardinus [n = 197]). We believe that this data set may stimulate the publication of other European countries data sets that would certainly contribute to ecology and conservation-related research, and therefore assisting on the development of more accurate and tailored conservation management strategies for each species. There are no copyright restrictions; please cite this data paper when the data are used in publications., (© 2022 The Authors. Ecology © 2022 The Ecological Society of America.)

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is regarded as the most successful pathogen of humankind and a major threat to global health. The mycobacterial cell wall is vital for cell growth, virulence, and resistance to antibiotics, and thus constitutes a unique target for drug development. To characterize the enzymes catalyzing the synthesis of the cell wall components, considerable amounts of substrates are required. Since many mycobacterial cell wall lipids, particularly phosphatidylinositol mannosides (PIMs), are not commercially available, isolation from cell biomass is the most straightforward way to obtain these compounds. In this study, we optimized a protocol to extract and purify PIM species, in particular Ac 1 PIM 2 and Ac 1 PIM 4 , which can be further used for the identification and characterization of target enzymes. PIMs were extracted from Mycobacterium smegmatis mc 2 155 ΔPimE using organic solvents, and purified through three consecutive chromatography steps. Thin-layer chromatography (TLC) was used in-between purification steps to evaluate the success of lipid separation, and nuclear magnetic resonance (NMR) was used for product quantification and to assess purity. Typically, from a 60 g batch of M. smegmatis biomass we were able to isolate approximately 9 mg of Ac 1 PIM 2 and 1.8 mg of Ac 1 PIM 4 . This is the first time the purification of phosphatidylinositol tetramannoside has been reported. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Growth of M. smegmatis mc 2 155 ∆PimE Basic Protocol 2: Extraction of lipids from M. smegmatis mc 2 155 ∆PimE Basic Protocol 3: Treatment of the lipid extract for isolation of phospholipids Basic Protocol 4: Isolation of phosphatidylinositol mannosides Basic Protocol 5: Quantification of phosphatidylinositol mannosides., (© 2022 Wiley Periodicals LLC.)

Assuming the multidimensionality of health literacy, new complex and comprehensive approaches are more adequate to specific disease contexts, such as cancer. Assessing cancer literacy levels is a priority, since it entails potential serious implications for disease outcomes and patient's quality of life. This article reports on the translation and cultural adaptation of the Cancer Health Literacy Test to measure cancer literacy in Portuguese cancer patients. A multidisciplinary team of experts ensured the translation and cultural adaptation of the CHLT-30. A pre-test was conducted in two stages to evaluate the Portuguese version (CHLT-30 PT) in a sample of cancer patients (n = 71). Descriptive statistics were used to characterize the sample. Reliability (test-retest and internal consistency) and construct validity of CHLT-30 PT were assessed. The results obtained show a good internal consistency of the tool, respectively (Cronbach's alpha = 0.86 in the test and 0.80 in the retest). Patients' raw score mean in both test (23.96) and retest (25.97) and the distribution of scores categories are not statistically different. A suggestive association between higher education level and better total score was found compared to the results reported in CHLT-30-DKspa. The results obtained in the pre-test are favorable, and the instrument is now suitable for the next steps of the validation process. A Portuguese version of this tool will allow outlining patients' cancer literacy along the cancer care continuum, enabling the identification and implementation of adequate socio-educational strategies with highly positive impacts on health outcomes.

Parasitic infections caused by protozoans that infect the mucosal surfaces are widely neglected worldwide. Collectively, Entamoeba histolytica, Giardia lamblia, Cryptosporidium spp. and Trichomonas vaginalis infect more than a billion people in the world, being a public health problem mainly in developing countries. However, the exact incidence and prevalence data depend on the population examined. These parasites ultimately cause pathologies that culminate in liver abscesses, malabsorption syndrome, vaginitis, and urethritis, respectively. Despite this, the antimicrobial agents currently used to treat these diseases are limited and often associated with adverse side effects and refractory cases due to the development of resistant parasites. The paucity of drug treatments, absence of vaccines and increasing problems of drug resistance are major concerns for their control and eradication. Herein, potential candidates are reviewed with the overall aim of determining the knowledge gaps and suggest future perspectives for research. This review focuses on this public health problem and focuses on the progress of drug repositioning as a potential strategy for the treatment of mucosal parasites., 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 Santos and Rebello.)

Despite the scientific advances observed in the recent decades and the emergence of new methodologies, the diagnosis of systemic fungal infections persists as a problematic issue. Fungal cultivation, the standard method that allows a proven diagnosis, has numerous disadvantages, as low sensitivity (only 50% of the patients present positive fungal cultures), and long growth time. These are factors that delay the patient's treatment and, consequently, lead to higher hospital costs. To improve the accuracy and quickness of fungal infections diagnosis, several new methodologies attempt to be implemented in clinical microbiology laboratories. Most of these innovative methods are independent of pathogen isolation, which means that the diagnosis goes from being considered proven to probable. In spite of the advantage of being culture-independent, the majority of the methods lack standardization. PCR-based methods are becoming more and more commonly used, which has earned them an important place in hospital laboratories. This can be perceived now, as PCR-based methodologies have proved to be an essential tool fighting against the COVID-19 pandemic. This review aims to go through the main steps of the diagnosis for systemic fungal infection, from diagnostic classifications, through methodologies considered as "gold standard", to the molecular methods currently used, and finally mentioning some of the more futuristic approaches., Competing Interests: Declaration of competing interest All authors report no conflicts of interest relevant to this article., (Copyright © 2021 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To investigate knowledge and practice of Brazilian public primary and secondary health care dentists during the coronavirus disease (COVID-19) pandemic., Methods: An online questionnaire with sociodemographic and COVID-19 knowledge questions was used., Results: A total of 4048 dentists working in the Brazilian public primary and secondary health care system were investigated; 4024 (99.41%) believe that COVID-19 can be transmitted through dental procedures. A fair level of COVID-19 symptoms knowledge by these dentists was observed (3.76±1.27 of 6.00), as well as the skepticism in personal protective equipment (3382; 83.55%) and biosafety procedures (3278; 80.98%) used as an efficient form of COVID-19 transmission prevention. Country region, performance of social distancing, dental specialty, the use of personal protective equipment, and biosafety preventive measures influenced the likelihood of dentists to perform dental treatment, either elective or urgent, during the COVID-19 pandemic., Conclusion: The need of extra preventive barriers for dental treatment may bring an extra financial stress in the Brazilian public primary and secondary health care system, as well as in the patient-dentist relationship, which may have to be reframed. Internationally accepted public guideline policies regarding dental treatment safety, as well as the technological development of preventive tools, are needed to deal with the challenges brought by COVID-19.

Objectives: To estimate the relationship between EQ5D (three levels, UK version) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) for use in the economic evaluation of health technologies for people with axial spondyloarthritis (axSpA). To compare against the relationship with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)., Methods: An electronic, prospective, Portuguese, nationwide, rheumatic disease register (Reuma.pt) provided data on 1140 patients (5483 observations) with a confirmed diagnosis of axSpA. We estimated models of EQ5D as a function of ASDAS, alone or in combination with measures of functional impairment, using bespoke mixture models which reflect the complex distributional features of EQ5D. The SPondyloArthritis Caught Early cohort provided data from 344 patients (1405 observations) in four European countries and was used for validation. A previously published model of BASDAI/Bath Ankylosing Spondylitis Functional Index (BASFI) was also used to generate predicted EQ5D scores and model performance compared., Results: A non-linear relationship exists between EQ5D from ASDAS. The final model included ASDAS, ASDAS squared, age and age squared and demonstrated close fit in both datasets except where data were sparse for patients with very high levels of disease activity (ASDAS >4). This finding held in the validation dataset. Models that included BASFI improved model fit. The ASDAS based models fit the data marginally less well than models using BASDAI., Conclusions: Mapping models linking ASDAS to EQ5D allow results from clinical studies to be used in economic evaluation of health technologies with confidence. There is some loss of information compared with BASDAI but this has only a marginal impact., Competing Interests: Competing interests: MvdS has received consulting fees/speaker’s fees/research grants from Novartis, UCB, Abbvie, Janssen, Eli Lilly and MSD. FAvG has received grants from Stichting vrienden van Sole Mio, Stichting ASAS, Jacobus Stichting, Novartis and UCB, and consulting fees from Novartis, Eli Lilly, MSD, AbbVie and Bristol Myers Squibb. MB has received consulting/speaker’s fees from AbbVie, Eli Lilly, Janssen and Novartis. RR has received consulting/speaker’s fees from AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB Pharma. SE has received consulting fees from AbbVie, Janssen and Novartis. DvdH has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and serves as director of Imaging Rheumatology bv. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB Pharma., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

People with disabilities have greater need for healthcare on average, but often face barriers when accessing these services. The Brazilian government launched the National Health Policy for People with Disabilities (PNSPD) in 2002 to address this inequality. PNSPD has six areas of focus: quality of life, impairment prevention, comprehensive health care, organization and functioning of health services, information mechanisms, and training of human resources. The aim of this article was to undertake a scoping review to assess the evidence on the experience of people with disabilities in Brazil with respect to the six themes of the PNSPD. The scoping review included articles published between 2002 and 2019, from four electronic databases: PUBMED/MEDLINE, LILACS, Science Direct, and Scielo. In total, 8076 articles were identified, and after review of titles, abstracts, and full texts by two independent reviewers, 98 were deemed eligible for inclusion. The evidence was relatively limited in availability and scope. However, it consistently showed large gaps in delivery of healthcare to people with disabilities across the six dimensions considered. There was lack of actions aimed at promoting quality of life; insufficient professional training about disability; little evidence on the health profile of people with disabilities; large gaps in the availability of care due to widespread physical, informational, and attitudinal barriers; and poor distribution of the supply and integration of services. In conclusion, the policy framework in Brazil is supportive of the inclusion of people with disabilities in health services; however, large inequalities remain due to poor implementation of the policy into practice.

The aroma of grapes is cultivar dependent and is influenced by terroir , vineyard practices, and abiotic and biotic stresses. Trincadeira is a non-aromatic variety associated with low phenolic content and high sugar and organic acid levels. This cultivar, widely used in Portuguese wines, presents high susceptibility to Botrytis cinerea . This work aimed to characterise the volatile profile of Trincadeira grapes and how it changes under infection with B. cinerea . Thirty-six volatile organic compounds were identified, from different functional groups, namely alcohols, ester acetates, fatty acid esters, fatty acids, aldehydes, and products of the lipoxygenase pathway. Both free and glycosidic volatile organic compounds were analysed by Gas Chromatography and Gas Chromatography coupled to Mass Spectrometry for component quantification and identification, respectively. A multivariance analysis showed a clear discrimination between healthy and infected grapes with 2- trans -hexenal and isoamyl-acetate among the compounds identified as negative and positive markers of infection, respectively. Ester acetates such as 2-phenylethyl acetate, isoamyl acetate, and 2-methylbutyl acetate were present in higher contents in infected samples, whereas the contents of several fatty acid esters, such as ethyl decanoate and ethyl dodecanoate, decreased. These data were integrated with quantitative PCR data regarding genes involved in volatile metabolism and showed up-regulation of a gene coding for Hydroperoxide Lyase 2 in infected grapes. Altogether, these changes in volatile metabolism indicate an impact on the grape quality and may be related to defence against B. cinerea . The presence/absence of specific compounds might be used as infection biomarkers in the assessment of Trincadeira grapes' quality.

Objective: To update the recommendations for the treatment of rheumatoid arthritis (RA) with biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs), endorsed by the Portuguese Society of Rheumatology (SPR)., Methods: These treatment recommendations were formulated by Portuguese rheumatologists taking into account previous recommendations, new literature evidence and consensus opinion. At a national meeting, in a virtual format, three of the ten previous recommendations were re-addressed and discussed after a more focused literature review. A first draft of the updated recommendations was elaborated by a team of SPR rheumatologists from the SPR rheumatoid arthritis study group, GEAR. The resulting document circulated among all SPR rheumatologists for discussion and input. The level of agreement with each of all the recommendations was anonymously voted online by all SPR rheumatologists., Results: These recommendations cover general aspects such as shared decision, treatment objectives, systematic assessment of disease activity and burden and its registry in Reuma.pt. Consensus was also achieved regarding specific aspects such as initiation of bDMARDs and tsDMARDs, assessment of treatment response, switching and definition of persistent remission., Conclusion: These recommendations may be used for guidance of treatment with bDMARDs and tsDMARDs in patients with RA. As more evidence becomes available and more therapies are licensed, these recommendations will be updated.

Introduction: To date, no valid outcome measure has been developed in European Portuguese (EP) to evaluate the Parkinsons' Disease (PD) patients' (PwP) reports regarding their swallowing disturbances., Objectives: The aim of this study was to translate and cross-culturally adapt the Swallowing Disturbance Questionnaire (SDQ) and the Sialorrhea Clinical Scale for PD (SCS-PD) into EP and to determine its clinimetric properties in PwP., Materials and Methods: The original English SDQ and SCS-PD versions were cross-culturally adapted following recommendations established in international guidelines. The validation process involved 75 PwP and 65 healthy sex- and age-matched participants., Results: The EP versions of the SDQ and SCS-PD are equivalent to the original versions (content, depth, and scoring). Statistical analyses for the SDQ tool revealed good feasibility (missing data <5%), acceptability (no floor or ceiling effects), excellent internal consistency (Cronbach´s α = 0.95), good construct validity (78.5% revealed large to moderate loadings), moderate convergent validity ( r  = 0.60), good divergent validity ( r  = 0.40), good known-groups validity ( p -value < .05) and a fair sensitivity and specificity (AUC = 0.700). Statistical analyses for the SCS-PD tool shows good feasibility, reasonable acceptability (floor effect), good internal consistency (Cronbach´s α = 0.85), good construct validity (85.7% showed between large to moderate loadings), good convergent validity ( r  = 0.78), good divergent validity ( r  = 0.39), good known groups validity ( p -value < .05) and a fair sensitivity and specificity (AUC = 0.704)., Conclusions: The EP versions of the SDQ and SCS-PD maintained the characteristics of the original versions and therefore consistent tools to be used in PwP.

Integrator regulates the 3′-end processing and termination of multiple classes of noncoding RNAs. Depletion of INTS11, the catalytic subunit of Integrator, or ectopic expression of its catalytic dead enzyme impairs the 3′-end processing and termination of a set of protein-coding transcripts termed Integrator-regulated termination (IRT) genes. This defect is manifested by increased RNA polymerase II (RNAPII) readthrough and occupancy of serine-2 phosphorylated RNAPII, de novo trimethylation of lysine-36 on histone H3, and a compensatory elevation of the cleavage and polyadenylation (CPA) complex beyond the canonical polyadenylation sites. 3′ RNA sequencing reveals that proximal polyadenylation site usage relies on the endonuclease activity of INTS11. The DNA sequence encompassing the transcription end sites of IRT genes features downstream polyadenylation motifs and an enrichment of GC content that permits the formation of secondary structures within the 3′UTR. Together, this study identifies a subset of protein-coding transcripts whose 3′ end processing requires the Integrator complex.

The compatible solute mannosylglycerate (MG) has exceptional properties in terms of protein stabilization and protection under salt, heat, and freeze-drying stresses as well as against protein aggregation. Due to these characteristics, MG possesses large potential for clinical and biotechnological applications. To achieve efficient MG production, Corynebacterium glutamicum was equipped with a bifunctional MG synthase (encoded by mgsD and catalyzing the condensation of 3-phosphoglycerate and GDP-mannose to MG) from Dehalococcoides mccartyi . The resulting strain C. glutamicum (pEKEx3 mgsD ) intracellularly accumulated about 111 mM MG (60 ± 9 mg g CDW -1 ) with 2% glucose as a carbon source. To enable efficient mannose metabolization, the native manA gene, encoding mannose 6-phosphate isomerase, was overexpressed. Combined overexpression of manA and mgsD from two plasmids in C. glutamicum resulted in intracellular MG accumulation of up to ca. 329 mM [corresponding to 177 mg g  cell dry weight (CDW) -1 ] with glucose, 314 mM (168 mg g CDW -1 ) with glucose plus mannose, and 328 mM (176 mg g CDW -1 ) with mannose as carbon source(s), respectively. The product was successfully extracted from cells by using a cold water shock, resulting in up to 5.5 mM MG (1.48 g L -1 ) in supernatants. The two-plasmid system was improved by integrating the mgsD gene into the manA -bearing plasmid and the resulting strain showed comparable production but faster growth. Repeated cycles of growth/production and extraction of MG in a bacterial milking-like experiment showed that cells could be recycled, which led to a cumulative MG production of 19.9 mM (5.34 g L -1 ). The results show that the newly constructed C. glutamicum strain produces MG from glucose and mannose and that a cold water shock enables extraction of MG from the cytosol into the medium., 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 Schwentner, Neugebauer, Weinmann, Santos and Eikmanns.)

Intestinal cryptosporidiosis is a diarrheal disease caused by protists of genus Cryptosporidium that infect a wide variety of hosts, primarily vertebrates. Due to the close contact between humans and their companion animals, especially dogs and cats, there is concern about the potential for zoonotic transmission of this enteric protozoan parasite by infected animals. This study aimed to perform a microscopic and molecular diagnosis of Cryptosporidium spp. in fecal samples from domiciled dogs and cats. One hundred and nineteen fecal samples were processed using sugar centrifugal flotation followed by molecular detection of Cryptosporidium spp. DNA using nested PCR. Subtyping of isolates positive for C. parvum was performed by sequence analysis of the 60 kDa glycoprotein gene (GP60). Cryptosporidium oocysts were detected in 7.8% (5/64) and 5.4% (3/55) of the fecal samples from dogs and cats, respectively. Cryptosporidium canis (n = 3) and C. parvum (n = 2) were the main species found in dogs, whereas C. felis (n = 3) was prevalent in cats. Subtype IIaA17G2R2 (potentially zoonotic) was identified in samples positive for C. parvum. Despite the low prevalence of Cryptosporidium observed in the domiciled dogs and cats, the presence of potentially zoonotic C. parvum in dogs evidences a public health concern. Further research is needed to better understand the epidemiology, source, and potential impacts of Cryptosporidium infection in cats and dogs., Competing Interests: The authors have declared that no competing interests exist.