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KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies' clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders' molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient's molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.

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Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

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The golden lion tamarin (GLT) is an Endangered primate endemic to Brazil's lowland Atlantic Forest. After centuries of deforestation and capture for the pet trade, only a few hundred individuals survived, all in isolated forest fragments 85 km from Rio de Janeiro city. Intensive conservation actions, including reintroduction of zoo-born tamarins, increased numbers to about 3700 in 2014. The most severe yellow fever epidemic/epizootic in Brazil in 80 years reduced two of the largest GLT populations by over 90%. Herein we report the results of a 2023 survey of GLTs designed to examine the dynamics of population recovery following yellow fever. Results indicate that populations hard hit by yellow fever are recovering due in part to immigration from adjacent forest fragments. No local extirpations were observed. About 4800 GLTs live in the survey area. This represents a 31% increase since the baseline survey completed in 2014. Two factors explain most of the increase: four large areas that had no GLTs or very low-density populations in 2014 are now at moderate density (three areas) or low density (one area), explaining 71% of overall increase since 2014. Increase in forest area within our survey area may explain up to 16% of the increase in GLT numbers since 2014. Results of computer simulations suggest that strengthening forest connectivity will facilitate metapopulation resilience in the face of mortality factors such as yellow fever.

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Mosaic trisomy 8 is a condition characterized by a great phenotypic and cytogenetic variability whose incidence ranges around 1 in 25,000 to 50,000 live births. Here, we report a mosaic trisomy 8 patient presenting laryngotracheomalacia, an uncommon finding, analyzing its possible role over morbidity, and mortality. The patient was a boy who, after birth, had tachypnea and paleness. He presented periods of respiratory dysfunction with need of ventilatory support. Respiratory syncytial virus test was positive. Naso fibrobronchoscopy showed moderate laryngotracheomalacia. He also had recurrent episodes of pneumonia and difficulty in withdrawing continuous positive airway pressure. The patient also presented leucoma, abnormal and low-set ears, pectus excavatum, clenched fists with overlapping fingers, cryptorchidism, clubfeet, and deep longitudinal plantar creases. G-bands by Trypsin using giemsa (GTG-banding) karyotype from a peripheral blood sample revealed a mosaic trisomy 8: mos 47,XY, + 8[15]/46,XY[7]. At 4 months, the patient developed respiratory failure, and a chest computed tomography scan showed areas of atelectasis and gross fibroatelectatic striae. He ended up presenting clinical worsening and died at 4 months and 8 days. In our literature review, we found some reports describing patients with mosaic trisomy 8 and laryngotracheomalacia. However, we cannot rule out the possibility that this association could be casual, since laryngotracheomalacia is a relatively common finding in children. Therefore, more studies are still necessary to understand the possible relation between both conditions and the role of laryngotracheomalacia over morbidity and prognosis of mosaic trisomy 8 patients.

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BACKGROUND: Some maternal characteristics are related to alcohol intake during pregnancy, which irreversibly compromises the maternal-fetal binomial integrity. OBJECTIVES: To identify the frequency, impact, and factors associated with alcohol consumption during pregnancy. DESIGN AND SETTING: A cross-sectional study was performed at the Hospital Materno Infantil Presidente Vargas (HMIPV) in Porto Alegre/RS between March and December 2016. METHODS: A structured questionnaire was administered along with a medical records review. They refer to the maternal sociodemographic and gestational status, alcohol consumption patterns, and characteristics of the fetus/newborn. In the statistical analysis, P values < 0.05 were considered significant. RESULTS: The frequency of alcohol intake was 37.3%; this was characterized by the consumption of fermented beverages (89.3%), especially during the first trimester (79.6%). Risky consumption (high and/or early) occurred for 30.2% of participants. Risk factors associated with maternal alcohol consumption during pregnancy were tobacco use (P < 0.001) and abortion attempt (P = 0.023). Living with a partner (P = 0.002) and planning pregnancy (P = 0.009) were protective factors. Risky consumption was related to all of the aforementioned variables as well as threatened abortion (P = 0.023). CONCLUSIONS: Alcohol intake during pregnancy is common and affects nearly one-third of pregnant women. Knowledge of the population at risk and protective factors is essential for the development of campaigns that seek to reduce consumption and, therefore, its consequences for the mother and fetus.

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The pursuit of novel treatment alternatives to address the accumulated resistance to antimicrobials over the years has prompted the scientific community to explore biodiversity, particularly animal venom, as a potential source of new antimicrobial drugs. Snake venoms, with their complex mixtures of components, are particularly promising targets for investigation in this regard. The search for novel molecules exhibiting antimicrobial activity against multidrug-resistant strains is of paramount importance for public health and numerous research groups worldwide. High expectations within the healthcare field are supported by the scientific literature, which highlights the potential development of innovative drugs through in vivo and in vitro application, depending on dose titration. Snake venoms and their molecules and peptides offer exponential possibilities for biotechnological applications as antimicrobial agents. However, many uncertainties and unexplored avenues remain, presenting opportunities for discoveries and research.

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RN104 (2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole) is a thiazolylhydrazone derivative with prominent antifungal activity. This work aimed to develop a self-emulsifying drug delivery system (SEDDS) loaded with RN104 to improve its biopharmaceutical properties and enhance its oral bioavailability. Medium chain triglycerides, sorbitan monooleate, and polysorbate 80 were selected as components for the SEDDS formulation based on solubility determination and a pseudo-ternary phase diagram. The formulation was optimized using the central composite design in response surface methodology. The optimized condition consisted of medium chain triglycerides, sorbitan monooleate, and polysorbate 80 in a mass ratio of 65.5:23.0:11.5, achieving maximum drug loading (10 mg/mL) and minimum particle size (118.4 ± 0.7 nm). The developed RN104-SEDDS was fully characterized using dynamic light scattering, in vitro release studies, stability assessments, polarized light microscopy, and transmission electron microscopy. In vivo pharmacokinetic studies in mice demonstrated that RN104-SEDDS significantly improved oral bioavailability compared to free RN104 (the relative bioavailability was 2133 %). These results clearly indicated the successful application of SEDDS to improve the pharmacokinetic profile and to enhance the oral bioavailability of RN104, substantiating its potential as a promising antifungal drug candidate.

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ABSTRACT BACKGROUND: Some maternal characteristics are related to alcohol intake during pregnancy, which irreversibly compromises the maternal-fetal binomial integrity. OBJECTIVES: To identify the frequency, impact, and factors associated with alcohol consumption during pregnancy. DESIGN AND SETTING: A cross-sectional study was performed at the Hospital Materno Infantil Presidente Vargas (HMIPV) in Porto Alegre/RS between March and December 2016. METHODS: A structured questionnaire was administered along with a medical records review. They refer to the maternal sociodemographic and gestational status, alcohol consumption patterns, and characteristics of the fetus/newborn. In the statistical analysis, P values < 0.05 were considered significant. RESULTS: The frequency of alcohol intake was 37.3%; this was characterized by the consumption of fermented beverages (89.3%), especially during the first trimester (79.6%). Risky consumption (high and/or early) occurred for 30.2% of participants. Risk factors associated with maternal alcohol consumption during pregnancy were tobacco use (P < 0.001) and abortion attempt (P = 0.023). Living with a partner (P = 0.002) and planning pregnancy (P = 0.009) were protective factors. Risky consumption was related to all of the aforementioned variables as well as threatened abortion (P = 0.023). CONCLUSIONS: Alcohol intake during pregnancy is common and affects nearly one-third of pregnant women. Knowledge of the population at risk and protective factors is essential for the development of campaigns that seek to reduce consumption and, therefore, its consequences for the mother and fetus.

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BACKGROUND: The purpose of this network meta-analysis (NMA) is to investigate the efficacy of pharmacological and non-pharmacological therapy on pain intensity and disability of older people with chronic nonspecific low back pain, providing comprehensive evidence for an informed decision-making. METHODS: We will perform a systematic search to identify randomized controlled trials of pharmacological and non-pharmacological interventions for older people with chronic nonspecific low back pain. MEDLINE, Cochrane Library, Embase, AMED, PsycINFO, and PEDro will be searched without language or date restrictions. Our primary outcomes are pain intensity and disability. Risk of bias will be assessed for all studies using the revised Cochrane risk-of-bias (RoB) tool 2.0. For each pairwise comparison between the different interventions, estimated mean differences and their 95% confidence intervals will be presented. Standard pairwise meta-analyses will be performed using random effects models in STATA version 16. The competing interventions will be ranked using the surface under the cumulative ranking curve (SUCRA) for the outcomes of interest at short and long terms. The confidence in the results from NMA will be assessed using the Confidence in Network Meta-Analysis (CINeMA) framework. DISCUSSION: This NMA compares efficacy of interventions for nonspecific chronic low back pain in older people. It will provide reliable evidence for patients, clinicians, stakeholders, and researchers in this field where competing therapies, many of extraordinarily little value, are commonly used in clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022312565.

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BACKGROUND AND PURPOSE: The aim of the present systematic review was to investigate the effectiveness of pharmacological and non-pharmacological therapy on pain intensity and disability in older people with chronic nonspecific low back pain. METHODS: Searches were conducted in the MEDLINE, COCHRANE LIBRARY, EMBASE, AMED, PSYCINFO, and PEDRO databases up to 2022. Risk of bias was appraised using the Cochrane Risk of Bias 2.0 tool. Estimated mean differences and respective 95% confidence intervals were presented for each paired comparison and the strength of the current evidence was assessed using the GRADE approach. RESULTS AND DISCUSSION: Thirty-one original trials involving 2120 participants were included. All outcomes were self-rated. Pain intensity was measured using the Visual Analogue Scale or Numerical Rating Scale. Disability was evaluated using the Roland Morris Disability Questionnaire, Oswestry Disability Index or Hannover Functional Ability Questionnaire. Short-term: Moderate quality of evidence that mindfulness reduces disability compared to patient education (mean difference [MD] = - 1.38 [95% CI - 2.02 to - 0.73]); low-quality evidence that mixed exercise (MD = - 50.33 [95% CI - 57.11 to - 43.56]) reduces pain compared to no intervention, waiting list, placebo or sham; low quality of evidence that there is no effect for opioid compared to placebo (MD = - 8.26 [95% CI - 19.29 to 2.77]) with regards to reducing pain and opioid/acetaminophen reduces disability more compared to pregabalin (MD = 2.36 [95% CI] 1.86-2.86]). CONCLUSIONS: The findings showed low or very low quality of evidence for non-pharmacological interventions with a large effect in short- and long-term follow-up. The two studies that provided moderate quality of evidence had a small clinical effect. Only two studies were found that investigated pharmacological therapies-both with low quality of evidence. However, the studies were methodologically weak and had small sample sizes. Given the adverse effects of low back pain and the scarce information on the effectiveness of pharmacological and non-pharmacological treatments for older people, future randomized trials should be encouraged.

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BACKGROUND: The venom of Crotalus durissus terrificus, as well as its fractions, has intrigued research groups worldwide who are working to isolate, characterize, and find possible biotechnological applications. A number of studies have elucidated that these fractions and their derivatives possess pharmacological properties, which can enable the development of new drug prototypes with anti-inflammatory, antinociceptive, antitumor, antiviral, and antiparasitic applications. OBJECTIVE: This review presents a systematic study on Crotalus durissus terrificus, the most notable crotalid subspecies in South America, focusing on the composition, toxicological mechanisms, structural aspects, and applications of the main venom toxins (convulxin, gyroxin, crotamine, crotoxin, and their subunits). CONCLUSION: The authors have found that research on this snake and its toxins is still an area of focus, despite that almost a century has passed since the isolation of crotoxin. Several applications of these proteins in the development of novel drugs and bioactive substances have also been demonstrated.

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This study presents a methodology that combines experimental tests and the finite element method, which is able to analyse the influence of the geometry on the mechanical behaviour of stents made of bioabsorbable polymer PLA (PolyLactic Acid) during their expansion in the treatment of coarctation of the aorta (CoA). Tensile tests with standardized specimen samples were conducted to determine the properties of a 3D-printed PLA. A finite element model of a new stent prototype was generated from CAD files. A rigid cylinder simulating the expansion balloon was also created to simulate the stent opening performance. A tensile test with 3D-printed customized stent specimens was performed to validate the FE stent model. Stent performance was evaluated in terms of elastic return, recoil, and stress levels. The 3D-printed PLA presented an elastic modulus of 1.5 GPa and a yield strength of 30.6 MPa, lower than non-3D-printed PLA. It can also be inferred that crimping had little effect on stent circular recoil performance, as the difference between the two scenarios was on average 1.81%. For an expansion of diameters ranging from 12 mm to 15 mm, as the maximum opening diameter increases, the recoil levels decrease, ranging from 10 to 16.75% within the reported range. These results point out the importance of testing the 3D-printed PLA under the conditions of using it to access its material properties; the results also indicate that the crimping process could be disregarded in simulations to obtain fast results with lower computational cost and that new proposed stent geometry made of PLA might be suitable for use in CoA treatments-the approach that has not been applied before. The next steps will be to simulate the opening of an aorta vessel using this geometry.

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This study presents a methodology that combines experimental tests and the finite element method, which is able to analyse the influence of the geometry on the mechanical behaviour of stents made of bioabsorbable polymer PLA (PolyLactic Acid) during their expansion in the treatment of coarctation of the aorta (CoA). Tensile tests with standardized specimen samples were conducted to determine the properties of a 3D-printed PLA. A finite element model of a new stent prototype was generated from CAD files. A rigid cylinder simulating the expansion balloon was also created to simulate the stent opening performance. A tensile test with 3D-printed customized stent specimens was performed to validate the FE stent model. Stent performance was evaluated in terms of elastic return, recoil, and stress levels. The 3D-printed PLA presented an elastic modulus of 1.5 GPa and a yield strength of 30.6 MPa, lower than non-3D-printed PLA. It can also be inferred that crimping had little effect on stent circular recoil performance, as the difference between the two scenarios was on average 1.81%. For an expansion of diameters ranging from 12 mm to 15 mm, as the maximum opening diameter increases, the recoil levels decrease, ranging from 10 to 16.75% within the reported range. These results point out the importance of testing the 3D-printed PLA under the conditions of using it to access its material properties; the results also indicate that the crimping process could be disregarded in simulations to obtain fast results with lower computational cost and that new proposed stent geometry made of PLA might be suitable for use in CoA treatments-the approach that has not been applied before. The next steps will be to simulate the opening of an aorta vessel using this geometry.

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Bovine mastitis is an inflammation of the mammary gland in response to invasion by opportunistic agents. Due to the high economic importance of dairy production and the complexity related to animal health, the objective of this work was to identify and evaluate the antibacterial resistance profile of samples of mastitis milk, milking hand and milking equipment from small rural dairy farms belonging to the northwest region of the state of Paraná, Brazil. Five small, non-technical dairy farms in the municipalities of Boa Esperança, Juranda and Tapejara, all belonging to the northwest region of the state of Paraná, Brazil, were selected. The properties had Holstein and/or crossbred herds, carried out a bucket-by-foot milking system and all had the presence of animals with subclinical mastitis confirmed by the California Mastitis Test. Samples of sterile swabs from the milking insufflators, the milking hand and milk samples were collected-and later, isolation tests and phenotypic characterization of the samples, sensitivity tests to antimicrobials and phenotypic tests for the detection of beta-producing strains were performed with extended-spectrum beta-lactamase (ESBL), molecular identification of Staphylococcus aureus isolates and mecA gene research. Of the 199 samples collected from the 15 selected properties in the municipalities of Boa Esperança, Tapejara and Juranda, 72 (36.20%) were classified as multiresistant. Isolated from milkers' hands and milking machines, which phenotypically produce extended-spectrum beta-lactamase (ESBL), the presence of the mecA gene was also observed in 11 isolates of Staphylococcus spp. of milk samples, machines and milking hands. Mastitis can be spread to the herd through the milking process by the milkers' instruments and hands, and adequate management measures can prevent its transmission and the conscious use of antibiotics decreases the prevalence of multidrug-resistant pathogens. In this work, different pathogenic bacteria were detected in mastitic milk, milking equipment and milking hand with a high percentage (36.20%) of isolates classified as multidrug resistant. In addition, the presence phenotypically (ESBL) and molecularly (mecA gene) of isolates carrying resistance genes was also verified. These results directly reflect on the health of the animals, the health of the workers and the health of the respective environment, which can enable the continuity of the propagation of the etiological agents involved in the mastitis infection. The awareness of producers and workers on these properties about the disease, transmission, sanitary aspects and adequate management and treatment are essential for improving milk production and production efficiency.

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The use of fish as bioindicators of the effect of contaminants in the aquatic environment is usual. However, detritivorous species are less used for environmental monitoring. Thus, the aim of this study was to evaluate the use of Ancistrus brevipinnis as a potential bioindicator of water quality of the Ilha River, RS (southern Brazil) and compared to the result obtained for a routine species (Bryconamericus iheringii). For this purpose, the condition factor (CF), the presence of morphological changes in the gills and the quantification of metals in different tissues of the specimens collected in three sites of the Ilha River were evaluated. A homogeneity in the distribution of data was observed in the CF for the species B. iheringii, whereas the specimens of A. brevipinnis showed an oscillation in the distribution of data of the CF. Histological analysis showed greater sensitivity of B. iheringii in reproducing characteristics of the environment in its gill lamellae, which was not observed in A. brevipinnis. Conversely, Cr quantification was higher in the intestine samples of A. brevipinnis at all sites and in all collections due to its feeding behavior. The data reinforce the use of water column species as Bryconamericus iheringii for environmental monitoring, even if they do not reflect the whole aquatic ecosystem. Further studies evaluating other tissues and biomarkers, such as the gastrointestinal tract, may assist in describing the use of species more related to sediment.(AU)

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The early development of Markiana nigripinnis is described by morphological characters, pigmentation, and morphometry. Larvae were obtained through semi-natural breeding, collected, fixed, and identified according to their development. Eighty individuals with standard lengths ranging from 3.1 to 24.3 mm were analyzed. Larvae are poorly developed at hatching, with a relatively large yolk sac and finfold. At the preflexion stage, the eyes are pigmented, the mouth and anus are functional, the yolk is completely absorbed, and the pectoral fin bud emerges. At flexion, the first rays of the caudal, anal, and dorsal fins become evident. The pelvic fin bud emerges only at the postflexion stage, in addition to the complete absorption of the finfold. Pigmentation is distributed throughout the body, with a greater concentration on the top of the head, around the mouth, and at the base of the caudal fin. The myomere total number ranged from 34 to 49 (16-23 preanal, and 18-27 postanal). Juveniles show morphological characteristics like adults. The fins ray number are pectoral: 11-13, pelvic: 5-7, dorsal: 8-11, caudal: 16-27, and anal 30-47. The morphometric relationships reveal variations in growth along the early ontogeny of the species.

O desenvolvimento inicial de Markiana nigripinnis foi descrito considerando os caracteres morfológicos, a pigmentação e a morfometria. Indivíduos foram obtidos por meio de reprodução seminatural, coletados, acondicionados, fixados e identificados conforme seu período e estágio de desenvolvimento. Foram analisados 80 indivíduos com comprimento padrão variando de 3,1 a 24,3 mm. As larvas são pouco desenvolvidas à eclosão, com saco vitelino relativamente grande e presença de membrana embrionária. Em pré-flexão, os olhos estão pigmentados, a boca e o ânus são funcionais, o vitelo é completamente absorvido e surge o botão da nadadeira peitoral. Em flexão, os primeiros raios das nadadeiras caudal, anal e dorsal tornam-se evidentes. O botão da nadadeira pélvica aparece somente em pós-flexão, além da completa absorção da nadadeira embrionária. A pigmentação se distribui pelo corpo todo, com maior concentração no topo da cabeça, ao redor da boca e na base da nadadeira caudal. O número total de miômeros variou de 34 a 49 (16-23 pré e 18-27 pós-anal). Os juvenis apresentaram características morfológicas semelhantes ao adulto. O número de raios das nadadeiras é peitoral: 11-13, pélvica: 5-7, dorsal: 8-11, caudal: 16-27 e anal 30-47. As relações morfométricas revelam variações no crescimento ao longo da ontogenia inicial da espécie.

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INTRODUCTION: COVID-19 is a public health emergency all around the world. Severe illness occurred in about 14% of patients and 5% of patients developed critical illness, but the prognosis for these patients remains unclear. OBJECTIVE: To describe the prognosis in hospitalized adults with COVID-19. METHODS: The MEDLINE, EMBASE, AMED, and COCHRANE databases were searched for studies published up to 28 June 2021 without language restrictions. Descriptors were related to "COVID-19" and "prognosis". Prospective inception cohort studies that assessed morbidity, mortality and recovery in hospitalized people over 18 years old with COVID-19 were included. Two independent reviewers selected eligible studies and extracted the available data. Acute respiratory distress syndrome (ARDS) and multiple organ failure (MOFS) were considered as outcomes for morbidity and discharge was considered for recovery. The Quality in Prognosis Studies (QUIPS) tool was used to assess risk of bias. Analyses were performed using Comprehensive Meta-Analysis (version 2.2.064). RESULTS: We included 30 inception cohort studies investigating 13,717 people hospitalized with COVID-19 from different countries. The mean (SD) age was 60.90 (21.87) years, and there was high proportion of males (76.19%) and people with comorbidities (e.g., 49.44% with hypertension and 29.75% with diabetes). Findings suggested a high occurrence of morbidity, mainly related to ARDS. Morbidity rates varied across studies from 19% to 36% in hospital wards, and from 13% to 90% in Intensive Care Units-ICU. Mortality rates ranged from 4% to 38% in hospital wards and from 8% to 51% in ICU. Recovery rates ranged up to 94% and 65% in hospital wards and ICU, respectively. The included studies had high risk of bias in the confounding domain. CONCLUSIONS: The prognosis of people hospitalized with COVID-19 is an issue for the public health system worldwide, with high morbidity and mortality rates, mainly in ICU and for patients with comorbidities. Its prognosis emphasizes the need for appropriate prevention and management strategies.

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INTRODUCTION: Although several non-pharmacological interventions have been tested in the management of Fibromyalgia (FM), there is little consensus regarding the best options for the treatment of this health condition. The purpose of this network meta-analysis (NMA) is to investigate the comparative efficacy and acceptability of non-pharmacological interventions for FM, in order to assist clinical decision making through a ranking of interventions in relation to the most important clinical outcomes in these patients. METHODS AND ANALYSIS: We will perform a systematic search to identify randomised controlled trials of non-pharmacological interventions endorsed in guidelines and systematic reviews. Information sources searched will include major bibliographic databases without language or date restrictions (MEDLINE, Cochrane Library, EMBASE, AMED, PsycINFO and PEDro). Our primary outcomes will be pain intensity, patient-reported quality of life (QoL), and acceptability of treatment will be our secondary outcome. Risk of bias of the included trials will be assessed using the Cochrane risk of bias tool (RoB2). For each pairwise comparison between the different interventions, we will present mean differences (MDs) for pain intensity and QoL outcomes and Relative Risks (RRs) for acceptability, both with respective 95% confidence intervals (CIs). Initially, standard pairwise meta-analyses will be performed using a DerSimonian-Laird random effects model for all comparisons with at least two trials and then we will perform a frequentist NMA using the methodology of multivariate meta-analysis assuming a common heterogeneity parameter, using the mvmeta command and network suite in STATA. In the NMA, two different types of control group, such as placebo/sham and no intervention/waiting list will be combined as one node called "Control". The competing interventions will be ranked using the P-score, which is the frequentist analogue of surface under the cumulative ranking curve (SUCRA) for the outcomes of interest at immediate- (intervention duration of up to 2 weeks), short- (over 2 weeks up to 12 weeks) and long-terms (over 12 weeks). The confidence in the results from NMA will be assessed using the Confidence in Network Meta-analysis (CINeMA) framework. ETHICS AND DISSEMINATION: This work synthesises evidence from previously published studies and does not require ethics review or approval. A manuscript describing the findings will be submitted for publication in a peer-reviewed scientific journal. REGISTRATION: OSF (DOI: 10.17605/OSF.IO/7MS25) and registered in the PROSPERO database (CRD42020216374).

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Using the 1-(m-tolyl)-1H-1,2,3-triazole-4-(4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) (TlTrzNIT) radical and metal ß-diketonate complexes [M(hfac)2(H2O)2], where hfac is hexafluoroacetylacetonato, three new 2p-3d heterospin complexes were synthesized. Their structures were solved using single crystal X-ray diffraction data, and magnetic investigation was performed by DC and AC measurements and multifrequency EPR spectroscopy. Compounds 1 and 2 are isostructural complexes with molecular formula [M3(TlTrzNIT)2(hfac)6] (MII = Mn or Cu) while compound 3 is the mononuclear [Co(TlTrzNIT)(hfac)2] complex. In all complexes, the radical acts as a bidentate ligand through the oxygen atom of the nitroxide moiety and the nitrogen atom from the triazole group. Furthermore, in compounds 1 and 2, the TlTrzNIT is bridge-coordinated between two metal centers, leading to the formation of trinuclear complexes. The fitting of the static magnetic behavior reveals antiferromagnetic and ferromagnetic intramolecular interactions for complexes 1 and 2, respectively. The EPR spectra of 1 are well described by an isolated ferrimagnetic S = 13/2 (= 5/2 - 1/2 + 5/2 - 1/2 + 5/2) ground state with a biaxial zero-field splitting (ZFS) interaction characterized, respectively, by 2nd order axial and rhombic parameters, D and E, such that E/D is close to the maximum of 0.33. Meanwhile, EPR spectra for 2 are explained in terms of a ferromagnetic model with weakly anisotropic Cu-radical exchange interactions, giving rise to an isolated S = 5/2 (= 5 × 1/2) ground state with both an anisotropic g tensor and a weak ZFS interaction. Complex 2 represents one of only a few examples of Cu-radical moieties with measurable exchange anisotropy.